transforming-growth-factor-beta and Inflammation

Hepatocellular carcinoma is one of the major causes of cancer-related deaths worldwide and is associated with several inflammatory mediators, since 90% of HCCs occur based on chronic hepatitis B or C, alcoholism or increasingly metabolic syndrome-associated inflammation. EMT is a physiological process, with coordinated changes in epithelial gene signatures and is regulated by multiple factors, including cytokines and growth factors such as TGFβ, EGF, and FGF. Recent reports propose a strong association between EMT and inflammation, which is also correlated with tumor aggressiveness and poor outcomes. Cellular heterogeneity results collectively as an outcome of EMT, inflammation, and the tumor microenvironment, and it plays a fundamental role in the progression, complexity of cancer, and chemoresistance. In this review, we highlight recent developments concerning the association of EMT and inflammation in the context of HCC progression. Identifying potential EMT-related biomarkers and understanding EMT regulatory molecules will likely contribute to promising developments in clinical practice and will be a valuable tool for predicting metastasis in general and specifically in HCC.

Topics: Biomarkers; Carcinoma, Hepatocellular; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Liver Neoplasms; Transforming Growth Factor beta; Tumor Microenvironment

Nephropathy has become the most common reason for end-stage renal disease worldwide. The progression of end-stage renal disease occurs caused by decreased glomerular filtration rate, damage to capillaries in renal glomeruli or a higher risk of cardiovascular morbidity and mortality in diabetic patients. The involvement of mechanism in the development of nephropathy via generation of AGEs, the elevation of growth factors, altered hemodynamic and metabolic factors, inflammatory mediators, oxidative stress and dyslipidaemia. The prevalence of chronic kidney disease in India will rise from 3.7 million in 1990 to 7.63 million in 2020 becoming the main cause of mortality and morbidity. The pathogenesis of nephropathy mediates by various molecules that cause alterations in the structure and function of the kidney like growth factors, endothelins, transforming growth factor (TGF-β), and Angiotensin-converting enzymes (ACE), fibronectin and proinflammatory cytokines, mast cells and dyslipidemia. Growth factors like VEGF, IGFs, PDGF, EGFR and TGF-β contribute to excessive extracellular matrix accumulation, together with thickening of the glomerular and tubular basement membranes and an increase in the mesangial matrix, leading to glomerulosclerosis and tubulointerstitial fibrosis. Oxidative stress and inflammation factors like TNF-α, IL-1 and IL-6 are hypothesized to play a role in the development of pathological changes in nephropathy like renal hyperfiltration and hypertrophy, thickening of the glomerular basement membrane (GBM), glomerular lesion and tubulointerstitial fibrosis. Dyslipidemia is involved in the progression of nephropathy by impaired action of lipoprotein lipase, lecithincholesterol acyltransferase (LCAT) and cholesteryl ester transferase protein (CETP) resulting in the increased level of LDL-C, Triglyceride level and decrease HDL-C that enhance macrophage infiltration, excessive extracellular matrix production and accelerate inflammation with the development of proteinuria. Interruption in the RAS, oxidative stress and dyslipidemia have yielded much better results in terms of reno-protection and progression of nephropathy. In this review, we would focus on various factors that have been shown to contribute to renal injury in many experimental models of nephropathy.

Topics: Fibrosis; Humans; Inflammation; Interleukin-1; Interleukin-6; Kidney Failure, Chronic; Transforming Growth Factor beta

Alzheimer's disease (AD), a progressive disorder, has become a global health problem and is now the main cause of dementia. The aetiology of AD is complex and remains elusive making effective AD treatment difficult. Current drugs for AD only improve symptoms but do not interfere with pathogenic mechanisms. Three main hypotheses have been brought forward regarding AD aetiology, one of them being the 'inflammation hypothesis'. A number of studies have demonstrated that inflammation plays a critical role in AD. Self-limiting neuroinflammation is considered beneficial to AD, whereas chronic inflammation aggravates brain injury and neuronal death. Transforming growth factor β 1(TGF-β1) is an anti-inflammatory cytokine with neuroprotective properties. Smad proteins are downstream molecules of TGF-β signalling. They are cytoplasmic transcription factors that can regulate targeted gene expression. In AD, impairments of TGF-β1/Smad pathways have been observed. Moreover, microglia, astrocytes, inflammasomes, and insulin resistance also have been implicated in AD pathogenesis. Elucidating the molecular mechanisms underlying AD pathogenesis is a fundamental step toward designing new treatment options. In this review, we detail the changes in TGF-β1/Smad pathways in AD and hope this will facilitate further research on AD treatment.

Topics: Alzheimer Disease; Cytokines; Humans; Inflammation; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Transforming Growth Factor beta1

The "Thalidomide tragedy" is a landmark in the history of the pharmaceutical industry. Despite limited clinical trials, there is a continuous effort to investigate thalidomide as a drug for cancer and inflammatory diseases such as rheumatoid arthritis, lepromatous leprosy, and COVID-19. This review focuses on the possibilities of targeting inflammation by repurposing thalidomide for the treatment of idiopathic pulmonary fibrosis (IPF). Articles were searched from the Scopus database, sorted, and selected articles were reviewed. The content includes the proven mechanisms of action of thalidomide relevant to IPF. Inflammation, oxidative stress, and epigenetic mechanisms are major pathogenic factors in IPF. Transforming growth factor-β (TGF-β) is the major biomarker of IPF. Thalidomide is an effective anti-inflammatory drug in inhibiting TGF-β, interleukins (IL-6 and IL-1β), and tumour necrosis factor-α (TNF-α). Thalidomide binds cereblon, a process that is involved in the proposed mechanism in specific cancers such as breast cancer, colon cancer, multiple myeloma, and lung cancer. Cereblon is involved in activating AMP-activated protein kinase (AMPK)-TGF-β/Smad signalling, thereby attenuating fibrosis. The past few years have witnessed an improvement in the identification of biomarkers and diagnostic technologies in respiratory diseases, partly because of the COVID-19 pandemic. Hence, investment in clinical trials with a systematic plan can help repurpose thalidomide for pulmonary fibrosis.

Topics: COVID-19; Humans; Idiopathic Pulmonary Fibrosis; Inflammation; Lung; Pandemics; Thalidomide; Transforming Growth Factor beta

GDF11 (Growth differentiation factor 11) is a newly discovered member of family of transforming growth factors-β. Its crucial role was confirmed in physiology, i.e. embryogenesis due to its involvement in bone formation, skeletogenesis and it is essential to stating skeletal pattern. GDF11 is described as a rejuvenating and anti-aging molecule, that could even restore functions. Beside embryogenesis, GDF11 participates in the process of inflammation and carcinogenesis. An anti-inflammatory effect of GDF11 was found in experimental colitis, psoriasis and arthritis. Current data regarding liver fibrosis and renal injury indicate that GDF11 may act as pro-inflammatory agent. In this review, we describe its involvement in regulation of acute and chronic inflammatory disorders.

Topics: Bone Morphogenetic Proteins; Growth Differentiation Factors; Humans; Inflammation; Osteogenesis; Psoriasis; Transforming Growth Factor beta

Arterial wall damage in Takayasu arteritis (TAK) can progress despite immunosuppressive therapy. Vascular fibrosis is more prominent in TAK than in giant cell arteritis (GCA). The inflamed arterial wall in TAK is infiltrated by M1 macrophages [which secrete interleukin-6 (IL-6)], which transition to M2 macrophages once the inflammation settles. M2 macrophages secrete transforming growth factor beta (TGF-β) and glycoprotein non-metastatic melanoma protein B (GPNMB), both of which can activate fibroblasts in the arterial wall adventitia. Mast cells in the arterial wall of TAK also activate resting adventitial fibroblasts. Th17 lymphocytes play a role in both TAK and GCA. Sub-populations of Th17 lymphocytes, Th17.1 lymphocytes [which secrete interferon gamma (IFN-γ) in addition to interleukin-17 (IL-17)] and programmed cell death 1 (PD1)-expressing Th17 (which secrete TGF-β), have been described in TAK but not in GCA. IL-6 and IL-17 also drive fibroblast activation in the arterial wall. The Th17 and Th1 lymphocytes in TAK demonstrate an activation of mammalian target organ of rapamycin 1 (mTORC1) driven by Notch-1 upregulation. A recent study reported that the enhanced liver fibrosis score (derived from serum hyaluronic acid, tissue inhibitor of metalloproteinase 1, and pro-collagen III amino-terminal pro-peptide) had a moderate-to-strong correlation with clinically assessed and angiographically assessed vascular damage.

Topics: Fibrosis; Giant Cell Arteritis; Humans; Inflammation; Interleukin-17; Interleukin-6; Mechanistic Target of Rapamycin Complex 1; Membrane Glycoproteins; Takayasu Arteritis; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta

Tendon injury healing is a complex process that involves the participation of a significant number of molecules and cells, including growth factors molecules in a key role. Numerous studies have demonstrated the function of growth factors in tendon healing, and the recent emergence of EV has also provided a new visual field for promoting tendon healing. This review examines the tendon structure, growth, and development, as well as the physiological process of its healing after injury. The review assesses the role of six substances in tendon healing: insulin-like growth factor-I (IGF-I), transforming growth factor β (TGFβ), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and EV. Different growth factors are active at various stages of healing and exhibit separate physiological activities. IGF-1 is expressed immediately after injury and stimulates the mitosis of various cells while suppressing the response to inflammation. VEGF, which is also active immediately after injury, accelerates local metabolism by promoting vascular network formation and positively impacts the activities of other growth factors. However, VEGF's protracted action could be harmful to tendon healing. PDGF, the earliest discovered cytokine to influence tendon healing, has a powerful cell chemotaxis and promotes cell proliferation, but it can equally accelerate the response to inflammation and relieve local adhesions. Also useful for relieving tendon adhesion is TGF- β, which is active almost during the entire phase of tendon healing. As a powerful active substance, in addition to its participation in the field of cardiovascular and cerebrovascular vessels, tumour and chronic wounds, TGF- β reportedly plays a role in promoting cell proliferation, activating growth factors, and inhibiting inflammatory response during tendon healing.

Topics: Extracellular Vesicles; Humans; Inflammation; Platelet-Derived Growth Factor; Tendons; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Wound Healing

The main causative agent of malaria in humans is Plasmodium falciparum, which is spread through biting Anopheles mosquitoes. Immunoregulation in the host involving the pleiotropic cytokine transforming growth factor-β (TGF-β) has a vital role in controlling the immune response to P. falciparum infection. Based on a search of the published literature, this study investigated the correlation between malaria and immune cells, specifically the role of TGF-β in the immune response. The studies analyzed showed that, when present in low amounts, TGF-β promotes inflammation, but inhibits inflammation when present in high concentrations; thus, it is an essential regulator of inflammation. It has also been shown that the quantity of TGF-β produced by the host can influence how badly the parasite affects the host. Low levels of TGF-β in the host prevent the host from being able to manage the inflammation that Plasmodium causes, which results in a pathological situation that leaves the host vulnerable to fatal infection. Additionally, the amount of TGF-β fluctuates throughout the host's Plasmodium infection. At the beginning of a Plasmodium infection, TGF-β levels are noticeably increased, and as Plasmodium multiplies quickly, they start to decline, hindering further growth. In addition, it is also involved in the growth, proliferation, and operation of various types of immune cell and correlated with levels of cytokines associated with the immune response to malaria. TGF-β levels were positively connected with the anti-inflammatory cytokine interleukin-10 (IL-10), but negatively correlated with the proinflammatory cytokines interferon-γ (IFN-γ) and IL-6 in individuals with severe malaria. Thus, TGF-β might balance immune-mediated pathological damage and the regulation and clearance of infectious pathogens. Numerous domestic and international studies have demonstrated that TGF-β maintains a dynamic balance between anti-inflammation and pro-inflammation in malaria immunity by acting as an anti-inflammatory factor when inflammation levels are too high and as a pro-inflammatory factor when inflammation levels are deficient. Such information could be of relevance to the design of urgently needed vaccines and medications to meet the emerging risks associated with the increasing spread of malaria and the development of drug resistance.

Topics: Animals; Cytokines; Humans; Immunity; Inflammation; Malaria; Malaria, Falciparum; Transforming Growth Factor beta; Transforming Growth Factors

The process of wound healing involves a complex and vast interplay of growth factors and cytokines that coordinate the recruitment and interaction of various cell types. A series of events involving inflammation, proliferation, and remodeling eventually leads to the restoration of the damaged tissue. Abrogation in the regulation of these events has been shown to result in excessive scarring or non-healing wounds. While the process of wound healing is not fully elucidated, it has been documented that the early events of wound healing play a key role in the outcome of the wound. Furthermore, high levels of inflammation have been shown to lead to scarring. The regulation of these events may result in scarless wound healing, especially in adults. The inhibition of transforming growth factor-β (TGF-β) and the administration of keratinocyte growth factors (KGF), KGF-1 and KGF-2, has in recent years yielded positive results in the acceleration of wound closure and reduced scarring. Here, we encapsulate recent knowledge on the roles of TGF-β, KGF1, and KGF2 in wound healing and scar formation and highlight the areas that need further investigation. We also discuss potential future directions for the use of growth factors in wound management.

Topics: Adult; Cicatrix; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Transforming Growth Factor beta; Wound Healing

Mast cells (MC) are a key effector cell in multiple types of immune responses, including atopic conditions. Allergic diseases have been steadily rising across the globe, creating a growing public health problem. IgE-mediated activation of MCs leads to the release of potent mediators that can have dire clinical consequences. Current therapeutic options to inhibit MC activation and degranulation are limited; thus, a better understanding of the mechanisms that regulate MC effector functions in allergic inflammation are necessary in order to develop effective treatment options with minimal side effects. Several cytokines have been identified that play multifaceted roles in regulating MC activation, including TGFβ, IL-10, and IL-33, and others that appear to serve primarily anti-inflammatory functions, including IL-35 and IL-37. Here, we review the literature examining cytokines that regulate MC-mediated allergic immune responses.

Topics: Cell Degranulation; Cytokines; Humans; Immunoglobulin E; Inflammation; Interleukin-10; Interleukin-33; Mast Cells; Transforming Growth Factor beta

Diabetic kidney disease (DKD) is one of the most common complications of diabetes, and its prevalence is still growing rapidly. However, the efficient therapies for this kidney disease are still limited. The pathogenesis of DKD involves glucotoxicity, lipotoxicity, inflammation, oxidative stress, and renal fibrosis. Glucotoxicity and lipotoxicity can cause oxidative stress, which can lead to inflammation and aggravate renal fibrosis. In this review, we have focused on in vitro and in vivo experiments to investigate the mechanistic pathways by which natural compounds exert their effects against the progression of DKD. The accumulated and collected data revealed that some natural compounds could regulate inflammation, oxidative stress, renal fibrosis, and activate autophagy, thereby protecting the kidney. The main pathways targeted by these reviewed compounds include the Nrf2 signaling pathway, NF-κB signaling pathway, TGF-β signaling pathway, NLRP3 inflammasome, autophagy, glycolipid metabolism and ER stress. This review presented an updated overview of the potential benefits of these natural compounds for the prevention and treatment of DKD progression, aimed to provide new potential therapeutic lead compounds and references for the innovative drug development and clinical treatment of DKD.

Topics: Diabetes Mellitus; Diabetic Nephropathies; Fibrosis; Glycolipids; Humans; Inflammasomes; Inflammation; Kidney; NF-E2-Related Factor 2; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Transforming Growth Factor beta

Renal fibrosis contributes to progressive damage to renal structure and function. It is a common pathological process as chronic kidney disease develops into kidney failure, irrespective of diverse etiologies, and eventually leads to death. However, there are no effective drugs for renal fibrosis treatment at present. Lipid aggregation in the kidney and consequent lipotoxicity always accompany chronic kidney disease and fibrosis. Numerous studies have revealed that restoring the defective fatty acid oxidation in the kidney cells can mitigate renal fibrosis. Thus, it is an important strategy to reverse the dysfunctional lipid metabolism in the kidney, by targeting critical regulators of lipid metabolism. In this review, we highlight the potential "druggability" of lipid metabolism to ameliorate renal fibrosis and provide current pre-clinical evidence, exemplified by some representative druggable targets and several other metabolic regulators with anti-renal fibrosis roles. Then, we introduce the preliminary progress of noncoding RNAs as promising anti-renal fibrosis drug targets from the perspective of lipid metabolism. Finally, we discuss the prospects and deficiencies of drug targeting lipid reprogramming in the kidney.

Topics: Animals; Carnitine O-Palmitoyltransferase; CD36 Antigens; Epithelial Cells; Fatty Acids; Fibrosis; Inflammation; Kidney; Lipid Metabolism; MicroRNAs; Peroxisome Proliferator-Activated Receptors; Renal Insufficiency, Chronic; RNA, Untranslated; Sterol Regulatory Element Binding Proteins; Transforming Growth Factor beta

Topics: Animals; Extracellular Matrix; Fibronectins; Humans; Hyaluronic Acid; Inflammation; Myofibroblasts; Signal Transduction; Transforming Growth Factor beta

A plethora of cytokines are produced in the tumor microenvironment (TME) those play a vital role in cancer prognosis. Though it is completely contextual, cytokines produced from an inflammatory micro-environment can either modulate cancer progression at early stages of tumor development or in later stages cytokine derived cues can in turn control tumor cell invasion and metastasis. Therefore, understanding the crosstalk between the key cytokines regulating cancer prognosis is critical for the development of an effective therapy. In this regard, the role of transforming growth factor-beta (TGF-β) in cancer is controversially discussed in general inhibition of TGF-β promotes de novo tumorigenesis whereas paradoxically, TGF-β can promote malignancy in already established tumors. Another important cytokine, TNF-α have intense crosstalk with TGF-β from the fact that in a non-cancer context, TGF-β promotes fibrosis whereas TNF-α has anti-fibrotic activity. We have recently reported that TGF-β-induced differentiation of epithelial cells to mesenchymal type is suppressed by TNF-α through regulation of cellular homeostatic machinery- autophagy. Moreover, there are also rare reports of synergy between these two cytokines as well. The crosstalk between TGF-β and TNF-α is not only limited to regulating cancer cell differentiation and proliferation but also includes involvement in cell death. In this review, we hence summarize the molecular mechanisms by which these two important cytokines, TGF-β and TNF-α control cancer prognosis.

Topics: Animals; Apoptosis; Autophagy; Cell Death; Cell Differentiation; Cell Proliferation; Cellular Senescence; Cytokines; Epithelial-Mesenchymal Transition; Homeostasis; Humans; Inflammation; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Prognosis; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Diabetic kidney disease (DKD) is a leading cause of mortality and morbidity in diabetes. This review aims to discuss the major features of DKD, to identify the difficult barrier encountered in developing a therapeutic strategy and to provide a potentially superior novel approach to retard DKD.. Renal inflammation and fibrosis are prominent features of DKD. Transforming growth factor beta (TGFβ) with its activity enhanced in DKD plays a key pathological profibrotic role in promoting renal fibrosis. However, TGFβ is a difficult drug target because it has multiple important physiological functions, such as immunomodulation. These physiological functions of TGFβ can be interrupted as a result of complete blockade of the TGFβ pathway if TGFβ is directly targeted, leading to catastrophic side-effects, such as fulminant inflammation. Cell division autoantigen 1 (CDA1) is recently identified as an enhancer of profibrotic TGFβ signaling and inhibitor of anti-inflammatory SIRT1. Renal CDA1 expression is elevated in human DKD as well as in rodent models of DKD. Targeting CDA1, by either genetic approach or pharmacological approach in mice, leads to concurrent attenuation of renal fibrosis and inflammation without any deleterious effects observed.. Targeting CDA1, instead of directly targeting TGFβ, represents a superior approach to retard DKD.

Topics: Animals; Autoantigens; Cytokines; Diabetic Nephropathies; Fibrosis; Humans; Inflammation; Kidney; Mice; Protective Agents; Signal Transduction; Transforming Growth Factor beta

Recent advances in our understanding of the molecular pathways that control the link of inflammation with organ fibrosis and autoimmune diseases point to the epithelial to mesenchymal transition (EMT) as the common association in the progression of these diseases characterized by an intense inflammatory response. EMT, a process in which epithelial cells are gradually transformed to mesenchymal cells, is a major contributor to the pathogenesis of fibrosis. Importantly, the chronic inflammatory microenvironment has emerged as a decisive factor in the induction of pathological EMT. Transforming growth factor-β (TGF-β), a multifunctional cytokine, plays a crucial role in the induction of fibrosis, often associated with chronic phases of inflammatory diseases, contributing to marked fibrotic changes that severely impair normal tissue architecture and function. The understanding of molecular mechanisms underlying EMT-dependent fibrosis has both a basic and a translational relevance, since it may be useful to design therapies aimed at counteracting organ deterioration and failure. To this end, we reviewed the recent literature to better elucidate the molecular response to inflammatory/fibrogenic signals in autoimmune diseases in order to further the specific regulation of EMT-dependent fibrosis in more targeted therapies.

Topics: Animals; Autoimmunity; Epithelial-Mesenchymal Transition; Fibrosis; Humans; Inflammation; Transforming Growth Factor beta

Acute kidney injury (AKI) is a complex disorder and a clinical condition characterized by acute reduction in renal function. If AKI is not treated, it can lead to chronic kidney disease, which is associated with a high risk of death. SIRT1 (silent information regulator 1) is an NAD-dependent deacetylase. This enzyme is responsible for the processes of DNA repair or recombination, chromosomal stability, and gene transcription. This enzyme also plays a protective role in many diseases, including AKI. In this study, we review the mechanisms that mediate the protective effects of SIRT1 on AKI, including SIRT1 activators.

Topics: Acute Kidney Injury; Animals; Apoptosis; Enzyme Activators; Humans; Inflammation; Mitophagy; Molecular Targeted Therapy; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Protective Factors; Sirtuin 1; Transforming Growth Factor beta

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes pulmonary injury or multiple-organ injury by various pathological pathways. Transforming growth factor-beta (TGF-β) is a key factor that is released during SARS-CoV-2 infection. TGF-β, by internalization of the epithelial sodium channel (ENaC), suppresses the anti-oxidant system, downregulates the cystic fibrosis transmembrane conductance regulator (CFTR), and activates the plasminogen activator inhibitor 1 (PAI-1) and nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-kB). These changes cause inflammation and lung injury along with coagulopathy. Moreover, reactive oxygen species play a significant role in lung injury, which levels up during SARS-CoV-2 infection.. Pirfenidone is an anti-fibrotic drug with an anti-oxidant activity that can prevent lung injury during SARS-CoV-2 infection by blocking the maturation process of transforming growth factor-beta (TGF-β) and enhancing the protective role of peroxisome proliferator-activated receptors (PPARs). Pirfenidone is a safe drug for patients with hypertension or diabetes and its side effect tolerated well.. The drug as a theoretical perspective may be an effective and safe choice for suppressing the inflammatory response during COVID-19. The recommendation would be a combination of pirfenidone and N-acetylcysteine to achieve maximum benefit during SARS-CoV-2 treatment.

Topics: Anti-Inflammatory Agents, Non-Steroidal; COVID-19; COVID-19 Drug Treatment; Humans; Inflammation; Lung Injury; Pyridones; SARS-CoV-2; Signal Transduction; Transforming Growth Factor beta

When treating diseases related primarily to tissue remodeling and fibrosis, it is desirable to regulate TGFβ concentration and modulate its biological effects. The highest cellular concentrations of TGFβ are found in platelets, with about 40% of all TGFβ found in peripheral blood plasma being secreted by them. Therefore, an understanding of the mechanisms of TGFβ secretion from platelets may be of key importance for medicine. Unfortunately, despite the finding that platelets are an important regulator of TGFβ levels, little research has been carried out into the development of platelet-directed therapies that might modulate the TGFβ-dependent processes. Nevertheless, there are some very encouraging reports suggesting that platelet TGFβ may be specifically involved in cardiovascular diseases, liver fibrosis, tumour metastasis, cerebral malaria and in the regulation of inflammatory cell functions. The purpose of this review is to briefly summarize these few, extremely encouraging reports to indicate the state of current knowledge in this topic. It also attempts to better characterize the influence of TGFβ on platelet activation and reactivity, and its shaping of the roles of blood platelets in haemostasis and thrombosis.

Topics: Blood Platelets; Cardiovascular Diseases; Hemostasis; Humans; Inflammation; Liver Cirrhosis; Malaria, Cerebral; Neoplasm Metastasis; Platelet Activation; Thrombosis; Transforming Growth Factor beta

Transforming growth factor-β (TGF-β) plays a critical role in the pathological processes of various diseases. However, the signaling mechanism of TGF-β in the pathological response remains largely unclear. In this review, we discuss advances in research of Smad7, a member of the I-Smads family and a negative regulator of TGF-β signaling, and mainly review the expression and its function in diseases. Smad7 inhibits the activation of the NF-κB and TGF-β signaling pathways and plays a pivotal role in the prevention and treatment of various diseases. Specifically, Smad7 can not only attenuate growth inhibition, fibrosis, apoptosis, inflammation, and inflammatory T cell differentiation, but also promotes epithelial cells migration or disease development. In this review, we aim to summarize the various biological functions of Smad7 in autoimmune diseases, inflammatory diseases, cancers, and kidney diseases, focusing on the molecular mechanisms of the transcriptional and posttranscriptional regulation of Smad7.

Topics: Animals; Autoimmune Diseases; Autoimmunity; Gene Expression Regulation; Humans; Inflammation; NF-kappa B; Protein Processing, Post-Translational; Signal Transduction; Smad7 Protein; Transcription, Genetic; Transforming Growth Factor beta

Hydrocephalus is a common complication of aneurysmal subarachnoid hemorrhage (aSAH) and reportedly contributes to poor neurological outcomes. In this review, we summarize the molecular and cellular mechanisms involved in the pathogenesis of hydrocephalus following aSAH and summarize its treatment strategies. Various mechanisms have been implicated for the development of chronic hydrocephalus following aSAH, including alterations in cerebral spinal fluid (CSF) dynamics, obstruction of the arachnoid granulations by blood products, and adhesions within the ventricular system. Regarding molecular mechanisms that cause chronic hydrocephalus following aSAH, we carried out an extensive review of animal studies and clinical trials about the transforming growth factor-β/SMAD signaling pathway, upregulation of tenascin-C, inflammation-dependent hypersecretion of CSF, systemic inflammatory response syndrome, and immune dysregulation. To identify the ideal treatment strategy, we discuss the predictive factors of shunt-dependent hydrocephalus between surgical clipping and endovascular coiling groups. The efficacy and safety of other surgical interventions including the endoscopic removal of an intraventricular hemorrhage, placement of an external ventricular drain, the use of intraventricular or cisternal fibrinolysis, and an endoscopic third ventriculostomy on shunt dependency following aSAH were also assessed. However, the optimal treatment is still controversial, and it necessitates further investigations. A better understanding of the pathogenesis of acute and chronic hydrocephalus following aSAH would facilitate the development of treatments and improve the outcome.

Topics: Humans; Hydrocephalus; Inflammation; Retrospective Studies; Risk Factors; Signal Transduction; Smad Proteins; Subarachnoid Hemorrhage; Transforming Growth Factor beta

Atherosclerosis involves both innate and adaptive immunity. Here, we provide an overview of the role of regulatory T (Treg) cells in atherosclerotic diseases. Treg cells and their inhibitory cytokines, IL-10 and TGF-β, have been identified in atherosclerotic lesions and to inhibit progression through lipoprotein metabolism modulation. Treg cells have also been found to convert to T follicular helper (Tfh) cells and promote atherosclerosis progression. Treg cell involvement in different stages of atherosclerotic progression and Treg cell-mediated modulation of plaque development occurs via inflammation suppression and atheroma formation has been focused. Moreover, existing knowledge suggests that Treg cells are likely involved in the pathology of other specific circumstances including in-stent restenosis, neointimal hyperplasia, vessel graft failure, and ischemic arterial injury; however, there remain gaps regarding their specific contribution. Hence, advancements in the knowledge regarding Treg cells in diverse aspects of atherosclerosis offer translational significance for the management of atherosclerosis and associated diseases.

Topics: Atherosclerosis; Cytokines; Humans; Inflammation; Interleukin-10; Plaque, Atherosclerotic; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Tumor cells undergo invasion and metastasis through epithelial-to-mesenchymal cell transition (EMT) by activation of alterations in extracellular matrix (ECM) protein-encoding genes, enzymes responsible for the breakdown of ECM, and activation of genes that drive the transformation of the epithelial cell to the mesenchymal type. Inflammatory cytokines such as TGF

Topics: Cadherins; Cell Line, Tumor; Cytokines; Disease Progression; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Neoplasms; Neoplastic Stem Cells; Neovascularization, Pathologic; Signal Transduction; Transforming Growth Factor beta; Tumor Microenvironment; Tumor Necrosis Factor-alpha

CD8 positive, tissue resident memory T cells (T

Topics: Animals; Antigens; CD8-Positive T-Lymphocytes; Humans; Immunologic Memory; Inflammation; Inflammation Mediators; Interleukin-33; Interleukins; Phenotype; Signal Transduction; Transforming Growth Factor beta

Periostin is known to be a useful biomarker for various diseases. In this article, we focus on allergic diseases and pulmonary fibrosis, for which we and others are now developing detection systems for periostin as a biomarker. Biomarker-based precision medicine in the management of type 2 inflammation and fibrotic diseases since heterogeneity is of utmost importance. Periostin expression is induced by type 2 cytokines (interleukin-4/-13) or transforming growth factor-β, and plays a vital role in the pathogenesis of allergic inflammation or interstitial lung disease, respectively, andits serum levels are correlated disease severity, prognosis and responsiveness to the treatment. We first summarise the importance of type 2 biomarker and then describe the pathological role of periostin in the development and progression of type 2 allergic inflammation and pulmonary fibrosis. In addition, then, we summarise the recent development of assay methods for periostin detection, and analyse the diseases in which periostin concentration is elevated in serum and local biological fluids and its usefulness as a biomarker. Furthermore, we describe recent findings of periostin as a biomarker in the use of biologics or anti-fibrotic therapy. Finally, we describe the factors that influence the change in periostin concentration under the healthy conditions.

Topics: Biomarkers; Cell Adhesion Molecules; Chronic Disease; Cytokines; Eosinophilia; Fibrosis; Humans; Idiopathic Pulmonary Fibrosis; Immunoglobulin E; Inflammation; Interleukin-13; Lung; Precision Medicine; Prognosis; Pulmonary Fibrosis; Rhinitis; Sinusitis; Transforming Growth Factor beta

Integrins promote cell adhesion and migration, but also control local activation of latent transforming growth factor (TGF)-β contained in extracellular matrix or cell-surface reservoirs. Integrin-dependent activation of TGF-β has emerged as a crucial mechanism whereby tissue-borne cells instruct circulating and resident immune cells. Moreover, this regulation has wide pathophysiological implications in wound healing, tissue fibrosis, antibody production, pathogen clearance, inflammation, autoimmunity, cancer, and possibly metabolic disorders including diabetes. Here we review the spatiotemporal control of TGF-β activation by integrins, and its effects on immune cell signaling and function. We discuss the underlying molecular and cell-biological mechanisms, the implications for human health and disease, and possibilities for future therapeutic exploitation.

Topics: Animals; Cytoskeleton; Humans; Immunity; Inflammation; Integrins; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Despite a decline in the incidence of squamous cell carcinomas (SCCs) over the past 20 years, their survival rate has remained nearly the same, indicating that treatment options have not improved relative to other cancer types. Immunotherapies have a high potential for a sustained effect in SCC patients, but their response rate is low. Here, we review the suppressive role of transforming growth factor-beta (TGFβ) on the antitumor immune response in SCC and present its potential as a therapeutic target in combination with the current range of immunotherapies available for SCC patients. We conclude that SCCs are an optimal cancer type to study the effectiveness of TGFβ inhibition due to the prevalence of dysregulated TGFβ signaling in them.

Topics: Animals; Carcinoma, Squamous Cell; Humans; Immunotherapy; Inflammation; Signal Transduction; Transforming Growth Factor beta

Extracellular matrix (ECM) is the foundation on which all cells and organs converge to orchestrate normal physiological functions. In the setting of pathology, the ECM is modified to incorporate additional roles, with modifications including turnover of existing ECM and deposition of new ECM. The fibroblast is center stage in coordinating both normal tissue homeostasis and response to disease. Understanding how fibroblasts work under normal conditions and are activated in response to injury or stress will provide mechanistic insight that triggers discovery of new therapeutic treatments for a wide range of disease. We highlight here fibroblast roles in the cancer, lung, and heart as example systems where fibroblasts are major contributors to homeostasis and pathology.

Topics: Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Gene Expression Regulation; Homeostasis; Humans; Hypertension; Inflammation; Lung; Myocardial Infarction; Myocardium; Neoplasms; Stromal Cells; Transforming Growth Factor beta; Wnt Signaling Pathway

Ubiquitination is a three-step enzymatic cascade for posttranslational protein modification. It includes the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3). RING-type E3 ubiquitin ligases catalyse the posttranslational proteolytic and nonproteolytic functions in various physiological and pathological processes, such as inflammation-associated signal transduction. Resulting from the diversity of substrates and functional mechanisms, RING-type ligases regulate microbe recognition and inflammation by being involved in multiple inflammatory signalling pathways. These processes also occur in autoimmune diseases, especially inflammatory bowel disease (IBD). To understand the importance of RING-type ligases in inflammation, we have discussed their functional mechanisms in multiple inflammation-associated pathways and correlation between RING-type ligases and IBD. Owing to the limited data on the biology of RING-type ligases, there is an urgent need to analyse their potential as biomarkers and therapeutic targets in IBD in the future.

Topics: Animals; Autophagy; Biomarkers; Colitis; Humans; Immune System; Inflammation; Inflammatory Bowel Diseases; MAP Kinase Signaling System; Mice; Phosphatidylinositol 3-Kinases; Protein Processing, Post-Translational; RNA, Untranslated; Signal Transduction; Transforming Growth Factor beta; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination

Disabled-2 (DAB2) is a clathrin and cargo binding endocytic adaptor protein recognized for its multifaceted roles in signaling pathways involved in cellular differentiation, proliferation, migration, tumor suppression, and other fundamental homeostatic cellular mechanisms. The requirement for DAB2 in the canonical TGFβ signaling in fibroblasts suggested that a similar mechanism may exist in immune cells and that DAB2 may contribute to immunological tolerance and suppression of inflammatory responses. In this review, we synthesize the current state of knowledge on the roles of DAB2 in the cells of the innate and adaptive immune system, with particular focus on antigen presenting cells (APCs; macrophages and dendritic cells) and regulatory T cells (Tregs). The emerging role of DAB2 in the immune system is that of an immunoregulatory molecule with significant roles in Treg-mediated immunosuppression, and suppression of TLR signaling in APC. DAB2 itself is downregulated by inflammatory stimuli, an event that likely contributes to the immunogenic function of APC. However, contrary findings have been described in neuroinflammatory disorders, thus suggesting a highly context-specific roles for DAB2 in immune cell regulation. There is need for better understanding of DAB2 regulation and its roles in different immune cells, their specialized sub-populations, and their responses under specific inflammatory conditions.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antigen Presentation; Apoptosis Regulatory Proteins; Dendritic Cells; Humans; Inflammation; Lymphocytes; Signal Transduction; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by the progressive growth of cysts but it is also accompanied by diffuse tissue scarring or fibrosis. A number of recent studies have been published in this area, yet the role of fibrosis in ADPKD remains controversial. Here, we will discuss the stages of fibrosis progression in ADPKD, and how these compare with other common kidney diseases. We will also provide a detailed overview of some key mechanistic pathways to fibrosis in the polycystic kidney. Specifically, the role of the 'chronic hypoxia hypothesis', persistent inflammation, Transforming Growth Factor beta (TGFβ), Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) and microRNAs will be examined. Evidence for and against a pathogenic role of extracellular matrix during ADPKD disease progression will be provided.

Topics: Disease Progression; Fibrosis; Humans; Inflammation; Janus Kinases; Kidney; MicroRNAs; Polycystic Kidney, Autosomal Dominant; STAT Transcription Factors; Transforming Growth Factor beta

Islet dysfunction is a hallmark of type 2 diabetes mellitus (T2DM). Compelling evidence suggests that accumulation of islet amyloid in the islets of Langerhans significantly contribute to β-cell dysfunction and diabetes. Emerging evidence implicates a role for cystic fibrosis transmembrane-conductance regulator in the regulation of insulin secretion from pancreatic islets. Impaired first-phase insulin responses and glucose homeostasis have also been reported in cystic fibrosis patients. The transforming growth factor-β protein superfamily is central regulators of pancreatic cell function, and has a key role in pancreas development and pancreatic disease, including diabetes and islet dysfunction. It is also becoming clear that islet inflammation plays a key role in the development of islet dysfunction. Inflammatory changes, including accumulation of macrophages, have been documented in type 2 diabetic islets. Islet dysfunction leads to hyperglycemia and ultimately the development of diabetes. In this review, we describe these risk factors and their associations with islet dysfunction.

Topics: Amyloid; Animals; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Diabetes Mellitus, Type 2; Disease Progression; Glucose; Homeostasis; Humans; Hyperglycemia; Inflammation; Insulin; Insulin Secretion; Islets of Langerhans; Macrophages; Pancreas; Risk Factors; Transforming Growth Factor beta

The helper T cell 9 (Thelper-9, Th9), as a functional subgroup of CD4

Topics: Animals; Cell Differentiation; GATA3 Transcription Factor; Gene Expression Regulation; Humans; Inflammation; Interleukin-4; Interleukin-9; Lupus Erythematosus, Systemic; Mice; Mice, Knockout; Neoplasms; Proto-Oncogene Proteins; Signal Transduction; STAT6 Transcription Factor; T-Lymphocytes, Helper-Inducer; Trans-Activators; Transforming Growth Factor beta

Cartilage homeostasis is governed by articular chondrocytes via their ability to modulate extracellular matrix production and degradation. In turn, chondrocyte activity is regulated by growth factors such as those of the transforming growth factor β (TGFβ) family. Members of this family include the TGFβs, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs). Signaling by this protein family uniquely activates SMAD-dependent signaling and transcription but also activates SMAD-independent signaling via MAPKs such as ERK and TAK1. This review will address the pivotal role of the TGFβ family in cartilage biology by listing several TGFβ family members and describing their signaling and importance for cartilage maintenance. In addition, it is discussed how (pathological) processes such as aging, mechanical stress, and inflammation contribute to altered TGFβ family signaling, leading to disturbed cartilage metabolism and disease.

Topics: Aging; Animals; Bone Morphogenetic Proteins; Cartilage, Articular; Homeostasis; Humans; Inflammation; Signal Transduction; Stress, Mechanical; Transforming Growth Factor beta

Immune dysfunction has been posited as a key element in the aetiology of chronic fatigue syndrome (CFS) since the illness was first conceived. However, systematic reviews have yet to quantitatively synthesise inflammatory biomarkers across the literature. We undertook a systematic review and meta-analysis to quantify available data on circulating inflammatory proteins, examining studies recruiting patients with a CFS diagnosis and a non-affected control group. Results were meta-analysed from 42 studies. Patients with CFS had significantly elevated tumour necrosis factor (ES = 0.274, p < 0.001), interleukin-2 (ES = 0.203, p = 0.006), interleukin-4 (ES = 0.373, p = 0.004), transforming growth factor-β (ES = 0.967, p < 0.001) and c-reactive protein (ES = 0.622, p = 0.019). 12 proteins did not differ between groups. These data provide some support for an inflammatory component in CFS, although inconsistency of results indicates that inflammation is unlikely to be a primary feature in all those suffering from this disorder. It is hoped that further work will elucidate whether there are subgroups of patients with clinically-relevant inflammatory dysfunction, and whether inflammatory cytokines may provide a prognostic biomarker or moderate treatment effects.

Topics: Biomarkers; C-Reactive Protein; Fatigue Syndrome, Chronic; Humans; Inflammation; Interleukin-2; Interleukin-4; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Aging is broadly defined as the functional decline that occurs in all body systems. The accumulation of senescent cells is considered a hallmark of aging and thought to contribute to the aging pathologies. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that regulates a myriad of cellular processes and has important roles in embryonic development, physiological tissue homeostasis, and various pathological conditions. TGF-β exerts potent growth inhibitory activities in various cell types, and multiple growth regulatory mechanisms have reportedly been linked to the phenotypes of cellular senescence and stem cell aging in previous studies. In addition, accumulated evidence has indicated a multifaceted association between TGF-β signaling and aging-associated disorders, including Alzheimer's disease, muscle atrophy, and obesity. The findings regarding these diseases suggest that the impairment of TGF-β signaling in certain cell types and the upregulation of TGF-β ligands contribute to cell degeneration, tissue fibrosis, inflammation, decreased regeneration capacity, and metabolic malfunction. While the biological roles of TGF-β depend highly on cell types and cellular contexts, aging-associated changes are an important additional context which warrants further investigation to better understand the involvement in various diseases and develop therapeutic options. The present review summarizes the relationships between TGF-β signaling and cellular senescence, stem cell aging, and aging-related diseases.

Topics: Aging; Alzheimer Disease; Cell Proliferation; Cellular Senescence; Fibrosis; Hematopoietic Stem Cells; Homeostasis; Inflammation; Ligands; Mesenchymal Stem Cells; Muscular Atrophy; Obesity; Signal Transduction; Stem Cells; Transforming Growth Factor beta

Pulmonary arterial hypertension (PAH) is a severe condition characterised by remodelling of precapillary pulmonary arteries sometimes associated with mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene. Even in the absence of BMPR2 mutations, increased transforming growth factor (TGF)β receptor signalling and decreased BMPRII signalling have been shown to contribute to PAH pathogenesis. In this Keynote, we review the potential mechanisms by which the imbalance of BMP/TGFβ signalling contributes to endothelial dysfunction, vascular remodelling, inflammation and disordered angiogenesis in PAH. Additionally, we highlight how currently used drugs can influence BMP/TGFβ signalling. Finally, we browse the newly developed therapeutic approaches targeting BMPRII and TGFβ signalling pathways by focusing on preclinical studies and clinical trials and put them into perspectives.

Topics: Animals; Bone Morphogenetic Protein Receptors, Type II; Humans; Hypertension, Pulmonary; Inflammation; Neovascularization, Physiologic; Signal Transduction; Transforming Growth Factor beta

Platelets are no longer recognized solely as cell fragments regulating hemostasis. They have pleiotropic functions and they are linked directly or indirectly with the three cornerstones of systemic sclerosis (SSc): vasculopathy, autoimmunity, and fibrosis. In this review, we summarize the current knowledge on the potential role of platelets in the pathogenesis of SSc.. Experimental evidence suggests that vasculopathy, a universal and early finding in SSc, may activate platelets which subsequently release several profibrotic mediators such as serotonin and transforming growth factor β (TGFβ). Platelets may also cross-react with the endothelium leading to the release of molecules, such as thymic stromal lymphopoietin (TSLP), that may trigger fibrosis or sustain vascular damage. Finally, activated platelets express CD40L and provide costimulatory help to B cells, something that may facilitate the breach in immune tolerance. Preclinical studies point to the direction that platelets are actively involved in SSc pathogenesis. Targeting platelets may be an attractive therapeutic approach in SSc.

Topics: Autoimmunity; Blood Platelets; Fibrosis; Humans; Inflammation; Scleroderma, Systemic; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

The role of angiogenic factors in the onset of clinical manifestations of preeclampsia was demonstrated in 2003 by the implication of sFlt-1, PlGF and VEGF, and in 2006 by the implication of soluble endoglin. Placental ischemia and inflammation observed in preeclampsia alter both the production and progression of angiogenic factors during pregnancy. During the first trimester, the combination of PlGF with clinical, biophysical and biological factors results in a better test than the conventional one. However, the clinical value of this method remains to be confirmed. During the second and third trimesters, the sFlt-1/PlGF ratio may be used, with or without pre-existing renal disease, for short-term prediction, diagnosis, and prognosis, and to evaluate the effectiveness of preeclampsia treatment. While a sFlt-1/PlGF ratio<38 and≤33, respectively, rules out the short-term onset and diagnosis of preeclampsia, a sFlt-1/PlGF ratio≥85 between 20 and 34 weeks of pregnancy and≥110 beyond 34 weeks of pregnancy confirms a diagnosis of preeclampsia. Angiogenic and non-angiogenic preeclampsia are identified by a sFlt-1PlGF≥85 and<85, respectively, with the risk of maternal and fetal complications at two weeks differing between the two. Similarly, a sFlt-1/PlGF ratio>665 and>205, respectively, is a good short-term predictor of adverse outcomes of early and late-onset preeclampsia. These values could be incorporated into future guidelines for better clinical management of preeclampsia.

Topics: Adult; Aspirin; Biomarkers; Endoglin; Endothelium, Vascular; Female; Humans; Immune Tolerance; Inflammation; Kidney Diseases; Kidney Transplantation; Membrane Proteins; Oxidative Stress; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy Trimesters; Prognosis; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Transforming growth factor (TGF)-β is a crucial enforcer of immune homeostasis and tolerance, inhibiting the expansion and function of many components of the immune system. Perturbations in TGF-β signaling underlie inflammatory diseases and promote tumor emergence. TGF-β is also central to immune suppression within the tumor microenvironment, and recent studies have revealed roles in tumor immune evasion and poor responses to cancer immunotherapy. Here, we present an overview of the complex biology of the TGF-β family and its context-dependent nature. Then, focusing on cancer, we discuss the roles of TGF-β signaling in distinct immune cell types and how this knowledge is being leveraged to unleash the immune system against the tumor.

Topics: Adaptive Immunity; Animals; Dendritic Cells; Disease Progression; Epithelial-Mesenchymal Transition; Fibroblasts; Humans; Immunity, Innate; Inflammation; Macrophages; Mice, Knockout; Neoplasms; Neutrophils; Receptors, Transforming Growth Factor beta; Signal Transduction; T-Lymphocyte Subsets; Transforming Growth Factor beta; Tumor Escape; Tumor Microenvironment

Neurodegenerative diseases of the central nervous system progressively rob patients of their memory, motor function, and ability to perform daily tasks. Advances in genetics and animal models are beginning to unearth an unexpected role of the immune system in disease onset and pathogenesis; however, the role of cytokines, growth factors, and other immune signaling pathways in disease pathogenesis is still being examined. Here we review recent genetic risk and genome-wide association studies and emerging mechanisms for three key immune pathways implicated in disease, the growth factor TGF-β, the complement cascade, and the extracellular receptor TREM2. These immune signaling pathways are important under both healthy and neurodegenerative conditions, and recent work has highlighted new functional aspects of their signaling. Finally, we assess future directions for immune-related research in neurodegeneration and potential avenues for immune-related therapies.

Topics: Aging; Animals; Complement Activation; Disease Progression; Genetic Predisposition to Disease; Genome-Wide Association Study; Gliosis; Humans; Immunity, Innate; Inflammation; Membrane Glycoproteins; Mice; Mice, Knockout; Mice, Transgenic; Microglia; Models, Immunological; Neurodegenerative Diseases; Protein Aggregation, Pathological; Receptors, Immunologic; Signal Transduction; Transforming Growth Factor beta

Epithelial to mesencyhmal transition (EMT) has a central role in tumor metastasis and progression. EMT is regulated by several growth factors and pro-inflammatory cytokines. The most important role in this regulation could be attributed to transforming growth factor-β (TGF-β). In breast cancer, TGF-β effect on EMT could be potentiated by Fos-related antigen, oncogene HER2, epidermal growth factor, or mitogen-activated protein kinase kinase 5 - extracellular-regulated kinase signaling. Several microRNAs in breast cancer have a considerable role either in potentiation or in suppression of EMT thus acting as oncogenic or tumor suppressive modulators. At present, possibilities to target EMT are discussed but the results of clinical translation are still limited. In prostate cancer, many cellular events are regulated by androgenic hormones. Different experimental results on androgenic stimulation or inhibition of EMT have been reported in the literature. Thus, a possibility that androgen ablation therapy leads to EMT thus facilitating tumor progression has to be discussed. Novel therapy agents, such as the anti-diabetic drug metformin or selective estrogen receptor modulator ormeloxifene were used in pre-clinical studies to inhibit EMT in prostate cancer. Taken together, the results of pre-clinical and clinical studies in breast cancer may be helpful in the process of drug development and identify potential risk during the early stage of that process.

Topics: Benzopyrans; Breast Neoplasms; Cadherins; Cell Plasticity; Cytokines; Disease Progression; Epidermal Growth Factor; Epithelial-Mesenchymal Transition; Female; Humans; Inflammation; Male; MAP Kinase Kinase 5; Metformin; MicroRNAs; Prostatic Neoplasms; Proto-Oncogene Proteins c-fos; Receptor, ErbB-2; Signal Transduction; Transforming Growth Factor beta

Renal tissue injury initiates inflammatory and fibrotic processes that occur to promote regeneration and repair. After renal injury, damaged tissue releases cytokines and chemokines, which stimulate activation and infiltration of inflammatory cells to the kidney. Normal tissue repair processes occur simultaneously with activation of myofibroblasts, collagen deposition, and wound healing responses; however, prolonged activation of pro-inflammatory and pro-fibrotic cell types causes excess extracellular matrix deposition. This review focuses on the physiological and pathophysiological roles of specialized cell types, cytokines/chemokines, and growth factors, and their implications in recovery or exacerbation of acute kidney injury.

Topics: Acute Kidney Injury; Animals; Cell Transdifferentiation; Cytokines; Extracellular Matrix; Fibrosis; Humans; Inflammation; Kidney; Myofibroblasts; Transforming Growth Factor beta

Sulfur mustard (SM) is a vesicating agent that has been employed as a chemical warfare agent. High-dose exposure to sulfur mustard may lead to the damage of rapidly proliferating cells of bone marrow and, therefore, suppression of the immune system. This may be continued as dysfunction of the immune system, and ultimately result in secondary immune disorders. Studies have suggested a role for T cells in SM-induced lung injury. Moreover, observations from animal studies indicate a delayed-type hypersensitivity (DTH) response after skin exposure to SM, providing an understanding that SM can stimulate specific T cell-mediated immune responses. On the other hand, T helper (Th) 17 cells, which are a subset of CD4+ T cells, have recently been reported to be involved in a number of inflammatory, autoimmune, and chronic fibrotic lung diseases. Furthermore, a strong association has been established between the overproduction of profibrotic cytokines like transforming growth factor (TGF)-β and Th17 cell number. In this review, we aimed to go through the new findings about the involvement and interactions of TGF-β and Th17 in SM-related injuries.

Topics: Humans; Inflammation; Lung; Mustard Gas; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

In systemic sclerosis (SSc) immuno-inflammatory events are central to disease development. Amongst other mediators of inflammation, interleukin 17 (IL-17) and Th17 cells have been reported to be increased in the peripheral blood and target organs including involved skin in SSc. They participate and amplify inflammatory responses by inducing the production of cytokines such as IL-6, chemokines such as CCL2 and CXCL8 (IL-8), matrix metalloproteinases-1, -2, -9 and the expression of adhesion molecules in stromal cells including fibroblasts and endothelial cells. In this respect, IL-17 and Th17 cells behave paradigmatically as documented in other autoimmune pathological conditions or infectious diseases. In experimental animal models of skin and lung fibrosis, IL-17 indirectly enhances the fibrotic process by favoring further inflammation by recruiting inflammatory cells, by activating and/or stimulating the production of TGF-β and other pro-fibrotic mediators, by inhibiting autophagy. Whether the findings generated in animal models of fibrosis can be translated to human SSc is unproven. Furthermore, it is controversial whether IL-17 directly promotes the transdifferentiation of human fibroblasts into myofibroblasts and enhances collagen production, with most of the available evidence against this possibility. The reductionist approach in which fibroblast in monolayers are cultured in plastic dishes under the influence of IL-17 limits the relevance of these findings. Further in vitro/ex vivo models with human tissues are being developed to investigate the real effect of IL-17 on extracellular matrix deposition, since agents blocking IL-17 are available for the clinic and it will be important to know whether their use in SSc would be beneficial or detrimental.

Topics: Animals; Fibroblasts; Fibrosis; Humans; Inflammation; Inflammation Mediators; Interleukin-17; Lung; Scleroderma, Systemic; Skin; Th17 Cells; Transforming Growth Factor beta

It is now well-established that members of the small leucine-rich proteoglycan (SLRP) family act in their soluble form, released proteolytically from the extracellular matrix (ECM), as danger-associated molecular patterns (DAMPs). By interacting with Toll-like receptors (TLRs) and the inflammasome, the two SLRPs, biglycan and decorin, autonomously trigger sterile inflammation. Recent data indicate that these SLRPs, besides their conventional role as pro-inflammatory DAMPs, additionally trigger anti-inflammatory signaling pathways to tightly control inflammation. This is brought about by selective employment of TLRs, their co-receptors, various adaptor molecules, and through crosstalk between SLRP-, reactive oxygen species (ROS)-, and sphingolipid-signaling. In this review, the complexity of SLRP signaling in immune and kidney resident cells and its relevance for renal inflammation is discussed. We propose that the dichotomy in SLRP signaling (pro- and anti-inflammatory) allows for fine-tuning the inflammatory response, which is decisive for the outcome of inflammatory kidney diseases.

Topics: Animals; Autophagy; Biglycan; Decorin; Fibrosis; Humans; Immunity, Innate; Inflammasomes; Inflammation; Kidney; Kidney Diseases; Signal Transduction; Small Leucine-Rich Proteoglycans; Transforming Growth Factor beta

It is evident that components of the extracellular matrix (ECM) act as danger-associated molecular patterns (DAMPs) through direct interactions with pattern recognition receptors (PRRs) including Toll-like receptors (TLRs) and inflammasomes. Through these interactions, ECM-derived DAMPs autonomously trigger sterile inflammation or prolong pathogen-induced responses through the production of proinflammatory mediators and the recruitment of leukocytes to sites of injury and infection. Recent research, however, suggests that ECM-derived DAMPs are additionally involved in the resolution and fine-tuning of inflammation by orchestrating the production of anti-inflammatory mediators that are required for the resolution of tissue inflammation and the transition to acquired immunity. Thus, in this review, we discuss the current knowledge of the interplay between ECM-derived DAMPs and the innate immune signaling pathways that are activated to provide temporal control of innate immunity.

Topics: Alarmins; Animals; Extracellular Matrix; Humans; Immunity, Innate; Inflammasomes; Inflammation; Receptor for Advanced Glycation End Products; Signal Transduction; Toll-Like Receptors; Transforming Growth Factor beta

GARP (glycoprotein-A repetitions predominant) is a type I transmembrane cell surface docking receptor for latent transforming growth factor-β (TGF-β) that is abundantly expressed on regulatory T lymphocytes and platelets. GARP regulates the availability of membrane-bound latent TGF-β and modulates its activation. For this reason, GARP expression on immune and non-immune cells is involved in maintaining peripheral tolerance. It plays an important role in preventing inflammatory diseases such as allergy and graft versus host disease (GvHD). GARP is also frequently hijacked by cancer cells to promote oncogenesis. This review summarizes the most important features of GARP biology described to date including gene regulation, protein expression and mechanism in activating latent TGF-β, and the function of GARP in regulatory T cell biology and peripheral tolerance, as well as GARP's increasingly recognized roles in platelet-mediated cancer immune evasion. The promise for GARP-targeted strategy as a novel immunotherapy of cancer is also highlighted.

Topics: Animals; Blood Platelets; Gene Expression Regulation, Neoplastic; Humans; Immune Tolerance; Inflammation; Membrane Proteins; Neoplasms; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Cytokines are required for normal growth and development of the mammary gland and TGF-β prominently represents an established effector of apoptosis, e.g., during involution of the mammary gland. By the control of intracellular signaling pathways, including JAK/STAT, MAPK, PI-3K, and NF-κB, cytokines efficiently regulate cell proliferation and inflammation in the breast. Therefore, cytokines are discussed also in a context of malignant mammary growth. As a group of tissue hormones produced by somatic cells or by cells from the immune system, cytokines are defined by their immunomodulatory potential. Over the past 40 years, multiple cytokines were identified in colostrum and milk. Importantly, cytokines derived from mammary secretions after birth are required for maturation of the immune system in the developing gastrointestinal tract from the suckling. Moreover, recent studies have further assessed the particular interactions between probiotic bacterial strains and cytokines. In light of the increasing prevalence of inflammatory diseases of the gastrointestinal system, the effects of probiotic microorganisms during milk fermentation may have immunotherapeutic potential in the future.

Topics: Animals; Colostrum; Cytokines; Female; Humans; Immune System; Immunity, Maternally-Acquired; Inflammation; Lactation; Mammary Glands, Animal; Milk; Milk, Human; Pregnancy; Signal Transduction; Transforming Growth Factor beta

Inflammatory signaling has been implicated in adipose tissue remodeling and metabolism. In this issue of

Topics: Adipogenesis; Adipose Tissue; Humans; Inflammation; Signal Transduction; Transforming Growth Factor beta

The myofibroblast is a highly specialized cell type that plays a critical role during normal tissue wound healing, but also contributes pathologically to chronic inflammatory conditions such as fibrosis and cancer. As fibrotic conditions continue to be a major burden to the public health system, novel therapies that target the function of myofibroblasts may show promise in the clinic. The cytokine transforming growth factor β (TGFβ) is the most potent known inducer of myofibroblast differentiation and thus represents a powerful target to modify myofibroblast function during disease. This review focuses on our current understanding of the key signaling pathways activated by TGFβ during myofibroblast differentiation.

Topics: Animals; Cell Differentiation; Cell Movement; Chronic Disease; Humans; Inflammation; Mitogen-Activated Protein Kinases; Myofibroblasts; Phenotype; rho GTP-Binding Proteins; Signal Transduction; Transforming Growth Factor beta

Almost 30 years ago, the protein, atrial natriuretic peptide, was identified as a heart-secreted hormone that provides a peripheral signal from the myocardium that communicates to the rest of the organism to modify blood pressure and volume under conditions of heart failure. Since then, additional peripheral factors secreted by the heart, termed cardiokines, have been identified and shown to coordinate this interorgan cross talk. In addition to this interorgan communication, cardiokines also act in an autocrine/paracrine manner to play a role in intercellular communication within the myocardium. This review focuses on the roles of newly emerging cardiokines that are mainly increased in stress-induced cardiac diseases. The potential of these cardiokines as clinical biomarkers for diagnosis and prognosis of cardiac disorders is also discussed.

Topics: Activins; Animals; Biomarkers; Fibroblast Growth Factors; Follistatin; Follistatin-Related Proteins; Growth Differentiation Factor 15; Heart Diseases; Humans; Inflammation; Interleukin-33; Myocardium; Myostatin; Paracrine Communication; Stress, Physiological; Transforming Growth Factor beta

Craniofacial mesenchymal stem cells (MSCs), isolated from an abundant and accessible source of craniofacial tissues, possess self-renewal and multilineage differentiation potential. It has been reported that craniofacial MSCs show elevated proliferation and regeneration capacities compared to bone marrow mesenchymal stem cells (BMMSCs). Furthermore, the immunomodulatory property has generated an emerging multidisciplinary research field that translates MSC-based therapies to the clinic for the treatment of inflammatory and autoimmune diseases. Due to tremendous unmet clinical needs, it was extensively investigated how craniofacial MSCs impose their therapeutic effects, especially by interacting with immune cells. Mechanically, MSCs take advantage of a variety of pathways to regulate immune cells, including paracrine signaling such as transforming growth factor (TGF)-β and hepatocyte growth factor (HGF) pathways, and cell-cell contact Fas/FasL signaling-induced apoptosis. In return, immune cells attenuate MSC function by secreting inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β. This perspective review critically discusses the interaction of craniofacial MSCs with the immune milieu, as well as the underlying molecular mechanism contributing to the future improved therapeutic effects of craniofacial MSCs.

Topics: Animals; Autoimmune Diseases; Cell Differentiation; Cell Proliferation; Facial Bones; Hepatocyte Growth Factor; Humans; Inflammation; Interleukin-1beta; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Paracrine Communication; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

We found for the first time that IL-4 and IL-13, signature type 2 cytokines, are able to induce periostin expression. We and others have subsequently shown that periostin is highly expressed in chronic inflammatory diseases-asthma, atopic dermatitis, eosinophilc chronic sinusitis/chronic rhinosinusitis with nasal polyp, and allergic conjunctivitis-and that periostin plays important roles in the pathogenesis of these diseases. The epithelial/mesenchymal interaction via periostin is important for the onset of allergic inflammation, in which periostin derived from fibroblasts acts on epithelial cells or fibroblasts, activating their NF-κB. Moreover, the immune cell/non-immune cell interaction via periostin may be also involved. Now the significance of periostin has been expanded into other inflammatory or fibrotic diseases such as scleroderma and pulmonary fibrosis. The cross-talk of periostin with TGF-β or pro-inflammatory cytokines is important for the underlying mechanism of these diseases. Because of its pathogenic importance and broad expression, diagnostics or therapeutic drugs can be potentially developed to target periostin as a means of treating these diseases.

Topics: Anti-Inflammatory Agents; Cell Adhesion Molecules; Dermatitis, Atopic; Epithelial Cells; Fibroblasts; Gene Expression Regulation; Humans; Hypersensitivity; Inflammation; Interleukin-13; Interleukin-4; Mesenchymal Stem Cells; NF-kappa B; Signal Transduction; Transforming Growth Factor beta

Acute kidney injury (AKI) and chronic kidney disease (CKD) are interconnected. Although AKI-to-CKD transition has been intensively studied, the information of AKI on CKD is very limited. Nonetheless, AKI, when occurring in patients with CKD, is known to be more severe and difficult to recover. CKD is associated with significant changes in cell signaling in kidney tissues, including the activation of transforming growth factor-β, p53, hypoxia-inducible factor, and major developmental pathways. At the cellular level, CKD is characterized by mitochondrial dysfunction, oxidative stress, and aberrant autophagy. At the tissue level, CKD is characterized by chronic inflammation and vascular dysfunction. These pathologic changes may contribute to the heightened sensitivity of, and nonrecovery from, AKI in patients with CKD.

Topics: Acute Kidney Injury; Autophagy; Basic Helix-Loop-Helix Transcription Factors; DNA Methylation; Epigenesis, Genetic; Humans; Inflammation; Kidney; Mitochondria; Oxidative Stress; Renal Insufficiency, Chronic; Risk Factors; Signal Transduction; Transforming Growth Factor beta; Tumor Suppressor Protein p53

Ionizing radiation is often regarded as an element of danger. But, danger responses on the cellular and molecular level are often beneficial with regard to the induction of anti-tumor immunity and for amelioration of inflammation. We outline how in dependence of radiation dose and fraction, radiation itself-and especially in combination with immune modulators-impacts on the innate and adaptive immune system. Focus is set on radiation-induced changes of the tumor cell phenotype and the cellular microenvironment including immunogenic cancer cell death. Mechanisms how anti-tumor immune responses are triggered by radiotherapy in combination with hyperthermia, inhibition of apoptosis, the adjuvant AnnexinA5, or vaccination with high hydrostatic pressure-killed autologous tumor cells are discussed. Building on this, feasible multimodal radio-immunotherapy concepts are reviewed including overcoming immune suppression by immune checkpoint inhibitors and by targeting TGF-β. Since radiation-induced tissue damage, inflammation, and anti-tumor immune responses are interconnected, the impact of lower doses of radiation on amelioration of inflammation is outlined. Closely meshed immune monitoring concepts based on the liquid biopsy blood are suggested for prognosis and prediction of cancer and non-cancer inflammatory diseases. Finally, challenges and visions for the design of cancer radio-immunotherapies and for treatment of benign inflammatory diseases are given.

Topics: Animals; Cell Death; Humans; Immune System Diseases; Immunity; Immunomodulation; Inflammation; Molecular Targeted Therapy; Neoplasms; Radiation, Ionizing; Radioimmunotherapy; Transforming Growth Factor beta; Tumor Microenvironment; Vaccination

The aim of this article is to review the immunoregulatory actions of frog skin-derived peptides in order to assess their potential as candidates for immunomodulatory or anti-inflammatory therapy. Frog skin peptides with demonstrable immunomodulatory properties have been isolated from skin secretions of a range of species belonging to the families Alytidae, Ascaphidae, Discoglossidae, Leptodactylidae, Pipidae and Ranidae. Their effects upon production of inflammatory and immunoregulatory cytokines by target cells have been evaluated ex vivo and effects upon cytokine expression and immune cell activity have been studied in vivo by flow cytometry after injection into mice. The naturally-occurring peptides and/or their synthetic analogues show complex and variable actions on the production of proinflammatory (TNF-α, IL-1β, IL-12, IL-23, IL-8, IFN-γ and IL-17), pleiotropic (IL-4 and IL-6) and immunosuppressive (IL-10 and TGF-β) cytokines by peripheral and spleen cells, peritoneal cells and/or isolated macrophages. The effects of frenatin 2.1S include enhancement of the activation state and homing capacity of Th1-type lymphocytes and NK cells in the mouse peritoneal cavity, as well as the promotion of their tumoricidal capacities. Overall, the diverse effects of frog skin-derived peptides on the immune system indicate their potential for development into therapeutic agents.

Topics: Amphibian Proteins; Animals; Anti-Inflammatory Agents; Anura; Gene Expression; Immunologic Factors; Inflammation; Interferon-gamma; Interleukins; Killer Cells, Natural; Mice; Neoplasms; Peptides; Skin; Th1 Cells; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

During the last decade, the endothelial-to-mesenchymal transition (EndMT) process has attracted considerable attention due to associations with the onset of certain diseases, such as organ fibrosis and cancer. Several studies have assessed the mechanisms and signaling pathways that regulate endothelial fibrosis in the context of human pathologies. A number of inflammatory mediators, including pro-inflammatory cytokines, growth factors, oxidative stress, and toxins, induce the conversion of endothelial cells into mesenchymal fibroblast-like cells that promote disease progression. This review is separated into five chapters that critically present current knowledge on EndMT in the context of pathology. First, the main characteristics of EndMT are summarized, with a focus on the endothelial protein pattern changes that modulate the expressions of endothelial/fibrotic markers and extracellular matrix proteins. These expressions could serve as mechanisms for explaining potential EndMT contributions to human pathologies in adults. Second, the main findings supporting a connection between EndMT-mediated endothelial fibrosis and inflammatory conditions are presented. These connections could be linked to the onset and progression of pathological conditions. Third, EndMT inducers are described in detail. This includes considerations on the actions of the first and most well-known EndMT inducer, TGF-β; of the most prominent pro-inflammatory cytokines released during inflammation, such as IL 1-β and TNF-α; and of the NF-κB transcription factor, a common player during inflammation-induced EndMT. Furthermore, thorough attention is given to EndMT induction by endotoxins in the context of bacterial infectious diseases. Additionally, the participation of the inflammatory oxidative stress environment in the EndMT induction was also reviewed. Fourth, the pathophysiological findings of inflammation-induced EndMT are presented, and, fifth, special focus is placed on associations with cancer onset and development. Altogether, this review highlights the important role of EndMT-mediated endothelial fibrosis during inflammation in human pathologies.

Topics: Animals; Bacterial Toxins; Cytokines; Epithelial-Mesenchymal Transition; Fibrosis; Gene Expression Regulation; Humans; Inflammation; Interleukin-1beta; Mice; Oxidative Stress; Signal Transduction; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Tumor necrosis factor (TNF)-α is a potent pro-inflammatory cytokine exerting pleiotropic effects on various cell types. It is synthesized in a precursor form called transmembrane TNF-α (mTNF-α) which, after being processed by metalloproteinases, is released in a soluble form to mediate its biological activities through Type 1 and 2 TNF receptors in TNF receptor expressing cells. In addition to acting in soluble form, TNF-α also acts in the transmembrane form both as a ligand by activating TNF receptors, as well as a receptor that transmits outside-to-inside (reverse) signals back into mTNF-α bearing cells. Since the discovery that TNF-α plays a determining role in the pathogenesis of several chronic inflammatory diseases, anti-TNF agents are increasingly being used in the treatment of a rapidly expanding number of rheumatic and systemic autoimmune diseases, such as rheumatoid arthritis, Crohn's disease, psoriasis, psoriatic arthritis, ankyloting spondylitis, Wegener granulomatosis and sarcoidosis. There are 5 TNF antagonists currently available: etanercept, a soluble TNF receptor construct; infliximab, a chimeric monoclonal antibody; adalimumab and golimumab, fully human antibodies; and certolizumab pegol, an Fab' fragment of a humanized anti-TNF-α antibody. Though each compound can efficiently neutralize TNF-α, increasing evidence suggests that they show different efficacy in the treatment of these diseases. These observations indicate that in addition to neutralizing TNF-α, other biological effects induced by TNF-α targeting molecules dictate the success of the therapy. Recently, we found that mTNF-α reverse signaling leads to transforming growth factor (TGF)-β production in macrophages and anti-TNF agents selectively trigger this pathway. In this review we will focus on the potential contribution of the activation of the mTNF-α signaling pathway to the success of the anti-TNF therapy.

Topics: Animals; Anti-Inflammatory Agents; Humans; Inflammation; Macrophages; Membrane Proteins; Signal Transduction; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Topics: Animals; Autoimmunity; Forkhead Transcription Factors; Humans; Immunotherapy; Inflammation; Integrins; Membrane Proteins; Mice; Neoplasms; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Transforming Growth Factor beta1

Fibrosis is a complex chronic disease characterized by a persistent repair response. Its pathogenesis is poorly understood but it is typically the result of chronic inflammation and maintained with the required activity of transforming growth factor-β (TGFβ) and extracellular matrix (ECM) tension, both of which drive fibroblasts to transition into a myofibroblast phenotype.. As the effector cells of repair, myofibroblasts migrate to the site of injury to deposit excessive amounts of matrix proteins and stimulate high levels of contraction. Myofibroblast activity is a decisive factor in whether a tissue is properly repaired by controlled wound healing or rendered fibrotic by deregulated repair. Extensive studies have documented the various contributing factors to an abrogated repair response. Though these fibrotic factors are known, very little is understood about the opposing antifibrotic molecules that assist in a successful repair, such as prostaglandin E2 (PGE. The idea is to understand the ways in which the cell, after an injury and inflammatory response, normally controls its repair mechanisms through its homeostatic regulators so as to mimic them therapeutically to control abnormal pathways.

Topics: Animals; Fibrosis; Humans; Inflammation; Myofibroblasts; Transforming Growth Factor beta; Wound Healing

Aneurysms are characterized by structural deterioration of the vascular wall leading to progressive dilatation and, potentially, rupture of the aorta. While aortic aneurysms often remain clinically silent, the morbidity and mortality associated with aneurysm expansion and rupture are considerable. Over 13,000 deaths annually in the United States are attributable to aortic aneurysm rupture with less than 1 in 3 persons with aortic aneurysm rupture surviving to surgical intervention. Environmental and epidemiologic risk factors including smoking, male gender, hypertension, older age, dyslipidemia, atherosclerosis, and family history are highly associated with abdominal aortic aneurysms, while heritable genetic mutations are commonly associated with aneurysms of the thoracic aorta. Similar to other forms of cardiovascular disease, family history, genetic variation, and heritable mutations modify the risk of aortic aneurysm formation and provide mechanistic insight into the pathogenesis of human aortic aneurysms. This review will examine the relationship between heritable genetic and epigenetic influences on thoracic and abdominal aortic aneurysm formation and rupture.

Topics: Aged; Aging; Aorta, Thoracic; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Aortic Rupture; Disease Progression; Epigenesis, Genetic; Extracellular Matrix; Female; Genetic Predisposition to Disease; Humans; Inflammation; Lipids; Male; Marfan Syndrome; Models, Genetic; Muscle, Smooth; Mutation; Polymorphism, Single Nucleotide; Risk Factors; Sequence Analysis, DNA; Smoking; Transforming Growth Factor beta

Growth differentiation factor-15 (GDF-15) is a member of the transforming growth factor beta superfamily. GDF-15 expression is dramatically upregulated during acute brain injury, cancer, cardiovascular disease, and inflammation, suggesting its potential value as a disease biomarker. It has been suggested that GDF-15 has neurotropic effects in the nervous system. Our studies showed that GDF-15 modulated the expression of neuronal K

Topics: Animals; Brain Injuries; Calcium Channels; Cardiovascular Diseases; Disease Progression; Growth Differentiation Factor 15; Humans; Inflammation; Mice; Neoplasms; Nervous System; Potassium Channels; Prefrontal Cortex; Transforming Growth Factor beta; Up-Regulation

Topics: Adult; Chronic Disease; Humans; Inflammation; Male; Nasal Polyps; Oxidative Stress; Quality of Life; Rhinitis; Sinusitis; Transforming Growth Factor beta; Transforming Growth Factor beta1

Inflammatory cells and mediators form a major part of the tumor microenvironment and play important roles in the regulation of cancer initiation, tumor cell proliferation, and metastasis. MicroRNAs (miRNAs) play important roles in several physiological and pathological processes, including the regulation of the inflammatory microenvironment in cancer. Transforming growth factor-β (TGF-β) is an inflammation-related cytokine that functions in both tumor suppression and promotion; however, its underlying molecular mechanisms remain unclear. Recent evidence indicates an association between miRNAs and TGF-β signaling, providing new insight into the nature of the inflammatory microenvironment in cancer. The present review is an overview of the interaction between miRNAs and inflammatory cytokines, with emphasis on the cross talk between TGF-β signaling and miRNAs and their influence on cancer cell behavior. The emerging roles of miRNAs in cancer-related inflammation and the potential to target miRNA signaling pathways for cancer therapy are also discussed.

Topics: Animals; Cytokines; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Mice; MicroRNAs; Neoplasms; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Tumor Microenvironment; Up-Regulation

Circulating maternal cells transfer to the fetus during pregnancy, where they may integrate with the fetal immune and organ systems, creating a state of maternal microchimerism (MMc). MMc can persist throughout the child's life, and it has been implicated in the triggering or perpetuation of chronic inflammatory autoimmune diseases, in the context of specific major histocompatibility genes. Correlative data in humans have now been tested in animal model systems. Results suggest that maternal-fetal tolerance may have health implications far beyond the time of pregnancy and into the child's life.

Topics: Animals; Autoimmune Diseases; Chimerism; Female; Graft vs Host Disease; HLA Antigens; Humans; Immune Tolerance; Inflammation; Interleukin-10; Maternal-Fetal Exchange; Pregnancy; Programmed Cell Death 1 Receptor; T-Lymphocytes; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

The transforming growth factor-beta (TGF-β) family signalling pathways play essential roles in the regulation of different cellular processes, including proliferation, differentiation, migration or cell death, which are essential for the homeostasis of tissues and organs. Because of the diverse and pleiotropic TGF-β functions, deregulation of its pathways contributes to human disease. In the case of the liver, TGF-β signalling participates in all stages of disease progression, from initial liver injury through inflammation and fibrosis, to cirrhosis and cancer. TGF-β has cytostatic and apoptotic effects in hepatocytes, promoting liver differentiation during embryogenesis and physiological liver regeneration. However, high levels of TGF-β, as a consequence of chronic liver damage, result in activation of stellate cells to myofibroblasts and massive hepatocyte cell death, which contributes to the promotion of liver fibrosis and later cirrhosis. During liver tumorigenesis, TGF-β may behave as a suppressor factor at early stages; however, there is strong evidence that overactivation of TGF-β signalling might contribute to later tumour progression, once cells escape from its cytostatic effects. For these reasons, targeting the TGF-β signalling pathway is being explored to counteract liver disease progression. In this review, we aim to shed light on the state-of-the-art in the signalling pathways induced by TGF-β that are involved in different stages of liver physiology and pathology.

Topics: Carcinogenesis; Carcinoma, Hepatocellular; Hepatocytes; Humans; Inflammation; Liver Cirrhosis; Liver Neoplasms; Liver Regeneration; Signal Transduction; Transforming Growth Factor beta

Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease and a risk factor for cirrhosis and hepatocellular carcinoma. The pathological features of NASH include steatosis, hepatocyte injury, inflammation, and various degrees of fibrosis. Steatosis reflects disordered lipid metabolism. Insulin resistance and excessive fatty acid influx to the liver are two important contributing factors. Steatosis is also likely associated with lipotoxicity and cellular stresses such as oxidative stress and endoplasmic reticulum stress, which result in hepatocyte injury. Inflammation and fibrosis are frequently triggered by various signals such as proinflammatory cytokines and chemokines, released by injuried hepatocytes and activated Kupffer cells. Although much progress has been made, the pathogenesis of NASH is not fully elucidated. The purpose of this review is to discuss the current understanding of NASH pathogenesis, mainly focusing on factors contributing to steatosis, hepatocyte injury, inflammation, and fibrosis.

Topics: Adipose Tissue; Animals; Apoptosis; Autophagy; Carcinoma, Hepatocellular; Chemokines; Cytokines; Fatty Acids; Fibrosis; Gastrointestinal Microbiome; Genetic Predisposition to Disease; Hepatic Stellate Cells; Hepatocytes; Humans; Inflammation; Insulin Resistance; Kupffer Cells; Lipid Metabolism; Lipopolysaccharides; Liver; Liver Neoplasms; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Risk Factors; Signal Transduction; Transforming Growth Factor beta

Fibrosis occurs in systemic tissues other than the brain and finally induces dysfunction of the fibrotic organ. Kidney fibrosis is related to scarring after acute kidney injury and the progression of chronic kidney disease. Kidney function decreases with the progression of kidney fibrosis. As fibrotic tissue cannot return to its original status, advanced kidney fibrosis requires the administration of dialysis or kidney transplantation. Thus, elucidation the mechanism of kidney fibrosis is an important research theme. The proliferation and activation of (myo) fibroblasts and the excessive production of an extracellular matrix are common mechanisms in fibrosis in many organs, but it seems that kidney fibrosis has specific pathways. Tubular epithelial, mesangial cells, and erythropoietin producing cells, which exist only in the kidney, participate in forming kidney fibrosis. This review highlights an understanding of the cells and their underlying mechanisms, which are specific to kidney fibrosis process: transforming growth factor-β (TGF-β), epithelial-mesenchymal transition, wingless/int-1 (WNT) signaling, renal anemia, and uremia. Finally, we describe potential therapies that focus on the mechanisms of kidney fibrosis: anti-TGF-β antibody and mammalian target of rapamycin (mTOR).

Topics: Animals; Antibodies, Monoclonal; Epithelial-Mesenchymal Transition; Fibrosis; Humans; Inflammation; Kidney; Kidney Diseases; Molecular Targeted Therapy; Protein Serine-Threonine Kinases; TOR Serine-Threonine Kinases; Transforming Growth Factor beta; Uremia; Wnt Signaling Pathway

Glucocorticoids (GCs) have been widely used for decades as a first-line treatment for inflammatory and autoimmune diseases. However, their use is often hampered by the onset of adverse effects or resistance. GCs mediate their effects via binding to glucocorticoid receptor (GR), a transcription factor belonging to the family of nuclear receptors. An important aspect of GR's actions, including its anti-inflammatory capacity, involves its interactions with various proteins, such as transcription factors, cofactors, and modifying enzymes, which codetermine receptor functionality. In this review, we provide a state-of-the-art overview of the protein-protein interactions (PPIs) of GR that positively or negatively affect its anti-inflammatory properties, along with mechanistic insights, if known. Emphasis is placed on the interactions that affect its anti-inflammatory effects in the presence of inflammatory and microbial diseases.

Topics: Animals; Anti-Inflammatory Agents; Cell Nucleus; Communicable Diseases; Glucocorticoids; Humans; Inflammation; Protein Interaction Maps; Protein Processing, Post-Translational; Receptors, Glucocorticoid; Signal Transduction; STAT Transcription Factors; Transforming Growth Factor beta

Long-term peritoneal dialysis causes morphologic and functional changes in the peritoneal membrane. Although mesothelial-mesenchymal transition of peritoneal mesothelial cells is a key process leading to peritoneal fibrosis, and bioincompatible peritoneal dialysis solutions (glucose, glucose degradation products, and advanced glycation end products or a combination) are responsible for altering mesothelial cell function and proliferation, mechanisms underlying these processes remain largely unclear. Peritoneal fibrosis has 2 cooperative parts, the fibrosis process itself and the inflammation. The link between these 2 processes is frequently bidirectional, with each one inducing the other. This review outlines our current understanding about the definition and pathophysiology of peritoneal fibrosis, recent studies on key fibrogenic molecular machinery in peritoneal fibrosis, such as the role of transforming growth factor-β/Smads, transforming growth factor-β β/Smad independent pathways, and noncoding RNAs. The diagnosis of peritoneal fibrosis, including effluent biomarkers and the histopathology of a peritoneal biopsy, which is the gold standard for demonstrating peritoneal fibrosis, is introduced in detail. Several interventions for peritoneal fibrosis based on biomarkers, cytology, histology, functional studies, and antagonists are presented in this review. Recent experimental trials in animal models, including pharmacology and gene therapy, which could offer novel insights into the treatment of peritoneal fibrosis in the near future, are also discussed in depth.

Topics: Animals; Biomarkers; Biopsy; Dialysis Solutions; Disease Models, Animal; Epithelial Cells; Glucose; Glycation End Products, Advanced; Humans; Inflammation; Peritoneal Dialysis; Peritoneal Fibrosis; Peritoneum; RNA, Long Noncoding; RNA, Small Untranslated; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

Hepatic fibrosis develops or progresses in 25 % of patients with autoimmune hepatitis despite corticosteroid therapy. Current management regimens lack reliable noninvasive methods to assess changes in hepatic fibrosis and interventions that disrupt fibrotic pathways. The goals of this review are to indicate promising noninvasive methods to monitor hepatic fibrosis in autoimmune hepatitis and identify anti-fibrotic interventions that warrant evaluation. Laboratory methods can differentiate cirrhosis from non-cirrhosis, but their accuracy in distinguishing changes in histological stage is uncertain. Radiological methods include transient elastography, acoustic radiation force impulse imaging, and magnetic resonance elastography. Methods based on ultrasonography are comparable in detecting advanced fibrosis and cirrhosis, but their performances may be compromised by hepatic inflammation and obesity. Magnetic resonance elastography has excellent performance parameters for all histological stages in diverse liver diseases, is uninfluenced by inflammatory activity or body habitus, has been superior to other radiological methods in nonalcoholic fatty liver disease, and may emerge as the preferred instrument to evaluate fibrosis in autoimmune hepatitis. Promising anti-fibrotic interventions are site- and organelle-specific agents, especially inhibitors of nicotinamide adenine dinucleotide phosphate oxidases, transforming growth factor beta, inducible nitric oxide synthase, lysyl oxidases, and C-C chemokine receptors types 2 and 5. Autoimmune hepatitis has a pro-fibrotic propensity, and noninvasive radiological methods, especially magnetic resonance elastography, and site- and organelle-specific interventions, especially selective antioxidants and inhibitors of collagen cross-linkage, may emerge to strengthen current management strategies.

Topics: Adrenal Cortex Hormones; Antioxidants; Apoptosis; CCR5 Receptor Antagonists; Cytokines; Elasticity Imaging Techniques; Extracellular Matrix; Hepatitis, Autoimmune; Humans; Inflammation; Liver Cirrhosis; Magnetic Resonance Imaging; NADPH Oxidases; Nitric Oxide Synthase Type II; Oxidative Stress; Protein-Lysine 6-Oxidase; Receptors, CCR2; Severity of Illness Index; Transforming Growth Factor beta; Vitamin D Deficiency

Topics: Actins; Animals; Aortic Aneurysm; Atherosclerosis; Humans; Inflammation; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Polymerization; Transforming Growth Factor beta; Vascular Remodeling

The transforming growth factor-β (TGFβ) superfamily is encoded by 33 genes and includes TGFβ, bone morphogenetic proteins (BMPs) and activins. Although TGFβ is well recognized as a crucial regulator of immune responses, the immunoregulatory functions of other TGFβ family members are less clear. However, recent evidence suggests that BMPs and activins have important roles in regulating immune responses. In this Review, we briefly outline the signalling pathways of the TGFβ superfamily and discuss new insights into the immunoregulatory functions of BMPs and activins in the context of infection, inflammation and cancer.

Topics: Activins; Animals; Bone Morphogenetic Proteins; Gene Expression Regulation; Homeostasis; Humans; Immune System; Immunomodulation; Inflammation; Multigene Family; Neoplasms; Receptors, Transforming Growth Factor beta; Signal Transduction; Transforming Growth Factor beta

Secreted phosphoprotein 24 kD (Spp24) is a bone matrix protein that appears to be derived primarily from the liver and delivered to other tissues in a protective complex. A significant role in bone growth and turnover is suggested by genetic studies that associate the gene locus (SPP2) with bone mineral density and bone quality. The function of this protein in the normal bone environment is unknown but clues are given by the fact that Spp24, or proteolytic products of Spp24, bind cytokines of the TGF-β superfamily and also activate intracellular signaling pathways. Several potential biotherapeutics have been engineered from this protein including materials that enhance BMP-induced bone healing and, on the other hand, materials that inhibit BMPs in clinical situations where this is called for such as reducing BMP-induced inflammation and inhibiting tumors dependent on BMP autocrine systems. As understanding of the structure and function of this protein increases, more opportunities for rationally developed therapeutics will become apparent.

Topics: Animals; Bone and Bones; Bone Density; Bone Matrix; Bone Morphogenetic Proteins; Cattle; Chick Embryo; Cytokines; HEK293 Cells; Humans; Inflammation; Mice; Osteoporosis; Phosphoproteins; Signal Transduction; Transforming Growth Factor beta

To provide a perspective by investigating the potential cross-talk between the adipose tissue and the kidney during obesity.. It is well established that excessive caloric intake contributes to organ injury. The associated increased adiposity initiates a cascade of cellular events that leads to progressive obesity-associated diseases such as kidney disease. Recent evidence has indicated that adipose tissue produces bioactive substances that contribute to obesity-related kidney disease, altering the renal function and structure. In parallel, proinflammatory processes within the adipose tissue can also lead to pathophysiological changes in the kidney during the obese state.. Despite considerable efforts to better characterize the pathophysiology of obesity-related metabolic disease, there are still a lack of efficient therapeutic strategies. New strategies focused on regulating adipose function with respect to AMP-activated protein kinase activation, NADPH oxidase function, and TGF-β may contribute to reducing adipose inflammation that may also provide renoprotection.

Topics: Adipose Tissue; AMP-Activated Protein Kinases; Cytokines; Fibrosis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Insulin Resistance; Kidney; NADPH Oxidases; Nephritis; Obesity; Receptors, G-Protein-Coupled; Transforming Growth Factor beta

Pre-eclampsia is a multi-system condition in pregnancy that is characterised by the onset of hypertension and proteinuria in women after the 20th week and it remains a leading cause of maternal and fetal mortality. Despite this the causative molecular basis of pre-eclampsia remains poorly understood. As a result, an intensive research effort has focused on understanding the molecular mechanisms involved in pre-eclampsia and using this information to identify new pre-symptomatic bio-markers of the condition. Activin A and its receptor, ACVR2A, have been extensively studied in this regard. Activin A is a member of the transforming growth factor (TGF)-β superfamily that has a wide range of biological functions depending on the cellular context. Recent work has shown that polymorphisms in ACVR2A may be a genetic risk factor for pre-eclampsia. Furthermore, both placenta and serum levels of Activin A are significantly increased in pre-eclampsia suggesting that Activin A may be a possible biomarker for the condition. Here we review the latest advances in this field and link these with new molecular data that suggest that the oxidative stress and pro-inflammatory cytokine production seen in pre-eclampsia may result in increased placental Activin A secretion in an attempt to maintain placental function.

Topics: Activins; Biomarkers; Clinical Trials as Topic; Cytokines; Female; Genetic Predisposition to Disease; Humans; Inflammation; Oxidative Stress; Placenta; Polymorphism, Genetic; Pre-Eclampsia; Pregnancy; Risk Factors; Signal Transduction; Transforming Growth Factor beta

Although fibrosis is becoming increasingly recognized as a major cause of morbidity and mortality in chronic inflammatory diseases, available treatment strategies are limited. Tenascins constitute a family of matricellular proteins, primarily modulating interactions of cells with other matrix components and growth factors. Data obtained from tenascin C deficient mice show important roles of this molecule in several models of fibrosis. Moreover there is growing evidence that tenascin C has a strong impact on chronic inflammation, myofibroblast differentiation and recruitment. Tenascin C as well as tenascin X has furthermore been shown to affect TGF-β activation and signaling. Taken together these data suggest that these proteins might be important factors in fibrosis development and make them attractive both as biological markers and as targets for therapeutical intervention. So far most clinical research in fibrosis has been focused on tenascin C. This review aims at summarizing our up-to-date knowledge on the involvement of tenascin C in the pathogenesis of fibrotic disorders.

Topics: Animals; Fibrosis; Humans; Inflammation; Myofibroblasts; Signal Transduction; Tenascin; Transforming Growth Factor beta

Over the last 3 decades, scientific evidence advocates an association between traumatic brain injury (TBI) and accelerated fracture healing. Multiple clinical and preclinical studies have shown an enhanced callus formation and an increased callus volume in patients, respectively, rats with concomitant TBI. Over time, different substances (cytokines, hormones, etc.) were in focus to elucidate the relationship between TBI and fracture healing. Until now, the mechanism behind this relationship is not fully clarified and a consensus on which substance plays the key role could not be attained in the literature. In this review, we will give an overview of current concepts and opinions on this topic published in the last decade and both clinical and pathophysiological theories will be discussed.

Topics: Blood-Brain Barrier; Brain Injuries; Calcitonin Gene-Related Peptide; Cell Death; Fracture Healing; Humans; Inflammation; Interleukin-6; Leptin; Mesenchymal Stem Cells; Transforming Growth Factor beta

Regulatory B (Breg) cells are immunosuppressive cells that support immunological tolerance. Through the production of interleukin-10 (IL-10), IL-35, and transforming growth factor β (TGF-β), Breg cells suppress immunopathology by prohibiting the expansion of pathogenic T cells and other pro-inflammatory lymphocytes. Recent work has shown that different inflammatory environments induce distinct Breg cell populations. Although these findings highlight the relevance of inflammatory signals in the differentiation of Breg cells, they also raise other questions about Breg cell biology and phenotype. For example, what are the functional properties and phenotype of Breg cells? Can a Breg cell arise at every stage in B cell development? Is inflammation the primary requisite for Breg cell differentiation? Here, we use these questions to discuss the advances in understanding Breg cell biology, with a particular emphasis on their ontogeny; we propose that multiple Breg cell subsets can be induced in response to inflammation at different stages in development.

Topics: B-Lymphocytes, Regulatory; Cell Differentiation; Cell Lineage; Cell Proliferation; Dendritic Cells; Humans; Immune Tolerance; Immunity, Innate; Inflammation; Interleukin-10; Interleukins; Killer Cells, Natural; Phenotype; T-Lymphocytes; Transforming Growth Factor beta

Radiation-induced fibrosis (RIF) is a long-term side effect of external beam radiation therapy for the treatment of cancer. It results in a multitude of symptoms that significantly impact quality of life. Understanding the mechanisms of RIF-induced changes is essential to developing effective strategies to prevent long-term disability and discomfort following radiation therapy. In this review, we describe the current understanding of the etiology, clinical presentation, pathogenesis, treatment, and directions of future therapy for this condition.. A literature review of publications describing mechanisms or treatments of RIF was performed. Specific databases utilized included PubMed and clinicaltrials.gov, using keywords "Radiation-Induced Fibrosis," "Radiotherapy Complications," "Fibrosis Therapy," and other closely related terms.. RIF is the result of a misguided wound healing response. In addition to causing direct DNA damage, ionizing radiation generates reactive oxygen and nitrogen species that lead to localized inflammation. This inflammatory process ultimately evolves into a fibrotic one characterized by increased collagen deposition, poor vascularity, and scarring. Tumor growth factor beta serves as the primary mediator in this response along with a host of other cytokines and growth factors. Current therapies have largely been directed toward these molecular targets and their associated signaling pathways.. Although RIF is widely prevalent among patients undergoing radiation therapy and significantly impacts quality of life, there is still much to learn about its pathogenesis and mechanisms. Current treatments have stemmed from this understanding, and it is anticipated that further elucidation will be essential for the development of more effective therapies.

Topics: DNA Damage; Fibrosis; Humans; Inflammation; Neoplasms; Radiation Injuries; Radiotherapy; Transforming Growth Factor beta

The liver is known to be the metabolic centre of the organism and is under the control of the central nervous system. It has a peculiar tissue structure and its anatomic localisation defines it as part of the immune system having an individual role in the defence of the organism. The determinant of its particular tissue build-up is the sinusoid system. In addition to hepatocytes, one cell row "endothelium", stellate cells close to the external surface, Kupffer cells tightly to its inner surface, as well as dendritic cells and other cell types (T and B lymphocytes, natural killer and natural killer T-cells, mast cells, granulocytes) are present. The multitudes and variety of cells make it possible to carry out the tasks according to the assignment of the organism. The liver is a member of the immune system having immune cells largely in an activated state. Its principal tasks are the assurance of the peripheral immune tolerance of the organism with the help of the haemopoetic cells and transforming growth factor-β. The liver takes part in the determination of the manner of the non-specific immune response of the organism. In addition to acute phase reaction of the organism, the liver has a role in the adaptive/specific immune response. These functions include retardation of the T and B lymphocytes and the defence against harmful pathogens. With the collaboration of transforming growth factor-β, immunoglobulins and their subclasses are inhibited just as the response of the T lymphocytes. The only exception is the undisturbed immunoglobulin A production. Particularly important is the intensive participation of the liver in the acute phase reaction of the organism, which is organised and guided by the coordinated functions of the cortico-hypothalamo-hypophysis-adrenal axis. Beside cellular elements, hormones, adhesion molecules, chemokines and cytokines are also involved in the cooperation with the organs. Acute phase reactants play a central role in these processes. Until recently the α2-macroglobulin was not considered as an acute reactant of the organism, but it is now functionally included in the acute phase reaction presumably due to its close connection with the transforming growth factor-β. Transforming growth factor-β has extraordinarily important roles in all phases of inflammation and in the specific immune response. The peripheral immune tolerance of the organism involves tightly coupled regulation of proliferation, differentiation and survival of

Topics: Acute-Phase Reaction; alpha-Macroglobulins; B-Lymphocytes; Dendritic Cells; Granulocytes; Humans; Immune System; Immunity, Innate; Immunoglobulins; Inflammation; Liver; Liver Cirrhosis; Lymphocytes; T-Lymphocytes; Transforming Growth Factor beta

Glioblastoma is the most common intracranial malignancy that constitutes about 50 % of all gliomas. Despite aggressive, multimodal therapy consisting of surgery, radiation, and chemotherapy, the outcome of patients with glioblastoma remains poor with 5-year survival rates of <10 %. Resistance to conventional therapies is most likely caused by several factors. Alterations in the functions of local immune mediators may represent a critical contributor to this resistance. The tumor microenvironment contains innate and adaptive immune cells in addition to the cancer cells and their surrounding stroma. These various cells communicate with each other by means of direct cell-cell contact or by soluble factors including cytokines and chemokines, and act in autocrine and paracrine manners to modulate tumor growth. There are dynamic interactions among the local immune elements and the tumor cells, where primarily the protective immune cells attempt to overcome the malignant cells. However, by developing somatic mutations and epigenetic modifications, the glioblastoma tumor cells acquire the capability of counteracting the local immune responses, and even exploit the immune cells and products for their own growth benefits. In this review, we survey those immune mechanisms that likely contribute to glioblastoma pathogenesis and may serve as a basis for novel treatment strategies.

Topics: Blood-Brain Barrier; Brain Neoplasms; Cancer Vaccines; Cell Communication; Cytokines; Cytotoxicity, Immunologic; Epigenesis, Genetic; Extracellular Vesicles; Glioblastoma; Humans; Immunotherapy; Inflammation; Lymphocytes, Tumor-Infiltrating; Macrophages; Microglia; Mutation; Myeloid Cells; Neoplasm Proteins; Neoplastic Stem Cells; Transforming Growth Factor beta; Tumor Escape; Tumor Microenvironment; Vascular Endothelial Growth Factor A

Otosclerosis is a complex disease of the human otic capsule with highest incidence in adult Caucasians. So far, many possible etiological factors like genetics, HLA, autoimmunity, viruses, inflammation, and hormones have been investigated but still the development of the disease remains unclear. Currently, the surgical replacement of stapes (stapedotomy) remains the best possible treatment option. In this review, we analyze different etiological factors studied so far in otosclerosis pathophysiology and discuss most recent findings and possible new research pathways.

Topics: Angiotensin II; Animals; Autoimmunity; Collagen; Genetic Predisposition to Disease; Hearing Loss; HLA Antigens; Humans; Inflammation; Measles virus; Otosclerosis; Oxidative Stress; Parathyroid Hormone; Reactive Oxygen Species; Stapes; Transforming Growth Factor beta

The complement mediators are the major effectors of the immune balance, which operates at the interface between the innate and adaptive immunity, and is vital for many immunoregulatory functions. Activation of the complement cascade through the classical, alternative or lectin pathways thus generating opsonins like C3b and C5b, anaphylatoxins C3a and C5a, chemotaxin, and inflammatory mediators, which leads to cellular death. Complement mediators that accelerate the airway remodeling are not well defined; however, an uncontrolled Th2-driven adaptive immune response has been linked to the major pathophysiologic features of asthma, including bronchoconstriction, airway hyperresponsiveness, and airway inflammation. The mechanisms leading to complement mediated airway tissue remodeling, and the effect of therapy on preventing and/or reversing it are not clearly understood. This review highlights complement-mediated inflammation, and the mechanism through it triggers the airway tissue injury and remodeling in the airway epithelium that could serve as potential targets for developing a new drug to rescue the asthma patients.

Topics: Airway Remodeling; Anaphylatoxins; Animals; Asthma; Chemotactic Factors; Complement Activation; Complement C3a; Complement C5a; Humans; Immunity, Innate; Inflammation; Inflammation Mediators; Interleukin-13; Opsonin Proteins; Th2 Cells; Transforming Growth Factor beta

Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that controls an immense number of cellular responses and plays a prominent role in maintaining homeostasis of most human organs. In the intestine, the TGF-β is involved in mucosal defense, immune tolerance, inhibition of acute inflammation, promoting the wound-healing process, and suppressing tumor initiation. However, TGF-β exhibits Janus-like features under certain physiologic conditions and chronic inflammation (e.g., inflammatory bowel diseases [IBDs]). Excessive TGF-β in IBDs favors chronic inflammation, incurs pathologic remolding, and facilitates the progression of colitis-associated inflammation (CAC). Considering the increasingly crucial roles of TGF-Β in the development of IBDs, we overview its pathways and multifaceted effects at the steady-state and IBD conditions of the gut, respectively. In addition, we present potential therapeutic strategies aimed at restoring normal TGF-β signaling in IBDs.

Topics: Animals; Humans; Immune Tolerance; Immunity, Mucosal; Inflammation; Inflammatory Bowel Diseases; Signal Transduction; Transforming Growth Factor beta

Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm where severity as well as treatment complexity is mainly attributed to a long lasting disease and presence of bone marrow stroma alterations as evidenced by myelofibrosis, neoangiogenesis, and osteosclerosis. While recent understanding of mutations role in hematopoietic cells provides an explanation for pathological myeloproliferation, functional involvement of stromal cells in the disease pathogenesis remains poorly understood. The current dogma is that stromal changes are secondary to the cytokine "storm" produced by the hematopoietic clone cells. However, despite therapies targeting the myeloproliferation-sustaining clones, PMF is still regarded as an incurable disease except for patients, who are successful recipients of allogeneic stem cell transplantation. Although the clinical benefits of these inhibitors have been correlated with a marked reduction in serum proinflammatory cytokines produced by the hematopoietic clones, further demonstrating the importance of inflammation in the pathological process, these treatments do not address the role of the altered bone marrow stroma in the pathological process. In this review, we propose hypotheses suggesting that the stroma is inflammatory-imprinted by clonal hematopoietic cells up to a point where it becomes "independent" of hematopoietic cell stimulation, resulting in an inflammatory vicious circle requiring combined stroma targeted therapies.

Topics: Bone Marrow; Data Mining; DNA Methylation; Hematopoietic Stem Cells; Humans; Inflammation; Primary Myelofibrosis; Stromal Cells; Transforming Growth Factor beta

Biologic markers of chronic GVHD may provide insight into the pathogenesis of the syndrome, identify molecular targets for novel interventions, and facilitate advances in clinical management. Despite extensive work performed to date largely focused on prediction and diagnosis of the syndrome, little synthesis of findings and validation of promising candidate markers in independent populations has been performed. Studies suggest that risk for subsequent chronic GVHD development may be associated with donor-recipient genetic polymorphism, deficiency in regulatory immune cell populations (NK, Treg, DC2), and variation in inflammatory and immunoregulatory mediators post-HCT (increased TNFα, IL-10 and BAFF, and decreased TGFβ and IL-15). Established chronic GVHD is associated with alteration in immune cell populations (increased CD3(+) T cells, Th17, CD4(+) and CD8(+) effector memory cells, monocytes, CD86 expression, BAFF/B cell ratio, and deficiency of Treg, NK cells, and naïve CD8(+) T cells). Inflammatory and immunomodulatory factors (TNFα, IL-6, IL-1β, IL-8, sIL-2R, and IL-1Ra, BAFF, anti-dsDNA, sIL-2Rα, and sCD13) are also perturbed. Little is known about biologic markers of chronic GVHD phenotype and severity, response to therapy, and prognosis.

Topics: B-Cell Activating Factor; Biomarkers; CD3 Complex; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Graft vs Host Disease; Humans; Inflammation; Interleukin-10; Interleukin-15; Killer Cells, Natural; Phenotype; Polymorphism, Genetic; Th17 Cells; Tissue Donors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Atrial fibrillation is the most common sustained arrhythmia, but its mechanisms are poorly understood. In particular, little is known about the factors that contribute to the establishment of persistent or permanent atrial fibrillation. This review addresses possible common signaling pathways that might promote both structural and electrical remodeling of the atria, thus contributing to atrial fibrillation perpetuation.. Sustained atrial fibrillation may trigger an inflammatory response leading to activation of myofibroblasts and to the release of cytokines such as transforming growth factor-β and platelet-derived growth factor, as well as profibrotic proteins such as galectin-3. Activation of signaling cascades involving such proteins is critical for the development of fibrosis and may also lead to ion channel dysfunction, which, along with myocyte apoptosis and extracellular matrix generation and turnover, likely contributes to both electrical and structural remodeling and predisposes to atrial fibrillation.. Identifying upstream strategies targeting molecular pathways that are common to fibrosis and electrical remodeling leading to atrial fibrillation perpetuation is highly desirable. This would facilitate finding new target genes with pleiotropic effects on the expression of ion channel proteins in myocytes and profibrotic molecules in nonmyocyte cells that are important for pathologic remodeling, which could become an important goal in persistent atrial fibrillation therapy.

Topics: Apoptosis; Atrial Fibrillation; Atrial Remodeling; Extracellular Matrix; Fibrosis; Galectin 3; Heart Atria; Heart Conduction System; Humans; Inflammation; Myocytes, Cardiac; Myofibroblasts; Platelet-Derived Growth Factor; Signal Transduction; Transforming Growth Factor beta

Asthma markedly diminishes quality of life due to limited activity, absences from work or school and hospitalizations. Patients with severe asthma which are not controlled despite taking effective therapy are most in need of new treatment approaches. IL-13 was demonstrated as 'central mediator of allergic asthma'.. IL-13 has been implicated in the pathogenesis of asthma, idiopathic pulmonary fibrosis and COPD. IL-13 levels in the sputum and bronchial biopsy samples remain elevated in severe asthma despite the use of inhaled and systemic corticosteroids. Thus, IL-13 is a mediator involved in corticosteroid resistance. Periostin enhances profibrotic TGF-β signaling in subepithelial fibrosis associated with asthma. IL-13 induces bronchial epithelial cells to secrete periostin. Periostin may be a biomarker for Th2 induced airway inflammation. Lebrikizumab is a monoclonal antibody against IL-13. Lebrikizumab improved lung function in asthmatics who were symptomatic despite treatment with long acting beta agonist and inhaled corticosteroids and provided benefit in the treatment of severe uncontrolled asthma.. Lebrikizumab block IL-13 signaling through the IL-13Rα1/IL-4Rα receptor. There was a larger reduction in FENO in the high periostin subgroup than in the low periostin subgroup (34.4 vs 4.3%). Serum CCL17, CCL13 and total IgE levels decreased in the lebrikizumab group.

Topics: Adrenal Cortex Hormones; Animals; Antibodies, Monoclonal; Asthma; Biological Products; Biomarkers; Bronchi; Cell Adhesion Molecules; Eosinophils; Humans; Hypersensitivity; Inflammation; Interleukin-13; Interleukin-33; Interleukin-4; Interleukins; Lung; Nitric Oxide; Quality of Life; Transforming Growth Factor beta

The use of cytokines as therapeutic agents is important, given their potent biological effects. However, this very potency, coupled with the pleiotropic nature and short half-life of these molecules, has limited their therapeutic use. Strategies to increase the half-life and to decrease toxicity are necessary to allow effective treatment with these molecules.. A number of strategies are used to overcome the natural limitations of cytokines, including PEGylation, encapsulation in liposomes, fusion to targeting peptides or antibodies and latent cytokines. Latent cytokines are engineered using the latency-associated peptide of transforming growth factor-β to produce therapeutic cytokines/peptides that are released only at the site of disease by cleavage with disease-induced matrix metalloproteinases. The principles underlying the latent cytokine technology are described and are compared to other methods of cytokine delivery. The potential of this technology for developing novel therapeutic strategies for the treatment of diseases with an inflammatory-mediated component is discussed.. Methods of therapeutic cytokine delivery are addressed. The latent cytokine technology holds significant advantages over other methods of drug delivery by providing simultaneously increased half-life and localised drug delivery without systemic effects. Cytokines that failed clinical trials should be reassessed using this delivery system.

Topics: Animals; Cytokines; Drug Delivery Systems; Humans; Inflammation; Peptides; Protein Precursors; Transforming Growth Factor beta

The microenvironment of established tumours is often immunosuppressed, and this allows tumours to grow and disseminate without being eliminated by the patient's immune system. The recent FDA approval of immunotherapies such as ipilimumab and sipuleucel-T that directly activate the adaptive and innate immune responses has triggered interest in developing other novel anti-cancer approaches that modulate the immune system. Understanding how the different constituents of the tumour microenvironment influence the immune system is thus crucial and is expected to generate a plethora of factors that can be targeted to boost immunity and trigger long lasting anti-tumour efficacy. Cancer associated fibroblasts (CAFs) are a crucial component of the tumour microenvironment. Through secretion of multiple growth factors, cytokines and proteases, CAFs are known to be key effectors for tumour progression and can promote cancer cell growth, invasiveness and angiogenesis. However, recent publications have also linked CAF biology to innate and adaptive immune cell recruitment and regulation. Here, we review recent findings on how CAFs can influence the immune status of tumours through direct and indirect interaction with immune cells and other key components of the tumour microenvironment.

Topics: Adaptive Immunity; Animals; Fibroblasts; Humans; Immunity, Cellular; Immunity, Innate; Immunotherapy; Inflammation; Neoplasms; Transforming Growth Factor beta; Tumor Microenvironment

Myocardial infarction triggers an intense inflammatory response that is essential for cardiac repair, but which is also implicated in the pathogenesis of postinfarction remodelling and heart failure. Signals in the infarcted myocardium activate toll-like receptor signalling, while complement activation and generation of reactive oxygen species induce cytokine and chemokine upregulation. Leukocytes recruited to the infarcted area, remove dead cells and matrix debris by phagocytosis, while preparing the area for scar formation. Timely repression of the inflammatory response is critical for effective healing, and is followed by activation of myofibroblasts that secrete matrix proteins in the infarcted area. Members of the transforming growth factor β family are critically involved in suppression of inflammation and activation of a profibrotic programme. Translation of these concepts to the clinic requires an understanding of the pathophysiological complexity and heterogeneity of postinfarction remodelling in patients with myocardial infarction. Individuals with an overactive and prolonged postinfarction inflammatory response might exhibit left ventricular dilatation and systolic dysfunction and might benefit from targeted anti-IL-1 or anti-chemokine therapies, whereas patients with an exaggerated fibrogenic reaction can develop heart failure with preserved ejection fraction and might require inhibition of the Smad3 (mothers against decapentaplegic homolog 3) cascade. Biomarker-based approaches are needed to identify patients with distinct pathophysiologic responses and to rationally implement inflammation-modulating strategies.

Topics: Biomarkers; Chemokines; Complement Activation; Cytokines; Humans; Immunity, Innate; Inflammation; Myocardial Infarction; Myofibroblasts; Reactive Oxygen Species; Signal Transduction; Toll-Like Receptors; Transforming Growth Factor beta; Ventricular Remodeling; Wound Healing

Semen deposition results in modulated immunity and an inflammatory response of the genital mucosa, which promotes conditions facilitating conception and pregnancy. These semen-induced alterations in the female reproductive tract can also have implications for the sexual transmission of viral infections such as HIV-1. Semen is not only a vector for HIV-1 but also a carrier for pro- and antiviral factors. Semen induces significant mucosal changes upregulating gene, and transcription factors leading to recruitment and activation of HIV target cells, stimulation of HIV replication and potentiation of Toll-like receptor responses. Although more research is needed to clearly elucidate the resulting collective effects of all these factors, semen modulation of the cervicovaginal microenvironment and immune system appears to lead, through multiple mechanisms, to mucosal changes facilitating viral entry and replication, likely resulting in enhanced susceptibility to acquire HIV-1 infection.

Topics: CD4-Positive T-Lymphocytes; Cellular Microenvironment; Cervix Uteri; Chemokine CCL20; Coitus; Disease Susceptibility; Female; HIV Infections; Humans; Inflammation; Interleukin-7; Male; Mucous Membrane; NF-kappa B; Prostaglandins E; Receptors, CCR6; Semen; Transforming Growth Factor beta; Vagina

Tumor necrosis factor, a regulatory cytokine, is extremely important signaling protein in the immune system. Among TNF family, TNF-alpha, TNF-beta are most the significant family members. Receptor of TNF namely TNFR1 and TNFR2 stimulates two different signaling pathways. TNFR1 signaling induces apoptosis pathway. Conversely, TNFR2 signaling triggers cell survival pathways. In this paper, we discuss about the TNF family with special reference to TNF-alpha/TNF-beta, different hypothesis related to autoimmunity and role of TNF, structure of TNF-alpha/TNF-beta, distribution and normal activity in human body of TNF, receptors and signaling pathway for drug targeting. Finally, we also discuss about the therapy for autoimmune diseases and immune-mediated inflammatory diseases (IMIDs) using small molecules or therapeutic proteins.

Topics: Autoimmune Diseases; Humans; Inflammation; Molecular Targeted Therapy; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Signal Transduction; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Acute inflammation is a response to an alteration induced by a pathogen or a physical or chemical insult, which functions to eliminate the source of the damage and restore homeostasis to the affected tissue. However, chronic inflammation triggers cellular events that can promote malignant transformation of cells and carcinogenesis. Several inflammatory mediators, such as TNF-α, IL-6, TGF-β, and IL-10, have been shown to participate in both the initiation and progression of cancer. In this review, we explore the role of these cytokines in important events of carcinogenesis, such as their capacity to generate reactive oxygen and nitrogen species, their potential mutagenic effect, and their involvement in mechanisms for epithelial mesenchymal transition, angiogenesis, and metastasis. Finally, we will provide an in-depth analysis of the participation of these cytokines in two types of cancer attributable to chronic inflammatory disease: colitis-associated colorectal cancer and cholangiocarcinoma.

Topics: Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinogenesis; Cholangiocarcinoma; Chronic Disease; Colitis; Colorectal Neoplasms; Gene Expression; Humans; Inflammation; Interleukin-10; Interleukin-6; Oxidative Stress; Transforming Growth Factor beta; Tumor Microenvironment; Tumor Necrosis Factor-alpha

Fibrosarcoma belongs to the sarcoma cancer group, which are spindle cell malignancies of mesenchymal origin, and owe their name to the predominant cell line that is present within the tumor. The extracellular matrix (ECM) is a complicated structure that surrounds and supports cells within tissues. Its main components are proteoglycans, collagens, glycoproteins, hyaluronan (HA), and several matrix-degrading enzymes. During cancer progression, significant changes can be observed in the structural and mechanical properties of ECM components. The ECM provides a physical scaffold to which tumor cells attach and migrate. Thus, it is required for key cellular events such as cell motility, adhesion, proliferation, invasion, and metastasis. Importantly, fibrosarcomas were shown to have a high content and turnover of ECM components including HA, proteoglycans, collagens, fibronectin, and laminin. In this review, we will focus on the HA component of fibrosarcoma ECM and critically discuss its role and involved mechanisms during fibrosarcoma pathogenesis.

Topics: Animals; Cell Movement; Disease Progression; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblast Growth Factors; Fibrosarcoma; Gene Expression Regulation, Neoplastic; Glycoproteins; Humans; Hyaluronan Receptors; Hyaluronic Acid; Inflammation; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Mesenchymal Stem Cells; Mice; Neovascularization, Pathologic; Protein Binding; Proteoglycans; Signal Transduction; Transforming Growth Factor beta

Re-epithelialization is a complex process that involves migration and proliferation of keratinocytes, in addition to the production of cytokines and growth factors that affect other cells. The induction of transcription factors during these processes is crucial for successful wound healing. The transcription factor forkhead boxO-1 (FOXO1) has recently been found to be an important regulator of wound healing. In particular, FOXO1 has significant effects through regulation of transforming growth factor-beta (TGF-β) expression and protecting keratinocytes from oxidative stress. In the absence of FOXO1, there is increased oxidative damage, reduced TGF-β1 expression, reduced migration and proliferation of keratinocytes and increased keratinocytes apoptosis leading to impaired re-epithelialization of wounds.

Topics: Forkhead Transcription Factors; Humans; Inflammation; Matrix Metalloproteinases; Oxidative Stress; Reactive Oxygen Species; Transforming Growth Factor beta; Wound Healing

The JmjC protein Mina is an important immune response regulator. Classical forward genetics first discovered its immune role in 2009 in connection with the development of T helper 2 (Th2) cells. This prompted investigation into Mina's role in the two best-studied contexts where Th2 responses are essential: atopic asthma and helminth expulsion. In work focused on a mouse model of atopic asthma, Mina deficiency was found to ameliorate airway hyper-resistance and pulmonary inflammation. And, in a case-control study genetic variation at the human MINA locus was found to be associated with the development of childhood atopic asthma. Although the underlying cellular and molecular mechanism of Mina's involvement in pulmonary inflammation remains unknown, our recent work on parasitic helminth expulsion suggests the possibility that, rather than T cells, epithelial cells responding to TGFβ may play the dominant role. Here we review the growing body of literature on the emerging Mina pathway in T cells and epithelial cells and attempt to set these into a broader context.

Topics: Animals; Asthma; Dioxygenases; Disease Models, Animal; Genetic Loci; Genetic Variation; Helminthiasis; Histone Demethylases; Humans; Inflammation; Mice; Neoplasm Proteins; Nuclear Proteins; Th2 Cells; Transforming Growth Factor beta

In recent years, there has been considerable interest in cellular and tissue responses to injury that result in the deposition of extracellular matrix, collagen, elastic fibers, and the histopathological development of fibrosis. In the myocardium, fibrosis results in many recognizable clinical features, including PR interval prolongation, heart block, bundle branch block, left ventricular dyssynergy, anisotropy, atrial fibrillation, ventricular arrhythmias, systolic and diastolic dysfunction, heart failure, and cardiac death. In the kidneys, fibrosis in the glomerulus leads to glomerular sclerosis, and in the inner cortex and medulla, tubulointerstitial fibrosis leads to a reduction in renal filtration function and rapidly progressive chronic kidney disease. There are a great number of potential early mediators of cellular damage in response to events such as ischemia, neurohormonal activation, biomechanical stretch, and abnormal cell signaling. However, many studies suggest that interstitial cells in both organs, including macrophages, T lymphocytes, fibroblasts, and myofibroblasts, have common communication systems that utilize galectin-3 and transforming growth factor-β that result in the upregulation and proliferation of fibroblasts and myofibroblasts, which produce and secrete procollagen I. Procollagen I cross-links in the extracellular space to form mature collagen, which is a fundamental unit of organ fibrosis. Future research will be concentrating on the pathogenic mechanisms that turn on fibrosis and on therapeutic targets that can either prevent the activation of fibroblasts or limit their repair response to injury.

Topics: Acute Kidney Injury; Animals; Cardio-Renal Syndrome; Chronic Disease; Collagen Type I; Extracellular Matrix; Fibrosis; Galectin 3; Heart; Heart Failure; Humans; Inflammation; Interleukin-1 Receptor-Like 1 Protein; Kidney; Models, Biological; Myocardium; Myofibroblasts; Natriuretic Agents; Receptors, Cell Surface; Stress, Mechanical; Transforming Growth Factor beta

Diabetes is the single largest contributor to the growing prevalence of chronic kidney disease (CKD), and episodes of acute kidney injury (AKI) increase the risk of advanced CKD in diabetic patients. Here we discuss whether the pathophysiological changes that occur in the tubular system of the diabetic kidney affect the intrinsic susceptibility to AKI. There is abundant data showing that drug-induced nephrotoxicity is attenuated in rodents with experimental diabetes mellitus, and some mechanistic explanations have been provided, in particular in response to aminoglycosides. Besides downregulation in proximal tubular megalin, which mediates the aminoglycoside uptake in proximal tubules, a role for hyperglycemia-induced activation of regenerative mechanisms has been proposed. The available clinical data, however, indicates that diabetes is a risk factor for AKI, including aminoglycoside nephrotoxicity. While much needs to be learned about this disconnect, the isolated induction of diabetes in otherwise healthy young adult rodents may simply not fully mimic the influence that diabetes exerts in the setting of a critically ill and often elderly patient. We speculate that diabetic tubular growth and the associated molecular signature (including upregulation of TGF-β, senescence, and inflammation) set up the development of diabetic nephropathy and renal failure in part by increasing the susceptibility to AKI, which further promotes hypoxia and apoptosis. Considering the strong association between AKI episodes and the cumulative risk of developing advanced CKD in diabetes, strategies that reduce AKI in these patients are expected to help reduce the growing burden of end-stage renal disease.

Topics: Acute Kidney Injury; Age Factors; Aminoglycosides; Animals; Anti-Bacterial Agents; Cell Cycle; Cellular Senescence; Critical Illness; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Susceptibility; Fibrosis; Gene Expression Profiling; Glomerular Filtration Rate; Humans; Hypertrophy; Inflammation; Kidney Failure, Chronic; Kidney Tubules, Proximal; Meta-Analysis as Topic; Observational Studies as Topic; Risk Factors; Sodium Chloride, Dietary; Transforming Growth Factor beta

Effects of mineralocorticoids are not restricted to regulation of epithelial salt transport, extracellular volume and blood pressure; mineralocorticoids also influence a wide variety of seemingly unrelated functions such as inflammation and fibrosis. The present brief review addresses the role of mineralocorticoids in the orchestration of these latter processes. Mineralocorticoids foster inflammation as well as vascular, cardiac, renal and peritoneal fibrosis. Mechanisms involved in mineralocorticoid-sensitive inflammation and fibrosis include the serum- and glucocorticoid-inducible kinase 1 (SGK1), which is genomically upregulated by mineralocorticoids and transforming growth factor β (TGF-β), and stimulated by mineralocorticoid-sensitive phosphatidylinositide 3-kinase. SGK1 upregulates the inflammatory transcription factor nuclear factor-κB, which in turn stimulates the expression of diverse inflammatory mediators including connective tissue growth factor. Moreover, SGK1 inhibits the degradation of the TGF-β-dependent transcription factors Smad2/3. Mineralocorticoids foster the development of TH17 cells, which is compromised following SGK1 deletion. Excessive SGK1 expression is observed in a wide variety of fibrosing diseases including lung fibrosis, diabetic nephropathy, glomerulonephritis, obstructive kidney disease, experimental nephrotic syndrome, obstructive nephropathy, liver cirrhosis, fibrosing pancreatitis, peritoneal fibrosis, Crohn's disease and celiac disease. The untoward inflammatory and fibrosing effects of mineralocorticoids could be blunted or even reversed by mineralocorticoid receptor blockers, which may thus be considered in the treatment of inflammatory and/or fibrosing disease.

Topics: Animals; Fibrosis; Inflammation; Mice; Mineralocorticoids; Protein Serine-Threonine Kinases; Rats; Receptors, Mineralocorticoid; Th17 Cells; Transforming Growth Factor beta; Up-Regulation

Neonatal sepsis is a major cause of morbidity and mortality and its signs and symptoms are nonspecific, which makes the diagnosis difficult. The routinely used laboratory tests are not effective methods of analysis, as they are extremely nonspecific and often cause inappropriate use of antibiotics. Sepsis is the result of an infection associated with a systemic inflammatory response with production and release of a wide range of inflammatory mediators. Cytokines are potent inflammatory mediators and their serum levels are increased during infections, so changes from other inflammatory effector molecules may occur. Although proinflammatory and anti-inflammatory cytokines have been identified as probable markers of neonatal infection, in order to characterize the inflammatory response during sepsis, it is necessary to analyze a panel of cytokines and not only the measurement of individual cytokines. Measurements of inflammatory mediators bring new options for diagnosing and following up neonatal sepsis, thus enabling early treatment and, as a result, increased neonatal survival. By taking into account the magnitude of neonatal sepsis, the aim of this review is to address the role of cytokines in the pathogenesis of neonatal sepsis and its value as a diagnostic criterion.

Topics: Biomarkers; Cytokines; Humans; Infant, Newborn; Inflammation; Interleukin-10; Interleukin-1beta; Interleukin-6; Interleukin-8; Sepsis; Transforming Growth Factor beta; Treatment Outcome; Tumor Necrosis Factor-alpha

Curcumin is a principal polyphenolic curcuminoid extracted from turmeric rhizome, which has been used for treating inflammation of joints, ulcers, jaundice and other disorders in Asian traditional medicine. In recent years, many studies have indicated that curcumin plays important roles in treatment of liver diseases. Curcumin attenuates liver injury and non-alcoholic fatty liver disease by lowering the release of inflammation cytokines, minimizing oxidative stress, enhancing the sensitivity of insulin and altering lipid metabolism. Curcumin shows potent anti-fibrosis activity, contributing to inhibit the activation of hepatic stellate cells and reduce the deposition of extracellular matrix by its regulation of PPAR-γ, NF-ΚB and TGF-β signaling pathways. Moreover, curcumin exhibits anti-cancer effect by inducing G2/M phase cell cycle arrest and apoptosis in several hepatoma cell lines. However, poor water solubility and low bioavailability of curcumin limit its clinical applications. To overcome its limited systemic bioavailability, many new approaches have been explored to deliver curcumin effectively. This article focuses on advances in the effects of curcumin and its derivatives for treatment of liver injury, non-alcoholic fatty liver disease, liver fibrosis and hepatocarcinoma.

Topics: Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Curcumin; Hepatic Stellate Cells; Humans; Inflammation; Liver Diseases; NF-kappa B; Oxidative Stress; PPAR gamma; Signal Transduction; Transforming Growth Factor beta

The incidence of acute and chronic conditions of the tendo Achillis appear to be increasing. Causation is multifactorial but the role of inherited genetic elements and the influence of environmental factors altering gene expression are increasingly being recognised. Certain individuals' tendons carry specific variations of genetic sequence that may make them more susceptible to injury. Alterations in the structure or relative amounts of the components of tendon and fine control of activity within the extracellular matrix affect the response of the tendon to loading with failure in certain cases. This review summarises present knowledge of the influence of genetic patterns on the pathology of the tendo Achillis, with a focus on the possible biological mechanisms by which genetic factors are involved in the aetiology of tendon pathology. Finally, we assess potential future developments with both the opportunities and risks that they may carry.

Topics: ABO Blood-Group System; Achilles Tendon; Apoptosis; Cartilage Oligomeric Matrix Protein; Collagen Type V; Epigenesis, Genetic; Extracellular Matrix Proteins; Fibrillar Collagens; Genetic Markers; Glycoproteins; Humans; Inflammation; Matrilin Proteins; Matrix Metalloproteinases; Rupture; Tenascin; Tendinopathy; Tendon Injuries; Transforming Growth Factor beta

It is now largely admitted that a pro-inflammatory environment may curtail anti-tumor immunity and favor cancer initiation and progression. The discovery that small non-coding regulatory RNAs, namely microRNAs (miRNAs), regulate all aspects of cell proliferation, differentiation, and function has shed a new light on regulatory mechanisms linking inflammation and cancer. Thus, miRNAs such as miR-21, miR-125b, miR-155, miR-196, and miR-210 that are critical for the immune response or hypoxia are often overexpressed in cancers and leukemias. Given the high number of their target transcripts, their deregulation may have a number of deleterious consequences, depending on the cellular context. In this review, we focus on how the factors encoded by transcripts targeted by these five miRNAs, be they transcription factors, tumor-suppressors, or regulators of different signaling pathways, can deregulate the immune response and favor pro-tumor immunity. Furthermore, we expose how the misdirected action of the main regulators of these miRNAs, such as nuclear factor κB (NF-κB), activator protein-1 (AP-1), and signal transduction and activators of transcription (STAT) transcription factors, or AKT and transforming growth factor β (TGFβ) signaling pathways, can contribute to decrease anti-tumor immunity and enhance cell proliferation and oncogenesis. We conclude by briefly discussing about how these discoveries may possibly lead to the development of new miRNA-based cancer therapies.

Topics: Animals; Biological Therapy; Cell Proliferation; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Humans; Immunity; Inflammation; MicroRNAs; Neoplasms; Signal Transduction; Transcription Factors; Transforming Growth Factor beta; Tumor Escape

Keloids are common cutaneous pathological scars that are characterised by the histological accumulation of fibroblasts, collagen fibres, and clinically significant invasive growth. Although increasing lines of research on keloids have revealed genetic and environmental factors that contribute to their formation, the etiology of these scars remains unclear. Several studies have suggested the involvement of lipid metabolism, from a nutritional point of view. However, the role that lipid metabolism plays in the pathogenesis and progression of keloids has not previously been reviewed. The progress that has been made in understanding the roles of the pro- and anti-inflammatory lipid mediators in inflammation, and how they relate to the formation and progression of keloids, is also outlined. In particular, the possible relationships between mechanotransduction and lipid metabolites in keloids are explored. Mechanotransduction is the process by which physical forces are converted into biochemical signals that are then integrated into cellular responses. It is possible that lipid rafts and caveolae provide the location of lipid signaling and interactions between these signaling pathways and mechanotransduction. Moreover, interactions between lipid signaling pathway molecules and mechanotransduction molecules have been observed. A better understanding of the lipid profile changes and the functional roles lipid metabolism plays in keloids will help to identify target molecules for the development of novel interventions that can prevent, reduce, or even reverse pathological scar formation and/or progression.

Topics: Cicatrix; Fibroblasts; Humans; Inflammation; Keloid; Lipid Metabolism; Mechanotransduction, Cellular; Signal Transduction; Transforming Growth Factor beta

GDF-15 (also MIC-1, NAG-1, PLAB, PTGFB) is a member of the TGF-β superfamily, which is widely distributed in mammalian tissues and has been shown to play multiple roles in various pathologies, including inflammation, cancer, cardiovascular diseases, and obesity. GDF-15 serum levels are a highly reliable predictor of disease progression. Both the anti-tumorigenic potential of GDF-15 and its capacity to promote metastasis have been documented for a large variety of cancers, yet its opposing functions, which are typical for members of the TGF-β superfamily, have only partly been resolved on the molecular level. Knowledge on physiological functions in the non-diseased organism is scarce. In the nervous system GDF-15 knockout analyses have revealed that GDF-15 is essential for the postnatal maintenance of various neuron populations. When applied exogenously GDF-15 is a powerful factor for promoting survival of developing and lesioned neurons in vitro and in vivo. Receptor activation by GDF-15 has only been partially resolved.

Topics: Animals; Cardiovascular Diseases; Gene Expression Regulation; Growth Differentiation Factor 15; Humans; Inflammation; Mice; Neoplasms; Obesity; Signal Transduction; Tissue Distribution; Transforming Growth Factor beta

TGF-β is a multifunctional cytokine involved in growth, cell differentiation and maintenanceof tissue homeostasis. In addition, TGF-β plays a key role in the pathogenesis of many diseases, including cancer. TGF-β-induced signaling pathways have either tumor-suppression or tumor-promoting effects in a cancer-type-specific and stage-dependent manner. TGF-β at an early stage of cancer development induces signaling pathways involved in inhibitionof cell proliferation, induction of differentiation, apoptosis or autophagy, suppression of angiogenesis and inflammation. At a later stage of disease, TGF-β exerts metastasis-promoting activity associated with epithelial-to-mesenchymal transition, modulation of cancer microenvironment and extracellular matrix components, inflammation and immune suppression. Furthermore, the TGF-β pathways play a pivotal role in the maintenance of stem cell-like properties of tumor cells. The pleiotropic action of TGF-β during tumorigenesis depends on interactions with different signaling pathways, including Hedgehog, WNT, PI3K--AKT, NOTCH, INF-γ, TNF-α, and RAS-ERK.

Topics: Apoptosis; Autophagy; Cell Transformation, Neoplastic; Cytokines; Epithelial-Mesenchymal Transition; Extracellular Matrix; Humans; Inflammation; Neoplasms; Neovascularization, Pathologic; Phosphatidylinositol 3-Kinases; Signal Transduction; Transforming Growth Factor beta; Tumor Microenvironment; Tumor Necrosis Factor-alpha

The intestinal mucosa possesses a complex epithelial barrier and a well-organized local immune system, which both efficiently protect this internal-external surface against potential microbial aggressions while guaranteeing tolerance towards harmless bacteria or antigens (oral tolerance). There is good experimental evidence that the intestinal microbiota is a main driver for the development of the mucosal immune system. Any perturbations/changes of this interaction with the intestinal microbiota or the microbial colonization process may cause health problems with short- and eventually long-term consequences, such as suspected for allergic or dysimmune disorders. Dendritic cells (DC) play a key role in the initiation of immune responses. Immune responses elicited by intestinal DC differ markedly from those initiated by spleen-derived DC: while intestinal DC induce anti-inflammatory and tolerogenic responses to harmless antigens such as derived from the resident microflora or harmless food allergens, systemic immune activation yields in a strong inflammatory TH1/TH17 reaction to the same antigens. The recent discovery how DC functions are regulated and imprinted by the microenvironment (DC conditioning) will be discussed in this review. High concentrations of retinoic acid or vitamin D metabolites, thymic stromal lymphopoietin and/or transforming growth factor-β (TGF-β) activate signaling programs in DC that yield in priming of regulatory and anti-inflammatory T cell responses. TGF-β is one of the key factors implicated in intestinal immune regulation; it is produced by a large variety of cells in the intestinal mucosa, including intestinal epithelial cells, lymphocytes and monocytes/macrophages/DC. An important anti-inflammatory effect of TGF-β on the immune system is the promotion and generation of FOXP3-positive regulatory T cells in the intestinal compartment. There are first and encouraging data from the treatment of Crohn's disease, an inflammatory GI condition, that targeted enteral therapy with optimized concentrations of immunoregulatory peptides, such as TGF-β, might of interest for the treatment of inflammatory disorders.

Topics: Crohn Disease; Dendritic Cells; Forkhead Transcription Factors; Humans; Inflammation; Intestinal Mucosa; Microbiota; Micronutrients; Transforming Growth Factor beta

Cancer growth is characterized by proliferation of tumor cells in conjunction with invasion of all different immune cells that also invade healing wounds. This inflammatory response is necessary for cell proliferation but a second purpose of the inflammatory process is so that a low Th1/Th2 ratio is present with overexpression of IL-10, TGF-β and IFN-γ. Down regulation of NO activity also shifts the balance between M1 and M2 macrophages. Both aspects allow the antigenous nature of the tumor to escape anti-tumor effects of the host. Support for this view comes from observations in pregnancy in which the placenta exhibits identical immune responses and downregulation of NO production to allow trophoblast cells to invade the uterine tissues without being rejected. Cell proliferation requires a metabolic set-up in which the organism produces adequate substrate for growth. This also bears the characteristics of a systemic inflammatory response delivering a similar substrate mix required for cancer and fetal growth. This arrangement is clearly beneficial in pregnancy and therefore supports the view that cancer growth is facilitated by the organism: the cancerous tumor elicits an immunological response opposing anti-tumor effects and induces the host to produce building blocks for growth.

Topics: Cell Proliferation; Down-Regulation; Female; Humans; Inflammation; Interferon-gamma; Interleukin-10; Neoplasms; Nitric Oxide; Pregnancy; Th1-Th2 Balance; Transforming Growth Factor beta; Trophoblasts

The injured central and peripheral nervous system (CNS and PNS) are difficult to regenerate due to the presence of growth inhibitory molecules which are upregulated around the lesion site. In addition, a strong inflammatory response triggering the production of so-called "pro"- and "anti-inflammatory" cytokines, adds to this dilemma. Both pro- and anti-inflammatory cytokines are involved in the regulation of diverse signaling pathways. One of the main aims to induce regeneration is to promote axonal outgrowth and stimulate the formation of new connections. Anti-inflammatory cytokines as modulators of neurite plasticity and outgrowth are of pivotal importance in neuroregeneration with different effects reported. Here we summarize the most relevant information about IL-4, IL-10, IL-13, LIF and TGF-β focusing on their direct and indirect role in axonal outgrowth.

Topics: Axons; Central Nervous System; Cytokines; Humans; Inflammation; Interleukin-10; Interleukin-13; Interleukin-4; Leukemia Inhibitory Factor; Nerve Regeneration; Peripheral Nervous System; Signal Transduction; Transforming Growth Factor beta

Inflammation is the physiological response to tissue injury caused by pathogens or trauma. Nevertheless, inflammation should be resolved in a timely manner, resulting in elimination of the inflammatory cells and mediators from the injured tissue, to avoid its deleterious consequences. Uncontrolled inflammation can lead to inflammatory, autoimmune, and cancerous disorders that are the result of improper resolution. The healing of the injured tissue during the termination of inflammation must also be tightly controlled since excessive tissue repair can lead to fibrosis and scarring of the affected organ. In the last three decades, it has been revealed that the resolution of inflammation is tightly orchestrated by specific cells, protein, and lipid mediators that are produced at proper timing and distinct locations. The bioactivity of these anti-inflammatory, pro-resolving, and immunoregulatory agents results in clearance of the tissue from inflammatory leukocytes and their products, and the return of homeostatic tissue architecture and function. Here, we will survey the current endogenous mechanisms governing the resolution of inflammation and directing it towards injury healing and halting of acquired immune responses while preventing excessive tissue repair and fibrosis. We focus on the role played by apoptotic polymorphonuclear cells (PMNs), 15-lipoxygenase (LO)-derived lipid mediators, and TGFβ in this macrophage-governed decision-making process and suggest new modes of action for fibrosis prevention and return to homeostasis.

Topics: Animals; Apoptosis; Arachidonate 15-Lipoxygenase; Fibrosis; Homeostasis; Humans; Inflammation; Macrophages; Neutrophils; Signal Transduction; Transforming Growth Factor beta; Wound Healing

Extracellular matrix (ECM) has both structural and regulatory roles. This update reviews the representative recent developments in diverse aspects of ECM biology relevant to inflammation, tissue destruction, fibrosis, and regeneration.. Biological regulation by ECM is emerging as a major research area, driven by several new directions. Sensing of mechanical cues provided by ECM was found to be crucial in regulating cell differentiation. Transforming growth factor-β (TGF-β) is a pivotal agent in fibrosis and inflammation. A combination of structural biology and cell biology provided novel insights on the mechanisms of its activation by cellular traction and ECM. Improved understanding of how fibrillin microfibrils and associated proteins regulated TGF-β sequestration and activation was achieved by analysis of inherited connective tissue disorders having TGF-β dysregulation as an underlying pathologic mechanism. Insights on microRNA-mediated ECM regulation suggest a key role for miR-29, for which potential therapeutic roles are emerging. Advances in understanding the ECM turnover by proteinases provided novel insights on cell regulation and identified useful disease biomarkers.. As a crucial modulator of cell behavior, ECM has exceptionally strong relevance and translational implications for human disease, opening novel opportunities for mechanistic understanding of disease pathogenesis as well as treatment.

Topics: Animals; Biomarkers; Extracellular Matrix; Humans; Inflammation; Mechanotransduction, Cellular; MicroRNAs; Neoplasm Metastasis; Transforming Growth Factor beta

B cells are generally considered to be positive regulators of the immune response because of their capability to produce antibodies, including autoantibodies. The production of antibodies facilitates optimal CD4(+) T-cell activation because B cells serve as antigen-presenting cells and exert other modulatory functions in immune responses. However, certain B cells can also negatively regulate the immune response by producing regulatory cytokines and directly interacting with pathogenic T cells via cell-to-cell contact. These types of B cells are defined as regulatory B (Breg) cells. The regulatory function of Breg cells has been demonstrated in mouse models of inflammation, cancer, transplantation, and particularly in autoimmunity. In this review, we focus on the recent advances that lead to the understanding of the development and function of Breg cells and the implications of B cells in human autoimmune diseases.

Topics: Animals; Autoimmune Diseases; B-Lymphocyte Subsets; Disease Models, Animal; Humans; Immunophenotyping; Inflammation; Interleukin-10; Mice; Transforming Growth Factor beta

Plasmacytoid dendritic cells (pDCs) belong to the family of dendritic cells and possess specific features that distinguish them from conventional dendritic cells. For instance, pDC are the main interferon-alpha-secreting cells. Plasmacytoid dendritic cells exert both proinflammatory and regulatory functions. This is attested by the involvement of pDC through interferon-alpha secretion in several autoimmune diseases, and by the implication of pDC in tolerance. The same is true for TGF-β that plays a dual role in inflammation. In this review, we discuss recent data on pDC and TGF-β interactions. As with many cell types, pDCs are able to respond to TGF-β using the classic Smad signaling pathway. In addition, pDCs are capable to secrete TGF-β, in particular in response to TGF-β exposure. Exposure of pDCs to TGF-β prevents type I interferon secretion in response to TLR7/9 ligands. In contrast, the consequences of TGF-β on the antigen-presenting cell capacities of pDC are less clear, since TGF-β-exposed pDCs may lead to both regulatory T-cell and interleukin-17-secreting cell polarization. Here, we discuss the factors that may influence this polarization. We also discuss how pDCs exposed to TGF-β may participate in tolerance induction and maintenance, or, on the contrary, in autoimmune diseases.

Topics: Adaptive Immunity; Animals; Apoptosis Regulatory Proteins; Dendritic Cells; Humans; Immune Tolerance; Immunity, Innate; Inflammation; Interleukin-17; Intracellular Signaling Peptides and Proteins; Mitochondrial Proteins; Signal Transduction; Toll-Like Receptors; Transforming Growth Factor beta

Age-related progression of cardiovascular disease is by far the largest health problem in the US and involves vascular damage, progressive vascular fibrosis and the accumulation of lipid-rich atherosclerotic lesions. Advanced lesions can restrict flow to key organs and can trigger occlusive thrombosis resulting in a stroke or myocardial infarction. Transforming growth factor-beta (TGF-β) is a major orchestrator of the fibroproliferative response to tissue damage. In the early stages of repair, TGF-β is released from platelets and activated from matrix reservoirs; it then stimulates the chemotaxis of repair cells, modulates immunity and inflammation and induces matrix production. At later stages, it negatively regulates fibrosis through its strong antiproliferative and apoptotic effects on fibrotic cells. In advanced lesions, TGF-β might be important in arterial calcification, commonly referred to as "hardening of the arteries". Because TGF-β can signal through multiple pathways, namely the SMADs, a MAPK pathway and the Rho/ROCK pathways, selective defects in TGF-β signaling can disrupt otherwise coordinated pathways of tissue regeneration. TGF-β is known to control cell proliferation, cell migration, matrix synthesis, wound contraction, calcification and the immune response, all being major components of the atherosclerotic process. However, many of the effects of TGF-β are essential to normal tissue repair and thus, TGF-β is often thought to be "atheroprotective". The present review attempts to parse systematically the known effects of TGF-β on both the major risk factors for atherosclerosis and to isolate the role of TGF-β in the many component pathways involved in atherogenesis.

Topics: Animals; Atherosclerosis; Fibrosis; Humans; Inflammation; Receptors, Transforming Growth Factor beta; Risk Factors; Smad Proteins; Transforming Growth Factor beta; Wound Healing

Transforming growth factor-β (TGF-β) has roles in embryonic development, the prevention of inappropriate inflammation and tumour suppression. However, TGF-β signalling also regulates pathological epithelial-to-mesenchymal transition (EMT), inducing or progressing a number of diseases ranging from inflammatory disorders, to fibrosis and cancer. However, TGF-β signalling does not proceed linearly but rather induces a complex network of cascades that mutually influence each other and cross-talk with other pathways to successfully induce EMT. Particularly, there is substantial evidence for cross-talk between αV integrins and TGF-β during EMT, and anti-integrin therapeutics are under development as treatments for TGF-β-related disorders. However, TGF-β's complex signalling network makes the development of therapeutics to block TGF-β-mediated pathology challenging. Moreover, despite our current understanding of integrins and TGF-β function during EMT, the precise mechanism of their role during physiological versus pathological EMT is not fully understood. This review focuses on the circle of regulation between αV integrin and TGF-β signalling during TGF-β induced EMT, which pose as a significant driver to many known TGF-β-mediated disorders.

Topics: Animals; Cell Adhesion; Epithelial-Mesenchymal Transition; Extracellular Matrix; Fibrosis; Gene Expression Regulation; Genes, Regulator; Humans; Inflammation; Integrin alphaV; Neoplasms; Protein Isoforms; Signal Transduction; Transforming Growth Factor beta

Chronic granulomatous disease (CGD) is an uncommon congenital immunodeficiency seen approximately in 1 of 250,000 individuals. It is caused by a profound defect in a burst of oxygen consumption that normally accompanies phagocytosis in all myeloid cells (neutrophils, eosinophils, monocytes, and macrophages). This "respiratory burst" involves the catalytic conversion of molecular oxygen to the oxygen free-radical superoxide, which in turn gives rise to hydrogen peroxide, hypochlorous acid, and hydroxyl radicals. These oxygen derivatives play a critical role in the killing of pathogenic bacteria and fungi. As a result of the failure to activate the respiratory burst in their phagocytes, the majority of CGD patients suffer from severe recurrent infections and rather unexplained prolonged inflammatory reactions that may result in granulomatous lesions. Both may cause severe organ dysfunction depending on the tissues involved. Preventive measures as well as rapid (invasive) diagnostic procedures are required to successfully treat CGD. Hematopoietic stem cell transplantation may be a serious option in some of the patients.

Topics: Animals; Female; Granulomatous Disease, Chronic; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inflammation; Interleukin-17; Kynurenine; Male; Mice; Models, Animal; NADPH Oxidases; NF-E2-Related Factor 2; Phagocyte Bactericidal Dysfunction; Phagocytes; Phagocytosis; Respiratory Burst; Superoxides; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Transforming growth factor beta (TGF-β) has been recognized as an important mediator in the genesis of chronic kidney diseases (CKD), which are characterized by the accumulation of extracellular matrix (ECM) components in the glomeruli (glomerular fibrosis, glomerulosclerosis) and the tubular interstitium (tubulointerstitial fibrosis). Glomerulosclerosis is a major cause of glomerular filtration rate reduction in CKD and all three major glomerular cell types (podocytes or visceral epithelial cells, mesangial cells and endothelial cells) participate in the fibrotic process. TGF-β induces (1) podocytopenia caused by podocyte apoptosis and detachment from the glomerular basement membrane; (2) mesangial expansion caused by mesangial cell hypertrophy, proliferation (and eventually apoptosis) and ECM synthesis; (3) endothelial to mesenchymal transition giving rise to glomerular myofibroblasts, a major source of ECM. TGF-β has been shown to mediate several key tubular pathological events during CKD progression, namely fibroblast proliferation, epithelial to mesenchymal transition, tubular and fibroblast ECM production and epithelial cell death leading to tubular cell deletion and interstitial fibrosis. In this review, we re-examine the mechanisms involved in glomerulosclerosis and tubulointerstitial fibrosis and the way that TGF-β participates in renal fibrosis, renal parenchyma degeneration and loss of function associated with CKD.

Topics: Extracellular Matrix; Fibrosis; Humans; Inflammation; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Tubules; Podocytes; Transforming Growth Factor beta

Foxp3(+) T regulatory cells (Tregs) consisting of natural and induced Treg subsets play a crucial role in the maintenance of immune homeostasis against self-antigen. The actions designed to correct defects in numbers or functions of Tregs may be therapeutic in the treatment of autoimmune diseases. While recent studies demonstrated that natural Tregs are instable and dysfunctional in the inflammatory condition, induced Tregs (iTregs) may have a different feature. Here we review the progress of iTregs, particularly focus on their stability and function in the established autoimmune diseases. The advantage of iTregs as therapeutics used under inflammatory conditions is highlighted. Proper generation and manipulation of iTregs used for cellular therapy may provide a promise for the treatment of many autoimmune and inflammatory diseases.

Topics: Adoptive Transfer; Animals; Autoimmune Diseases; Cell Differentiation; Cell Transplantation; Forkhead Transcription Factors; Humans; Inflammation; Interleukins; Mice; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Transplantation Immunology

The transforming growth factor-β (TGF-β) superfamily is a multifunctional, contextually acting family of cytokines that participate in the regulation of development, disease and tissue repair in the nervous system. The TGF-β family is composed of several members, including TGF-βs, bone morphogenetic proteins (BMPs) and activins. In this review, we discuss recent findings that suggest TGF-β function as important pleiotropic modulators of nociceptive processing both physiologically and under pathological painful conditions. The strategy of increasing TGF-β signaling by deleting "BMP and activin membrane-bound inhibitor" (BAMBI), a TGF-β pseudoreceptor, has demonstrated the inhibitory role of TGF-β signaling pathways in normal nociception and in inflammatory and neuropathic pain models. In particular, strong evidence suggests that TGF-β1 is a relevant mediator of nociception and has protective effects against the development of chronic neuropathic pain by inhibiting the neuroimmune responses of neurons and glia and promoting the expression of endogenous opioids within the spinal cord. In the peripheral nervous system, activins and BMPs function as target-derived differentiation factors that determine and maintain the phenotypic identity and circuit assembly of peptidergic nociceptors. In this context, activin is involved in the complex events of neuroinflammation that modulate the expression of pain during wound healing. These findings have provided new insights into the physiopathology of nociception. Moreover, specific members of the TGF-β family and their signaling effectors and modulator molecules may be promising molecular targets for novel therapeutic agents for pain management.

Topics: Animals; Disease Models, Animal; Humans; Inflammation; Neuralgia; Nociceptors; Transforming Growth Factor beta

Since its rediscovery in the mid-1990s, FOXP3(+) regulatory T cells (Tregs) have climbed the rank to become commander-in-chief of the immune system. They possess diverse power and ability to orchestrate the immune system in time of inflammation and infection as well as in time of harmony and homeostasis. To be the commander-in-chief, they must be equipped with both offensive and defensive weaponry. This review will focus on the function of transforming growth factor-β (TGF-β) as the sword, the wand, and the shield of Tregs. Functioning as a sword, this review will begin with a discussion of the evidence that supports how Tregs utilize TGF-β to paralyze cell activation and differentiation to suppress immune response. It will next provide evidence on how TGF-β from Tregs acts as a wand to convert naïve T cells into iTregs and Th17 to aid in their combat against inflammation and infection. Lastly, the review will present evidence on the role of TGF-β produced by Tregs in providing a shield to protect and maintain Tregs against apoptosis and destabilization when surrounded by inflammation and constant stimulation. This triadic function of TGF-β empowers Tregs with the responsibility and burden to maintain homeostasis, promote immune tolerance, and regulate host defense against foreign pathogens.

Topics: Animals; Apoptosis; Cell Differentiation; Cell Membrane; Forkhead Transcription Factors; Homeostasis; Humans; Inflammation; Lymphocyte Activation; Membrane Proteins; Mice; Signal Transduction; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta; Transplantation Tolerance

Recent advances have stimulated new interest in the area of crystal arthritis, as microcrystals can be considered to be endogenous "danger signals" and are potent stimulators of immune as well as non-immune cells. The best known microcrystals include urate (MSU), and calcium pyrophosphate (CPP) crystals, associated with gout and pseudogout, respectively. Acute inflammation is the hallmark of the acute tissue reaction to crystals in both gout and pseudogout. The mechanisms leading to joint inflammation in these diseases involve first crystal formation and subsequent coating with serum proteins. Crystals can then interact with plasma cell membrane, either directly or via membrane receptors, leading to NLRP3 activation, proteolytic cleavage and maturation of pro-interleukin-1β (pro-IL1β) and secretion of mature IL1β. Once released, this cytokine orchestrates a series of events leading to endothelial cell activation and neutrophil recruitment. Ultimately, gout resolution involves several mechanisms including monocyte differentiation into macrophage, clearance of apoptotic neutrophils by macrophages, production of Transforming Growth Factor (TGF-β) and modification of protein coating on the crystal surface. This review will examine these different steps.

Topics: Apoptosis; Arthritis, Gouty; Biomarkers; Calcium Phosphates; Carrier Proteins; Chondrocalcinosis; Endothelial Cells; Gout; Humans; Inflammasomes; Inflammation; Interleukin-1beta; Macrophages; Neutrophils; NLR Family, Pyrin Domain-Containing 3 Protein; Proteolysis; Transforming Growth Factor beta; Uric Acid

The transforming growth factor β (TGFβ) superfamily consists of multipotential secreting cytokines that mediate many key events in normal cellular growth and development, including differentiation, proliferation, motility, organization and death. TGFβs act as ligand for 3 classes of cell surface receptors, the transmembrane serine-threonine kinase receptors, TGFβ receptor type I (TGFβRI) and type 2 (TGFβRII), and TGFβRIII receptors which include an ubiquitous extracellular β-glycan and the membrane glycoprotein endoglin (CD105). Binding of TGFβs to their receptors initiates diverse cellular responses resulting in the phosphorilation of Smad proteins, which then translocate to the nucleus and regulate the transcription of target genes. Perturbation of TGFβ signaling has been implicated in various human disorders including cancer, fibrosis and auto-immune diseases. Recently, mutations in TGFβR1 and TGFβR2 genes have been found in association with a continuum of clinical features with widespread vascular involvement. The extreme of clinical severity is represented by the Loeys-Dietz syndrome (LDS), an autosomal dominant disorder characterized by hypertelorism, bifid uvula, and/or cleft palate, and aggressive arteriopathy causing arterial tortuosity as well as life-threatening complications such as vascular aneurysms and dissections. Elastin disarray, loss of elastic fibre architecture and increased collagen expression in the arterial wall are the pathologic hallmark of LDS. In the present review article we will provide details on the activation of TGFβ cascade, on the clinical features of LDS, as well as on the mechanisms of TGFβ signaling perturbation leading to this condition and the potential role of the antagonism of TGFβ activity in disease management.

Topics: Elastin; Endothelial Cells; Extracellular Matrix; Humans; Inflammation; Loeys-Dietz Syndrome; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

To review the current mechanisms and biologic processes leading to the formation of pathologic scars.. A computerised literature search was carried out using MEDLINE for all published articles on ''pathologic scarring''. The medical subject headings ''scarring'' were combined with ''mechanisms''. A review of selected relevant literature was then undertaken.. Scarless embryonal healing tends to be characterised by minimal inflammatory reaction mediated by reduced IL6,IL8 and hyaluronidase while there are elevated levels of hyaluronic acid MMP1to3, as well as IL10.The multifunctional cytokine TGF-B, its several isoforms as well as its postreceptor signalling mechanisms appears to play the key role in the scarring process . There is also evidence to show that PDGF, IGF and other cytokines regulate scarring . While conventional antiscarring agents target the fibroplasia phase, others such as tamoxifen ,calcium channel blockers, and imidazolaquinolines targets various phases of the scarring process .. It appears that multiple mechanisms are involved in the phenotypical appearance of abnormal scarring. A deeper understanding of these mechanisms is pivotal to the development of better antiscarring therapies in the very near future .

Topics: Cicatrix; Cytokines; Fibrosis; Humans; Inflammation; Keloid; Skin; Skin Physiological Phenomena; Transforming Growth Factor beta; Wound Healing

Metastatic spread of tumor cells to vital organs is the major cause of death in cancer. Accumulating data support an important role of infiltrating immune cells in promoting carcinoma progression into metastatic disease. Tumor-infiltrating immune cells produce and secrete cytokines, growth factors and proteases that re-activate latent developmental processes including epithelial-mesenchymal transition (EMT). EMT provides tumor cells with invasive, migratory and stem cell properties allowing them to disseminate and propagate at distant sites. Induction of EMT requires two criteria to be fulfilled: (i) cells are competent to undergo EMT (ii) an EMT-permissive microenvironment exists. The cytokine TGF-β, which is expressed by tumor-infiltrating immune cells, stands out as a master regulator of the pro-invasive tumor microenvironment. TGF-β cooperates with stem cell pathways, such as Wnt and Ras signaling, to induce EMT. In addition, TGF-β contributes to an EMT-permissive microenvironment by switching the phenotypes of tumor-infiltrating immune cells, which thereby mount pro-invasive and pro-metastatic immune responses. In this review, we discuss the role of TGF-β-induced EMT as a link between cancer and inflammation in the context of questions, which from our point of view are key to answer in order to understand the functionality of EMT in tumors.

Topics: Animals; Cell Movement; Cytokines; Epithelial-Mesenchymal Transition; Humans; Inflammation; Neoplasms; Signal Transduction; Transforming Growth Factor beta; Tumor Microenvironment

Transforming growth factor-β (TGFβ) suppresses tumor formation since it inhibits cell growth and promotes apoptosis. However, in advanced cancers TGFβ elicits tumor promoting effects through its ability to induce epithelial-mesenchymal transition (EMT) which enhances invasiveness and metastasis; in addition, TGFβ exerts tumor promoting effects on non-malignant cells of the tumor, including suppression of immune surveillance and stimulation of angiogenesis. TGFβ promotes EMT by transcriptional and posttranscriptional regulation of a group of transcription factors that suppresses epithelial features, such as expression of components of cell junctions and polarity complexes, and enhances mesenchymal features, such as production of matrix molecules and several cytokines and growth factors that stimulate cell migration. The EMT program has certain similarities with the stem cell program. Inducers and effectors of EMT are interesting targets for the development of improved diagnosis, prognosis and therapy of cancer.

Topics: Animals; Cell Adhesion; Cell Nucleus; Epigenesis, Genetic; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Inflammation; MAP Kinase Signaling System; Mice; Models, Biological; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neoplastic Stem Cells; Platelet-Derived Growth Factor; RNA Processing, Post-Transcriptional; RNA Splicing; Signal Transduction; Transcription, Genetic; Transforming Growth Factor beta

The transcription factors nuclear factor-κB (NF-κB) and activating protein-1 (AP-1) are critical regulators of stress responses, immunity, inflammation and cancer. A large variety of cellular stimuli utilize these signaling pathways through a common upstream kinase transforming growth factor-β-activated kinase 1 (TAK1). TAK1 was originally identified as a mitogen-activated kinase kinase kinase (MAP3K) activated by transforming growth factor-β (TGF-β); however, it has been characterized as a key regulator in inflammatory and immune signaling pathways. In addition, microbial proteins and components of host cell signaling scramble for the TAK1 complex in innate immunity. This review highlights the recent advances in the activation mechanisms and physiological functions of TAK1. Research targeting TAK1 raises the potential for new therapeutic options for inflammatory disorders, including cancer.

Topics: Animals; Humans; Immunity, Innate; Inflammation; MAP Kinase Kinase Kinases; Neoplasms; NF-kappa B; Signal Transduction; Transforming Growth Factor beta

Transforming growth factor-β (TGF-β) influences the development of myocardiopathy in Chagas disease through regulation of (i) parasite invasion of heart cells, (ii) an intracellular parasite cycle, (iii) inflammation and immune response, (iv) heart fibrosis and remodeling, and (v) gap junction modulation and heart conduction. In this review, we discuss the rationale for developing TGF-β signaling-interfering therapies as adjuvant approaches for the management of the cardiac alterations of Chagas disease-affected patients.

Topics: Animals; Chagas Cardiomyopathy; Chagas Disease; Drug Design; Gap Junctions; Heart Conduction System; Humans; Inflammation; Signal Transduction; Transforming Growth Factor beta; Trypanosoma cruzi

Feedback regulatory circuits provided by regulatory T cells (T(reg) cells) and suppressive cytokines are an intrinsic part of the immune system, along with effector functions. Here we discuss some of the regulatory cytokines that have evolved to permit tolerance to components of self as well as the eradication of pathogens with minimal collateral damage to the host. Interleukin 2 (IL-2), IL-10 and transforming growth factor-β (TGF-β) are well characterized, whereas IL-27, IL-35 and IL-37 represent newcomers to the spectrum of anti-inflammatory cytokines. We also emphasize how information accumulated through in vitro as well as in vivo studies of genetically engineered mice can help in the understanding and treatment of human diseases.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Humans; Inflammation; Inflammation Mediators; Interleukin-1; Interleukin-10; Interleukin-17; Interleukin-2; Interleukins; Mice; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Autoimmune and inflammatory phenomena are characteristically present in systemic sclerosis (SSc) and impact on dysregulated fibroblast extracellular matrix deposition, hallmark of the disease in conjunction with fibroproliferative vasculopathy. Oligoclonal T helper 2-like cells are present in the skin and peripheral blood in early diffuse disease. Type 2 cytokines synergize with profibrotic cytokines including transforming growth factor beta, favoring collagen deposition and metalloproteinase inhibition by fibroblasts. Furthermore, chemokine with pro-fibrotic and pro-angiogenic properties are preferentially produced by fibroblasts under the influence of Th2-like cells. The profibrotic monocyte chemotactic protein 1 is also produced by fibroblasts, partially in response to Toll-like receptor 4 (TLR4) recognition, when autoantibodies (autoAb) bind to fibroblast surface. In addition, immune-complex formed by autoAb and ubiquitous antigens including topoisomerase-1 favor the production of interferon-alpha (IFN-α) possibly by interacting with intravesicular TLRs. Consistent with this findings, unbiased gene screening has revealed that SSc peripheral blood cells express genes induced by IFN-α, a characteristic shared with systemic lupus erythematosus and other autoimmune disorders. These findings highlight the complex relationship between adaptive and acquired immune responses, which may participate to the pathogenesis of SSc in manners until now unsuspected, which may help in identifying novel therapeutic targets.

Topics: Adaptive Immunity; Animals; Antigen-Antibody Complex; Autoantibodies; Chemokine CCL2; Collagen; Extracellular Matrix; Fibroblasts; Fibrosis; Gene Expression; Humans; Inflammation; Interferon-alpha; Mice; Scleroderma, Systemic; Signal Transduction; Skin; Th1-Th2 Balance; Th2 Cells; Toll-Like Receptor 4; Transforming Growth Factor beta

Vascular calcification is a major risk factor for cardiovascular morbidity and mortality. A full understanding of the signalling pathways mediating vascular calcification is crucial not just because of the importance of this pathology in disease, but also for exploring potential therapeutic targets. Clinically there is a need to develop therapies to prevent or even reverse calcification in situations of atherosclerosis, chronic kidney disease, diabetes, and aging. In this brief review, we intend to explore the initial triggers, which are commonly related to calcification in different disease scenarios and examine the downstream signalling pathways that instigate the process of vascular calcification. In particular, we try to dissect these pathways and also examine cross-talk between different signalling pathways. Our focus is the vascular smooth muscle cell (VSMC) as it is ultimately the phenotypic modulation of these cells that may drive the calcification process.

Topics: Aging; Bone Morphogenetic Proteins; Calcinosis; Humans; Hypercalcemia; Hyperphosphatemia; Inflammation; Interleukin-6; Muscle, Smooth, Vascular; Oxidative Stress; Receptors, Notch; Signal Transduction; Transforming Growth Factor beta; Tumor Necrosis Factors; Vascular Diseases; Wnt Proteins

Unbalanced Th1/Th2 T-cell responses in the liver are a characteristic of hepatic inflammation and subsequent liver fibrosis. The recently discovered Th17 cells, a subtype of CD4(+) T-helper cells mainly producing IL-17 and IL-22, have initially been linked to host defense against infections and to autoimmunity. Their preferred differentiation upon TGFβ and IL-6, two cytokines abundantly present in injured liver, makes a contribution of Th17 cells to hepatic inflammation very likely. Indeed, initial studies in humans revealed activated Th17 cells and Th17-related cytokines in various liver diseases. However, functional experiments in mouse models are not fully conclusive at present, and the pathogenic contribution of Th17 cells to liver inflammation might vary upon the disease etiology, for example, between infectious and autoimmune disorders. Understanding the chemokines and chemokine receptors promoting hepatic Th17 cell recruitment (possibly CCR6 or CCR4) might reveal new therapeutic targets interfering with Th17 migration or differentiation in liver disease.

Topics: Animals; Autoimmune Diseases; Autoimmunity; Cell Differentiation; Cell Movement; Chemical and Drug Induced Liver Injury; Concanavalin A; Disease Models, Animal; Humans; Infections; Inflammation; Interleukin-17; Interleukin-22; Interleukins; Liver; Liver Diseases; Mice; Receptors, Chemokine; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

Fibrosis affects multiple organs and is associated with hyperproliferation, cell transdifferentiation, matrix modification and contraction. It is therefore essential to discover the key drivers of fibrotic events, which in turn will facilitate the development of appropriate therapeutic strategies. The lens is an elegant experimental model to study the processes that give rise to fibrosis. The molecular and cellular organization of the lens is well defined and consequently modifications associated with fibrosis can be clearly assessed. Moreover, the avascular and non-innervated properties of the lens allow effective in vitro studies to be employed that complement in vivo systems and relate to clinical data. Using the lens as a model for fibrosis has direct relevance to millions affected by lens disorders, but also serves as a valuable experimental tool to understand fibrosis per se.

Topics: Cell Communication; Extracellular Matrix; Fibrosis; Humans; Inflammation; Lens Diseases; Lens, Crystalline; Models, Biological; Transforming Growth Factor beta

Cardiovascular disease is the biggest killer globally and the principal contributing factor to the pathology is atherosclerosis; a chronic, inflammatory disorder characterized by lipid and cholesterol accumulation and the development of fibrotic plaques within the walls of large and medium arteries. Macrophages are fundamental to the immune response directed to the site of inflammation and their normal, protective function is harnessed, detrimentally, in atherosclerosis. Macrophages contribute to plaque development by internalizing native and modified lipoproteins to convert them into cholesterol-rich foam cells. Foam cells not only help to bridge the innate and adaptive immune response to atherosclerosis but also accumulate to create fatty streaks, which help shape the architecture of advanced plaques. Foam cell formation involves the disruption of normal macrophage cholesterol metabolism, which is governed by a homeostatic mechanism that controls the uptake, intracellular metabolism, and efflux of cholesterol. It has emerged over the last 20 years that an array of cytokines, including interferon-γ, transforming growth factor-β1, interleukin-1β, and interleukin-10, are able to manipulate these processes. Foam cell targeting, anti-inflammatory therapies, such as agonists of nuclear receptors and statins, are known to regulate the actions of pro- and anti-atherogenic cytokines indirectly of their primary pharmacological function. A clear understanding of macrophage foam cell biology will hopefully enable novel foam cell targeting therapies to be developed for use in the clinical intervention of atherosclerosis.

Topics: Animals; Anti-Inflammatory Agents; Arteries; Atherosclerosis; Biological Transport; Cholesterol; Foam Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-1beta; Lipid Metabolism; Lipoproteins; Macrophages; Molecular Targeted Therapy; Plaque, Atherosclerotic; Receptors, Cytoplasmic and Nuclear; Transforming Growth Factor beta

The TGF-β (transforming growth factor-β) system signals via protein kinase receptors and Smad mediators to regulate a plethora of biological processes, including morphogenesis, embryonic development, adult stem cell differentiation, immune regulation, wound healing and inflammation. In addition, alterations of specific components of the TGF-β signalling pathway may contribute to a broad range of pathologies such as cancer, cardiovascular pathology, fibrosis and congenital diseases. The knowledge about the mechanisms involved in TGF-β signal transduction has allowed a better understanding of the disease pathogenicity as well as the identification of several molecular targets with great potential in therapeutic interventions.

Topics: Animals; Cardiovascular Diseases; Humans; Inflammation; Lung Diseases; Molecular Targeted Therapy; Musculoskeletal Diseases; Mutation; Neoplasms; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

This review explores the relationship between cytokines and microRNAs (miRNAs). In particular, the regulation of miRNAs by pro-inflammatory cytokines, anti-inflammatory cytokines, interferons and transforming growth factor beta are examined, highlighting how miRNAs can mediate some of the known functions of these cytokines, as well as identifying novel gene targets, mechanisms and cross-talk between pathways.

Topics: Animals; Cytokines; Humans; Inflammation; Interferons; Interleukin-1; Interleukin-10; Interleukin-6; MicroRNAs; Models, Biological; Neoplasms; Receptors, Cytokine; Signal Transduction; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Activin-A is a pleiotropic cytokine that belongs to the TGF-β superfamily and plays an important role in fundamental biological processes, such as development and tissue repair. Growing evidence proposes a crucial role for activin-A in immune-mediated responses and associated diseases, with both enhancing and suppressive effects depending on the cell type, the cytokine micromilieu and the context of the response. Several recent studies have demonstrated a striking increase in activin-A expression in experimental models of asthma, as well as, in the asthmatic airway in humans. Importantly, a strong immunoregulatory role for activin-A in allergic airway disease, with suppression of T helper (Th) type 2 cell-driven allergic responses and protection against the development of cardinal features of the asthmatic phenotype was revealed by in vivo functional studies. Activin-A-mediated immunosuppression is associated with induction of functional allergen-specific regulatory T cells. In human asthma, although activin-A levels are increased in the airway epithelium and submucosal cells, the expression of its signalling components is markedly decreased, pointing to decreased regulation. Nevertheless, a rapid activation of the activin-A signalling pathway is observed in the airway of individuals with asthma following inhalational allergen challenge, suggestive of an inherent protective mechanism to control disease. In support, in vitro studies using human airway epithelial cells have demonstrated that endogenous activin-A suppresses the release of inflammatory mediators, while it induces epithelial repair. Collectively, compelling evidence suggests that activin-A orchestrates the regulation of key events involved in the pathogenesis of allergic asthma. The critical role of activin-A in allergic airway responses places this cytokine as an exciting new therapeutic target for asthma.

Topics: Activins; Airway Remodeling; Animals; Asthma; Cytokines; Humans; Inflammation; Signal Transduction; Transforming Growth Factor beta

The use and "off-label" indications for recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal arthrodesis have been significantly expanded over the last decade. New surgical approaches and pathologies treated often place the exogenous protein near the spinal cord or peripheral nerves, yet little data exist to the potential interaction between rhBMP-2 and the nervous system. The current review was undertaken to provide a basic science perspective on the wide-ranging effects that rhBMP-2, a potent growth factor, has on the injured spinal cord and the local dorsal root ganglia (DRG). Results from the early animal studies on neural safety of rhBMP-2 were compared with the more recent in vivo work characterizing protein impact on the injured spinal cord. Potential mechanism of the rhBMP-2-induced radiculitis after lumbar arthrodesis is also discussed. The original pre-FDA approval animal study did not uncover any interaction between rhBMP-2 and the spinal cord or the nerve rootlets comprising the cauda equina. Recent in vivo work indicated, however, that in a penetrating injury model, rhBMP-2 triggers direct signaling in all spinal cord cells. In the rat, this interaction was deleterious to spontaneous recovery by exacerbating the inflammatory response to injury, increasing the glial scar, and making it more inhibitory to axonal regeneration. With respect to posterolateral lumbar arthrodesis in a noninjury model, rhBMP-2 use contributed to a transient postoperative mechanical hyperalgesia. Potential mechanism of this allodynia is through an observed inflammatory response within and around the local DRG. In summary, contrary to the original beliefs in the clinical community, rhBMP-2 does elicit a profound signaling response within the spinal cord and the peripheral ganglia. Recent preclinical studies indicate that rhBMP-2, if provided direct access to the spinal cord parenchyma or the DRG, can trigger significant inflammation and morphologic changes within these tissues that could be deleterious to neurologic recovery.

Topics: Animals; Bone Morphogenetic Protein 2; Ganglia, Spinal; Humans; Inflammation; Recombinant Proteins; Spinal Cord; Spinal Fusion; Transforming Growth Factor beta

The epithelial to mesenchymal transition (EMT) converts epithelial cells into migratory and invasive cells and is a fundamental event in morphogenesis. Although its relevance in the progression of cancer and organ fibrosis had been debated until recently, the EMT is now established as an important step in the metastatic cascade of epithelial tumors. The similarities between pathological and developmental EMTs validate the embryo as the best model to understand the molecular and cellular mechanisms involved in this process, identifying those that are hijacked during the progression of cancer and organ degeneration. Our ever-increasing understanding of how transcription factors regulate the EMT has revealed complex regulatory loops coupled to posttranscriptional and epigenetic regulatory programs. The EMT is now integrated into the systemic activities of whole organisms, establishing links with cell survival, stemness, inflammation, and immunity. In addition, the EMT now constitutes a promising target for the treatment of cancer and organ-degenerative diseases.

Topics: Animals; Cadherins; Cell Differentiation; Cell Movement; Cell Transformation, Neoplastic; Disease; Disease Progression; Epigenesis, Genetic; Epithelial Cells; Epithelial-Mesenchymal Transition; Extracellular Matrix; Humans; Hypoxia; Immunity; Inflammation; Mesoderm; Neoplasms; RNA, Untranslated; Transforming Growth Factor beta

CD4+ T-helper (TH) cells that selectively produce interleukin (IL)-17 (TH17) are thought to be critical for host defense and autoimmunity. Three major dogmas were established, based on initial studies performed in murine models, and initially extrapolated by many researchers to human pathophysiology. First, TH17 cells represent a fixed CD4+ T-cell effector phenotype without any developmental relationship with TH1 cells. Second, TH17 cells are exclusively responsible for pathogenicity in several chronic inflammatory disorders, TH1 cell being instead protective. Finally, TH17 cells originate from naïve TH cells in response to the combined activity of transforming growth factor (TGF)-β and IL-6, whereas in the presence of TGF-β alone the same cells develop into Foxp3+ T regulatory cells. Studies performed in human demonstrated apparent species-specific differences, such as the expression by TH17 cells of the TH1-related transcription factor T-bet, the IL-12-inducible plasticity of TH17 cells into TH1 cells, and the dispensability of TGF-β signaling for their development. As discussed in this short review, recent studies in mice have led to reassessment of the three above-mentioned dogmas regarding the TH17 phenotype, suggesting that studies in humans actually better depicted TH17 cells than initial studies in mice did.

Topics: Animals; Chronic Disease; Humans; Inflammation; Mice; Models, Immunological; Phenotype; Th17 Cells; Transforming Growth Factor beta

Chronic rhinosinusitis (CRS) is a heterogeneous group of inflammatory diseases of the nasal and paranasal cavities either accompanied by polyp formation (CRSwNP) or without polyps (CRSsNP). CRSsNP and CRSwNP are prevalent medical conditions associated with substantial impaired quality of life, reduced workplace productivity, and serious medical treatment costs. Despite recent research evidence that contributes to further unveiling the pathophysiology of these chronic airway conditions, the cause remains poorly understood and appears to be multifactorial. A diverse spectrum of alterations involving histopathology, inflammatory cell and T-cell patterns, remodeling parameters (eg, TGF-β), eicosanoid and IgE production, microorganisms, and epithelial barrier malfunctions is reported in the search to describe the pathogenesis of this heterogeneous group of upper airway diseases. Furthermore, novel evidence indicates considerable heterogeneity within the CRSwNP subgroup determining the risk of comorbid asthma. The characterization of specific disease subgroups is a challenging scientific and clinical task of utmost importance in the development of diagnostic tools and application of individualized treatments. This review focuses on recent evidence that sheds new light on our current knowledge regarding the inflammatory process of CRS to further unravel its pathogenesis.

Topics: Animals; Asthma; Chronic Disease; Eicosanoids; Humans; Immunoglobulin E; Inflammation; Rhinitis; Risk Factors; Sinusitis; T-Lymphocytes; Transforming Growth Factor beta

Using an immortalized human bronchial epithelial cell line, we showed previously that the transforming growth factor beta-induced (TGFBI) gene was consistently downregulated by six- to sevenfold among radiation-induced tumorigenic human cells when compared with controls. Transfection of TGFBI gene into tumor cells resulted in a significant reduction in tumor growth as well as in vitro anchorage independent growth. The observations that TGFBI knock-out animals showed increased spontaneous tumor incidence and chemically induced tumors highlight the suppressive nature of the gene. There is evidence that extranuclear/extracellular targets are important in low-dose radiation response and that the cyclo-oxygenase-2 signaling pathway mediates the process. The involvement of NFκB-dependent cytokines and the resultant inflammatory response works in concert with in modulating radiation-induced bronchial carcinogenesis.

Topics: Animals; Chromosome Aberrations; Cyclooxygenase 2 Inhibitors; Extracellular Matrix Proteins; Gene Expression Profiling; Humans; Inflammation; MAP Kinase Signaling System; Neoplasms, Radiation-Induced; NF-kappa B; Signal Transduction; Transforming Growth Factor beta

Chronic inflammation is thought to be the leading cause of many human cancers including colorectal cancer (CRC). Accordingly, epidemiologic and clinical studies indicate that patients affected by ulcerative colitis and Crohn's disease, the two major forms of inflammatory bowel disease, have an increased risk of developing CRC. In recent years, the role of immune cells and their products have been shown to be pivotal in initiation and progression of colitis-associated CRC. On the other hand, activation of the immune system has been shown to cause dysplastic cell elimination and cancer suppression in other settings. Clinical and experimental data herein reviewed, while confirming chronic inflammation as a risk factor for colon carcinogenesis, do not completely rule out the possibility that under certain conditions the chronic activation of the mucosal immune system might protect from colonic dysplasia.

Topics: Animals; Cell Transformation, Neoplastic; Chemokines; Colorectal Neoplasms; Humans; Immune System; Inflammation; Inflammatory Bowel Diseases; Interleukin-10; Interleukin-6; Intestines; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

TGF-β1 has been long considered as a key mediator in renal fibrosis and induces renal scarring largely by activating its downstream Smad signaling pathway. Interestingly, while mice overexpressing active TGF-β1 develop progressive renal injury, latent TGF-β1 plays a protective role in renal fibrosis and inflammation. Under disease conditions, Smad2 and Smad3 are highly activated, while Smad7 is degraded through the ubiquitin proteasome degradation mechanism. In addition to TGF-β1, many pathogenic mediators such as angiotensin II and advanced glycation end products can also activate the Smad pathway via both TGF-β-dependent and independent mechanisms. Smads interact with other signaling pathways, such as the MAPK and NF-κB pathways, to positively or negatively regulate renal inflammation and fibrosis. Studies from gene knockout mice demonstrate that TGF-β1 acts by stimulating its downstream Smads to diversely regulate kidney injury. In the context of renal fibrosis and inflammation, Smad3 is pathogenic, while Smad2 and Smad7 are protective. Smad4 exerts its diverse roles by transcriptionally enhancing Smad3-mediated renal fibrosis while inhibiting NF-κB-driven renal inflammation via a Smad7-dependent mechanism. Furthermore, we also demonstrated that TGF-β1 acts by stimulating Smad3 to positively or negatively regulate microRNAs to exert its fibrotic role in kidney disease. In conclusion, TGF-β/Smad signaling is a major pathway leading to kidney disease. Smad3 is a key mediator in renal fibrosis and inflammation, whereas Smad2 and Smad7 are renoprotective. Smad4 exerts its diverse role in promoting renal fibrosis while inhibiting inflammation. Thus, targeting the downstream TGF-β/Smad3 signaling pathway by gene transfer of either Smad7 or Smad3-dependent microRNAs may represent a specific and effective therapeutic strategy for kidney disease.

Topics: Animals; Fibrosis; Humans; Inflammation; Kidney Diseases; Mice; MicroRNAs; Smad Proteins; Transforming Growth Factor beta

Deregulation of transforming growth factor-beta (TGFbeta) signaling has been reported in human psoriasis. Our recent study using a keratin 5 promoter (K5.TGFbeta1(wt)) showed that transgenic mice expressing wild-type TGFbeta1 in the epidermis developed severe skin inflammation. Additional experimental data further support a direct role for TGFbeta1 overexpression in skin inflammation. First, we temporally induced TGFbeta1 expression in keratinocytes in our gene-switch TGFbeta1(wt) transgenic mice and found inflammation severity correlated with TGFbeta1(wt) transgene expression. Second, deletion of T cells in K5.TGFbeta1(wt) mice significantly delayed skin inflammation and associated epidermal hyperplasia/hyperkeratosis. Third, therapeutic approaches effective for human psoriasis, that is, Etanercept and Rosiglitazone, are effective in alleviating the symptoms observed in K5.TGFbeta1(wt) mice. Future studies will analyze specific mechanisms and identify key factors in TGFbeta1-induced skin inflammation. Our mouse models will provide a useful tool for understanding the molecular mechanisms of inflammatory skin disorders in which TGFbeta1 is overexpressed.

Topics: Animals; Epidermis; Humans; Immune System; Inflammation; Keratinocytes; Mice; Mice, Transgenic; Psoriasis; Rosiglitazone; Signal Transduction; Skin; Skin Physiological Phenomena; Thiazolidinediones; Transforming Growth Factor beta; Transgenes

The transforming growth factor beta (TGF-beta) has been studied with regard to the regulation of cell behavior for over three decades. A large body of research has been devoted to the regulation of epithelial cell and derivative carcinoma cell populations in vitro and in vivo. TGF-beta has been shown to inhibit epithelial cell cycle progression and promote apoptosis that together significantly contribute to the tumor suppressive role for TGF-beta during carcinoma initiation and progression. TGF-beta is also able to promote an epithelial to mesenchymal transition that has been associated with increased tumor cell motility, invasion and metastasis. However, it has now been shown that loss of carcinoma cell responsiveness to TGF-beta stimulation can also promote metastasis. Interestingly, enhanced metastasis in the absence of a carcinoma cell response to TGF-beta stimulation has been shown to involve increased chemokine production resulting in recruitment of pro-metastatic myeloid derived suppressor cell (MDSC) populations to the tumor microenvironment at the leading invasive edge. When present, MDSCs enhance angiogenesis, promote immune tolerance and provide matrix degrading enzymes that promote tumor progression and metastasis. Further, the recruitment of MDSC populations in this context likely enhances the classic role for TGF-beta in immune suppression since the MDSCs are an abundant source of TGF-beta production. Importantly, it is now clear that carcinoma-immune cell cross-talk initiated by TGF-beta signaling within the carcinoma cell is a significant determinant worth consideration when designing therapeutic strategies to manage tumor progression and metastasis.

Topics: Animals; Epithelial Cells; Humans; Inflammation; Macrophages; Models, Biological; Monocytes; Myeloid Cells; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Signal Transduction; Transforming Growth Factor beta

Cellular responses to pathogens, growth factors, cytokines, extra- or intra-cellular stress, is a prerequisite for the cell to adapt to novel and potentially dangerous situations. If the changes in the extra- or intra-cellular milieu causes DNA-damage or revoke a signalling pathway utilized during morphogenesis, the epithelial cells might be forced to undergo programmed cell death (apoptosis) in the benefit for the whole organism or transform to a mesenchymal cell type (epithelial to mesenchymal transition; EMT), in respond to a specific stimuli. An overview is presented over the current knowledge for the key components in signal transduction in homeostasis, inflammation and cancer. A handful of transcription factors are crucial for the determination of the specific cellular responses, where the transforming growth factor-beta (TGF-beta) is an important factor as discussed in this review.

Topics: Adaptor Proteins, Signal Transducing; Animals; Enzyme Activation; Humans; Inflammation; Interleukin-1beta; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad Proteins; TNF Receptor-Associated Factor 6; Transforming Growth Factor beta; Ubiquitination

Breast milk cytokines have the potential to regulate the immune response to food antigens in infants. Cytokines are present in all mammalian milks and are capable of inhibiting excess inflammation and modulating epithelial proliferation. There are a range of candidate cytokines in milk such as transforming growth factor-beta (TGF-beta), the major cytokine present, and interleukin-10, which play a role in immune regulation in the developing infant. This article will be a review of the current literature with regard to TGF-beta in infant immune development. Our data on supplementation of formula with rTGF-beta2 will be discussed in view of the current literature. Oral antigen exposure also plays an important role in priming the developing immune response. The influence of early introduction of oral beta-lactoglobulin in allergy prone rat pups will also be discussed.

Topics: Allergens; Animals; Food Hypersensitivity; Humans; Immune Tolerance; Infant; Inflammation; Interleukin-10; Milk, Human; Transforming Growth Factor beta

Heart failure is strongly associated with aging. Elderly patients with heart failure often have preserved systolic function exhibiting left ventricular hypertrophy accompanied by a decline in diastolic function. Experimental studies have demonstrated that age-related cardiac fibrosis plays an important role in the pathogenesis of diastolic heart failure in senescent hearts. Reactive oxygen species and angiotensin II are critically involved in fibrotic remodeling of the aging ventricle; their fibrogenic actions may be mediated, at least in part, through transforming growth factor (TGF)-beta. The increased prevalence of heart failure in the elderly is also due to impaired responses of the senescent heart to cardiac injury. Aging is associated with suppressed inflammation, delayed phagocytosis of dead cardiomyocytes, and markedly diminished collagen deposition following myocardial infarction, due to a blunted response of fibroblasts to fibrogenic growth factors. Thus, in addition to a baseline activation of fibrogenic pathways, senescent hearts exhibit an impaired reparative reserve due to decreased responses of mesenchymal cells to stimulatory signals. Impaired scar formation in senescent hearts is associated with accentuated dilative remodeling and worse systolic dysfunction. Understanding the pathogenesis of interstitial fibrosis in the aging heart and dissecting the mechanisms responsible for age-associated healing defects following cardiac injury are critical in order to design new strategies for prevention of adverse remodeling and heart failure in elderly patients.

Topics: Age Factors; Aged; Aged, 80 and over; Aging; Angiotensin II; Fibroblasts; Fibrosis; Heart Failure, Diastolic; Humans; Inflammation; Muscle Cells; Phagocytes; Reactive Oxygen Species; Risk Factors; Transforming Growth Factor beta; United States; Ventricular Remodeling

Morphological changes of the peritoneal membrane that occur over time among patients on peritoneal dialysis include fibrosis and neoangiogenesis. While the pathophysiologic mechanisms underlying these changes are not fully understood, the activation of the renin-angiotensin-aldosterone system (RAAS) may have an important role. Components of the RAAS are constitutively expressed within peritoneal mesothelial cells, and are upregulated in the presence of acute inflammation and chronic exposure to peritoneal dialysate. The high glucose concentration, low pH, and the presence of glucose degradation products in peritoneal dialysis solutions have all been implicated in modulation of peritoneal RAAS. Furthermore, activation of the RAAS, as well as the downstream production of transforming growth factor-beta, contributes to epithelial-to-mesenchymal transformation of mesothelial cells, resulting in progressive fibrosis of the peritoneal membrane. This process also leads to increased vascular endothelial growth factor production, which promotes peritoneal neoangiogenesis. Functionally, these changes translate into reduced ultrafiltration capacity of the peritoneal membrane, which is an important cause of technique failure among patients on long-term peritoneal dialysis. This brief review will describe our current state of knowledge about the role of peritoneal RAAS in peritoneal membrane damage and potential strategies to protect the membrane.

Topics: Dialysis Solutions; Epithelial Cells; Epithelium; Fibrosis; Glucose; Humans; Inflammation; Kidney; Neovascularization, Pathologic; Peritoneal Dialysis; Peritoneum; Renin-Angiotensin System; Transforming Growth Factor beta; Ultrafiltration

Transforming growth factor-beta (TGF-beta) has been shown to play an essential role in the suppression of inflammation, yet recent studies have revealed the positive roles of TGF-beta in inflammatory responses. For example, TGF-beta induces Foxp3-positive regulatory T cells (iTregs) in the presence of interleukin-2 (IL-2), while in the presence of IL-6, it induces pathogenic IL-17 producing Th17 cells. TGF-beta inhibits the proliferation of immune cells as well as cytokine production via Foxp3-dependent and -independent mechanisms. Little is known about molecular mechanisms involved in immune suppression via TGF-beta; however, Smad2/3 have been shown to play essential roles in Foxp3 induction as well as in IL-2 and IFN-gamma suppression, whereas Th17 differentiation is promoted via the Smad-independent pathway. Interaction between TGF-beta and other cytokine signaling is important in establishing the balance of immunity and tolerance.

Topics: Animals; Cell Differentiation; Inflammation; Mice; Signal Transduction; Smad Proteins, Receptor-Regulated; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Dysregulated transforming growth factor beta (TGFbeta) signaling is observed in a variety of human cancers. TGFbeta is produced in large quantities by many tumor types and is known to be pro-oncogenic. Therapeutic strategies directed against TGFbeta signaling using neutralizing antibodies and small molecular inhibitors have been developed. However, TGFbeta is also found to function as a tumor suppressor. This switch from a tumor suppressor in premalignant stages of tumorigenesis to a tumor promoter in later stages of the disease poses great challenges in TGFbeta-targeted cancer therapy. It remains unclear what mechanisms underlie the dual role of TGFbeta and what factors mediate the switch. In the past, most work on dissecting underlying mechanisms was focused on differential regulation of signaling pathways by tumor cell autonomous TGFbeta signaling. Recent progress in elucidating TGFbeta effects on host immune/inflammatory reactions in the tumor microenvironment and distant organs brings exciting new perspectives to the field.

Topics: Genes, Tumor Suppressor; Humans; Inflammation; Neoplasm Metastasis; Neoplasms; Signal Transduction; Transforming Growth Factor beta

Alterations in TGFbeta signaling are common in human cancers. TGFbeta has significant impact on tumor initiation and progression. Therapeutic strategies including neutralizing antibodies and small molecular inhibitors have been developed to target TGFbeta signaling. However, TGFbeta can work as both a tumor suppressor and a tumor promoter. A significant challenge to the development of successful TGFbeta antagonism treatment is understanding how and when TGFbeta switches its function from a tumor suppressor to a tumor promoter. Recent studies demonstrate that TGFbeta regulates the infiltration of inflammatory cells and cancer associated fibroblasts into the tumor microenvironment, resulting in changes in signaling cascade in tumor cells. Additionally, TGFbeta exerts systemic immune suppression and significantly inhibits host tumor immune surveillance. Neutralizing TGFbeta in preclinical mouse models enhances CD8+ T-cell and natural killer cell-mediated anti-tumor immune response. This new understanding of TGFbeta signaling in regulation of tumor microenvironment and immune response may provide useful information, particularly for patient selection and inflammation/immune biomarkers for TGFbeta antagonism therapy in clinical trials.

Topics: Animals; Carcinogens; Humans; Immune Tolerance; Inflammation; Mice; Models, Biological; Neoplasm Metastasis; Neoplasms; Signal Transduction; Transforming Growth Factor beta; Tumor Suppressor Proteins

T-cell activation is mediated not only by antigen stimulation through T-cell receptors but also by costimulatory signals through costimulatory molecules. Among several costimulatory molecules, the tumor necrosis factor (TNF) receptor family member OX40 plays a key role in the survival and homeostasis of effector and memory T cells. According to the conventional understanding of OX40 costimulation, an interaction between OX40 and OX40 ligand (OX40L) occurs when activated T cells bind to professional antigen-presenting cells (APCs). The T-cell functions, including cytokine production, expansion, and survival, are then enhanced by the OX40 costimulatory signals. Over the last half-decade, evidence has accumulated that OX40 signals are critical for controlling the function and differentiation of Foxp3(+) regulatory T cells, indicating a new aspect of OX40-mediated autoimmunity. Furthermore, the expression of OX40L by mast cells was shown to be important for controlling inflammation through regulatory T-cell function. Besides the essential role played by OX40 signaling in generating memory CD4 T cells, recent reports show that it also has a unique role in generating memory CD8 T cells. In addition, recent genome-wide association studies have identified single-nucleotide polymorphisms of the OX40L and OX40 genes that are related to cardiovascular diseases and SLE, providing direct evidence for the involvement of the OX40-OX40L interaction in human diseases. Here, we review recent progress on how the OX40-OX40L interaction regulates T-cell tolerance, peripheral T-cell homeostasis, and T-cell-mediated inflammatory diseases.

Topics: Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Humans; Immunologic Memory; Inflammation; Interleukin-7; Mice; OX40 Ligand; Receptors, OX40; Signal Transduction; T-Lymphocytes; Transforming Growth Factor beta

The clinical and pathologic features of eosinophilic esophagitis (EE) include extensive tissue remodeling. Increasing evidence supports a key role for the eosinophil in multiple aspects of the esophageal remodeling and fibrosis seen in this allergic disease. This article reviews the clinical implications of esophageal remodeling and fibrosis in EE and discusses the possible pathogenic mechanisms inducing and regulating these responses. The focus is specifically on eosinophil and cytokine interactions with the esophageal epithelium, vascular endothelium, resident fibroblasts, and smooth muscle. Current and potential therapeutic interventions are discussed that may impact the development or resolution of chronic esophageal remodeling and fibrosis in EE.

Topics: Animals; Cell Communication; Cell Movement; Cell Survival; Chemotactic Factors, Eosinophil; Endothelial Cells; Eosinophilia; Eosinophils; Esophagitis; Fibroblasts; Fibrosis; Humans; Hypersensitivity; Inflammation; Intestinal Mucosa; Nerve Growth Factors; Transforming Growth Factor beta

Hepatocellular carcinoma (HCC) is a major health problem, being the sixth most common cancer world-wide. Dysregulation of the balance between proliferation and cell death represents a pro-tumorigenic principle in human hepatocarcinogenesis. This review updates the recent relevant contributions reporting molecular alterations for HCC that induce an imbalance in the regulation of apoptosis. Alterations in the expression and/or activation of p53 are frequent in HCC cells, which confer on them resistance to chemotherapeutic drugs. Many HCCs are also insensitive to apoptosis induced either by death receptor ligands, such as FasL or TRAIL, or by transforming growth factor-beta (TGF-beta). Although the expression of some pro-apoptotic genes is decreased, the balance between death and survival is dysregulated in HCC mainly due to overactivation of anti-apoptotic pathways. Indeed, some molecules involved in counteracting apoptosis, such as Bcl-X(L), Mcl-1, c-IAP1, XIAP or survivin are over-expressed in HCC cells. Furthermore, some growth factors that mediate cell survival are up-regulated in HCC, as well as the molecules involved in the machinery responsible for cleavage of their pro-forms to an active peptide. The expression and/or activation of the JAK/STAT, PI3K/AKT and RAS/ERKs pathways are enhanced in many HCC cells, conferring on them resistance to apoptotic stimuli. Finally, recent evidence indicates that inflammatory processes, as well as the epithelial-mesenchymal transitions that occur in HCC cells to facilitate their dissemination, are related to cell survival. Therefore, therapeutic strategies to selectively inhibit anti-apoptotic signals in liver tumor cells have the potential to provide powerful tools to treat HCC.

Topics: Aflatoxin B1; Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Death; Cell Division; Cell Survival; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Kinetics; Liver Neoplasms; Mice; Mice, Transgenic; Receptors, Death Domain; Transforming Growth Factor beta; Tumor Suppressor Protein p53

Various dietary components may modify chronic inflammatory processes at the stage of cytokine production, amplification of nuclear factor-kappaB-mediated inflammatory gene expression, and the release of anti-inflammatory cytokine, transforming growth factor-beta. This review provides a synopsis of the strengths and weaknesses of the evidence that specific bioactive food components influence inflammation-related targets linked to cancer. A target repeatedly surfacing as a site of action for several dietary components is transforming growth factor beta. Whereas the use of dietary intervention strategies offers intriguing possibilities for maintaining normal cell function by modifying a process that is essential for cancer development and progression, more information is needed to characterize the minimum quantity of the bioactive food components required to bring about a change in inflammation-mediated cancer, the ideal time for intervention, and the importance of genetics in determining the response. Unquestionably, the societal benefits of using foods and their components to prevent chronic inflammation and associated complications, including cancer, are enormous.

Topics: Anti-Inflammatory Agents; Diet; Food; Histone Deacetylases; Humans; Hydroxyprostaglandin Dehydrogenases; Inflammation; Models, Biological; Neoplasms; NF-kappa B; Nutritive Value; Phosphorylation; Signal Transduction; Transforming Growth Factor beta

Upon activation, naive CD4(+) T cells differentiate into different lineages of effector T(h) subsets. Each subset is characterized by its unique cytokine profile and biological functions. T(h)17, a newly described T(h) subset that produces IL-17, IL-17F and IL-22 in preference to other cytokines, has been shown to play an important role in clearing specific pathogens and in inducing autoimmune tissue inflammations. Over the last 2-3 years, significant progress has been made to understand the development and biological functions of T(h)17 subset. Transforming growth factor beta (TGF) together with IL-6 or IL-21 initiates the differentiation while IL-23 stabilizes the generation of T(h)17 cells. The transcription factors of T(h)17 cells [retinoid-related orphan receptor (ROR) gammat, ROR-alpha and signal transducer and activator of transcription-3] have been described recently. Since TGF-beta is essential for the generation of both T(h)17 and regulatory T (T(reg)) cells from naive T cells, which suggests a developmental link between T(h)17 and T(reg) cells. Functions of these two subsets of T cells are, however, opposite to each other; T(h)17 cells are highly pathogenic during the inflammatory process while T(reg) cells are crucial for inhibiting tissue inflammation and maintaining self-tolerance. Here, we review the recent information on differentiation and effector functions of T(h)17 cells during inflammatory conditions.

Topics: Animals; Autoimmunity; Cell Differentiation; Cytokines; Humans; Infections; Inflammation; Interleukin-17; T-Lymphocyte Subsets; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Transcription Factors; Transforming Growth Factor beta

The immune system is pivotal in mediating the interactions between host and microbiota that shape the intestinal environment. Intestinal homeostasis arises from a highly dynamic balance between host protective immunity and regulatory mechanisms. This regulation is achieved by a number of cell populations acting through a set of shared regulatory pathways. In this review, we summarize the main lymphocyte subsets controlling immune responsiveness in the gut and their mechanisms of control, which involve maintenance of intestinal barrier function and suppression of chronic inflammation. CD4(+)Foxp3(+) T cells play a nonredundant role in the maintenance of intestinal homeostasis through IL-10- and TGF-beta-dependent mechanisms. Their activity is complemented by other T and B lymphocytes. Because breakdown in immune regulatory networks in the intestine leads to chronic inflammatory diseases of the gut, such as inflammatory bowel disease and celiac disease, regulatory lymphocytes are an attractive target for therapies of intestinal inflammation.

Topics: Animals; Antigen-Presenting Cells; B-Lymphocytes; Homeostasis; Humans; Immunity, Innate; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inflammation; Interleukin-10; Intestinal Mucosa; Intestines; Lymphoid Tissue; Mice; Natural Killer T-Cells; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

TGF-beta is a multi-functional cytokine with a huge array of effects on a variety of cell types. It is rapidly emerging as a key major player in the way the airway epithelium behaves and its ability to repair itself. This is not only of relevance to allergic airway diseases such as asthma and allergic rhinitis, which are increasing in prevalence worldwide, but in many other diseases. The full impact any disruption of TGF-beta signalling may have in the development and persistence of allergic inflammatory airway diseases is yet to be fully realized and remains the subject of ongoing research. There has been a recent revival of interest in the role of regulatory T cells in controlling allergic inflammation. Evidence is emerging of a significant contribution by TGF-beta to this regulatory process. This review aims to summarize current knowledge relating to TGF-beta in relation to allergic inflammatory upper airways disease, and attempts to clarify some of the discrepancies and inconsistencies in this area. It also considers the therapeutic implications of novel TGF-beta therapy, including potential future applications in the treatment of nasal polyposis and reduction of post-operative scar tissue formation following endoscopic sinus surgery.

Topics: Desensitization, Immunologic; Humans; Inflammation; Nasal Provocation Tests; Respiratory Hypersensitivity; Signal Transduction; Transforming Growth Factor beta

Adaptive Foxp3(+)CD4(+) regulatory T (iTreg) cells develop outside the thymus under subimmunogenic antigen presentation, during chronic inflammation, and during normal homeostasis of the gut. iTreg cells are essential in mucosal immune tolerance and in the control of severe chronic allergic inflammation, and most likely are one of the main barriers to the eradication of tumors. The Foxp3(+) iTreg cell repertoire is drawn from naive conventional CD4(+) T cells, whereas natural Treg (nTreg) cells are selected by high-avidity interactions in the thymus. The full extent of differences and similarities between iTreg and nTreg cells is yet to be defined. We speculate that iTreg cell development is driven by the need to maintain a noninflammatory environment in the gut, to suppress immune responses to environmental and food allergens, and to decrease chronic inflammation, whereas nTreg cells prevent autoimmunity and raise the activation threshold for all immune responses.

Topics: Animals; Cell Differentiation; Dendritic Cells; Forkhead Transcription Factors; Humans; Immune Tolerance; Infections; Inflammation; Interleukin-15; Interleukin-2; Neoplasms; STAT Transcription Factors; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Thymus Gland; Transforming Growth Factor beta; Tretinoin

Cytokines play a major role in maintaining lymphocyte homeostasis under both steady-state and inflammatory conditions. Unregulated lymphocytes in steady-state conditions can lead to autoimmunity, whereas during inflammation they can cause excessive tissue damage. Regulatory cytokines function in combination with other environmental signals to properly modulate the function and the extent of lymphocyte activation. Many recent studies have highlighted the importance of regulatory cytokines in controlling the differentiation and function of lymphocytes under steady-state and inflammatory conditions, as well as minimizing tissue damage.

Topics: Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Cell Differentiation; Humans; Inflammation; Inflammation Mediators; Interleukin-10; Interleukin-22; Interleukins; Transforming Growth Factor beta

The action of transforming-growth-factor (TGF)-beta following inflammatory responses is characterized by increased production of extracellular matrix (ECM) components, as well as mesenchymal cell proliferation, migration, and accumulation. Thus, TGF-beta is important for the induction of fibrosis often associated with chronic phases of inflammatory diseases. This common feature of TGF-related pathologies is observed in many different organs. Therefore, in addition to the description of the common TGF-beta-pathway, this review focuses on TGF-beta-related pathogenetic effects in different pathologies/organs, i. e., arthritis, diabetic nephropathy, colitis/Crohn's disease, radiation-induced fibrosis, and myocarditis (including their similarities and dissimilarities). However, TGF-beta exhibits both exacerbating and ameliorating features, depending on the phase of disease and the site of action. Due to its central role in severe fibrotic diseases, TGF-beta nevertheless remains an attractive therapeutic target, if targeted locally and during the fibrotic phase of disease.

Topics: Animals; Arthritis, Rheumatoid; Diabetic Nephropathies; Fibrosis; Humans; Inflammation; Intestines; Myocarditis; Radiation, Ionizing; Signal Transduction; Transforming Growth Factor beta

Celiac disease (CD), an enteropathy caused by dietary gluten in genetically susceptible individuals, is histologically characterized by villous atrophy, crypt cell hyperplasia, and increased number of intra-epithelial lymphocytes. The nature of CD pathogenesis remains unclear, but recent evidence indicates that both innate and adaptive immune responses are necessary for the phenotypic expression and pathologic changes characteristic of CD. Extensive studies of molecules produced by immune cells in the gut of CD patients have led to identification of two cytokines, namely interleukin (IL)-15 and IL-21, which are thought to play a major role in orchestrating the mucosal inflammatory response in CD. Here we review the current knowledge of the expression and function of IL-15 and IL-21 in CD.

Topics: Celiac Disease; Humans; Immunity, Innate; Immunity, Mucosal; Inflammation; Interleukin-15; Interleukins; Peptides; Transforming Growth Factor beta

T helper (Th) cells are grouped into functionally different subsets (considered hitherto distinct and stable) according to their cytokine production. However, a number of recent findings show a much higher degree of Th cell plasticity and interconvertibility than previously assumed. Therefore, Th effector functions might be subject to therapeutic modulation even in late stages of immunopathological diseases.

Topics: Animals; Autoimmune Diseases; Cytokines; Epigenesis, Genetic; Humans; Immune Tolerance; Immunogenetics; Immunophenotyping; Inflammation; Interleukin-2; Interleukin-4; Lymphocyte Activation; Signal Transduction; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Transcription Factors; Transforming Growth Factor beta

Increasing evidence shows that transforming growth factor-beta TGF-beta1 (TGF-beta1) is upregulated and plays a diverse role in renal fibrosis by stimulating extracellular matrix (ECM) production, while inhibiting renal inflammation. Recent studies have identified that TGF-beta1, once activated, signals through its downstream signaling pathway to exert its biological effects. It is now well accepted that TGF-beta regulates fibrosis positively by receptor-associated Smads including Smad2 and Smad3, but negatively by an inhibitory Smad, called Smad7. We and other investigators have shown that gene transfer of Smad7 is able to inhibit renal fibrosis in a number of experimental models of chronic kidney diseases, including obstructive nephropathy, remnant kidney disease, and autoimmune crescentic glomerulonephritis. Blockade of Smad2/3 activation is a major mechanism by which overexpression of Smad7 inhibits renal scarring. Furthermore, our recent findings also demonstrate that Smad7 plays a critical role in anti-inflammation in chronic kidney diseases by blocking the NF.kappaB-dependent inflammatory pathway. Thus, Smad7 has a unique role in both anti-renal fibrosis and inflammation. These findings also indicate that targeting the TGF-beta/Smad signaling pathway by overexpressing Smad7 may provide a novel, specific, and effective therapy for chronic kidney diseases.

Topics: Epithelial Cells; Fibrosis; Humans; Inflammation; Kidney Diseases; Kidney Failure, Chronic; Kidney Tubules; NF-kappa B; Signal Transduction; Smad7 Protein; Transforming Growth Factor beta

Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), represents a group of chronic disorders characterized by inflammation of the gastrointestinal tract, typically with a relapsing and remitting clinical course. Mucosal macrophages play an important role in the mucosal immune system, and an increase in the number of newly recruited monocytes and activated macrophages has been noted in the inflamed gut of patients with IBD. Activated macrophages are thought to be major contributors to the production of inflammatory cytokines in the gut, and imbalance of cytokines is contributing to the pathogenesis of IBD. The intestinal inflammation in IBD is controlled by a complex interplay of innate and adaptive immune mechanisms. Cytokines play a key role in IBD that determine T cell differentiation of Th1, Th2, T regulatory and newly described Th17 cells. Cytokines levels in time and space orchestrate the development, recurrence and exacerbation of the inflammatory process in IBD. Therefore, several cytokine therapies have been developed and tested for the treatment of IBD patients.

Topics: Cell Differentiation; Cell Line; Cytokines; Humans; Inflammation; Inflammatory Bowel Diseases; Interleukin-10; Interleukin-17; Interleukin-18; Interleukin-4; Interleukins; Models, Biological; Monocytes; T-Lymphocytes; Transforming Growth Factor beta

Progression of diabetic nephropathy (DN) is manifested by gradual scarring of both the renal glomerulus and tubulointerstitial region. Over the past several years, the general understanding of the pathogenic factors that lead to renal fibrosis in DN has expanded considerably. In this review, some of the important factors that appear to be involved in driving this fibrosing process are discussed, with special emphasis on newer findings and insights. It is now clear that multiple cell types in the kidney contribute to progressive fibrosis in DN. New concepts about bradykinin, TGF-beta and eNOS signaling as well as JAK/STAT activation and the central role of inflammation in both glomerular and tubulointerstitial fibrosis are discussed.

Topics: Animals; Bradykinin B2 Receptor Antagonists; Diabetic Nephropathies; Disease Progression; Eicosanoids; Fibrosis; Humans; Inflammation; Janus Kinases; Kidney; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Tubules; Lipid Metabolism; MicroRNAs; Nitric Oxide Synthase Type III; Plasminogen Activator Inhibitor 1; Protein C; Sclerosis; STAT Transcription Factors; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Recent studies have challenged the conventional hypothesis that inflammation is the major player in the fibrosis cascade. Emerging evidence points to a critical role for interactions between tissue-resident and infiltrating, non-resident cells, in mediating fibrotic responses. Improved understanding of the biology of extracellular matrix (ECM) remodeling and the pathways that regulate assembly of the ECM and its interactions with growth factors/cytokines have led to the identification of new and attractive therapeutic targets. These include molecules that regulate fibrocytic cell infiltration, epithelial and myofibroblast differentiation, ECM synthesis and degradation. However, it is imperative that these new therapies be timed and compartmentalized to target the tissue of interest, as the dynamics of cellular differentiation and ECM remodeling may be different between organ systems. This review will summarize the current understanding of the mechanisms involved in the development of fibrosis, based on recent in vitro and in vivo studies, and comment on novel molecular pathways for drug discovery.

Topics: Animals; Chemokines; Chronic Disease; Cytokines; Drug Discovery; Epithelial Cells; Fibrosis; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Mesoderm; Stem Cells; Transforming Growth Factor beta

During the last decade, it has become clear that the mammalian immune system is able to recognize and partially suppress nascent tumors. Human T cells specific to oncogenes and onco-fetal antigens are present in human cancer patients and their tumors. At the same time, molecular links between tumor-associated inflammation and tumor progression have been uncovered, providing an explanation for the long recognized epidemiological link between inflammation and cancer. The synopsis of these findings suggests a new interpretation of tumor immunity. It appears that antigen recognition or antigen-specific T-cell expansion at large is not as profoundly impaired in tumor patients as the correct polarization, the survival and the effector function of tumor-infiltrating T cells. This review will focus on pro-inflammatory cytokines likely to contribute to the deregulation of tumor-specific immunity and its consequences.

Topics: Animals; Cell Proliferation; Cytokines; Humans; Immunologic Surveillance; Inflammation; Interleukin-12; Interleukin-23; Interleukin-6; Models, Biological; Neoplasms; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Systemic sclerosis (SSc) is a complex and heterogeneous chronic illness characterized by substantial patient to patient variability in clinical manifestations, internal organ involvement, and outcome. Genetic factors contribute to disease susceptibility, but environmental influences also play a significant role. The pathogenesis of SSc encompasses vascular, immunological, and fibrotic processes, which contribute to clinical manifestations and morbidity and must be addressed in the treatment plan. Although vascular interventions appear to reduce the frequency and severity of complications, such as scleroderma renal crisis and pulmonary hypertension, current therapies generally target the immune component of SSc in a non-selective fashion and have largely failed as diseases-modifying interventions. Newer insights into the mechanisms underlying autoimmunity, vascular injury and destruction, and particularly tissue fibrosis provide novel potential targets for therapy. Transforming growth factor-ss is a ubiquitous cytokine that appears to contribute to fibroblast activation, collagen overproduction, and pathological tissue fibrosis. Neutralizing antibodies and small molecules that block TGF-beta activation or function are effective in shutting down TGF-beta signaling and selectively inhibit the progression of fibrosis and may be entering clinical trials for the treatment of SSc.

Topics: Blood Vessels; Cardiovascular Agents; Fibrosis; Genetic Predisposition to Disease; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Inflammation; Kidney Diseases; Lung Diseases, Interstitial; Raynaud Disease; Scleroderma, Systemic; Skin; Transforming Growth Factor beta; Treatment Outcome

Therapies targeting transforming growth factor beta (TGFbeta) signaling using neutralizing antibodies and small molecular inhibitors are in multiple clinical trails. However, TGFbeta is known to work as both a tumor suppressor and a tumor promoter, and current knowledge does not provide sufficient information on what factors mediate this switch in function and when this switch occurs. Recent advances in multiple disciplines suggest that immune cells from the tumor host may provide the answer.

Topics: Animals; Carcinogens; CD11b Antigen; Humans; Immune System; Inflammation; Myeloid Cells; Receptors, Chemokine; Signal Transduction; Transforming Growth Factor beta; Tumor Suppressor Proteins

Regulatory T (Treg) cells are emerging as key players in the regulation of different immune responses, thereby representing potential candidates for therapeutic interventions in a broad variety of immunological disorders. While the reduction or loss in function would be of benefit during the treatment of cancer, induction and/or expansion of Treg cell function might be helpful to interfere with unwanted immune responses in transplantation medicine, during autoimmunity, allergy and inflammation. However, a better understanding of Treg cell biology is a prerequisite to specifically modulate its function during immune responses in vivo. In the present review we will discuss current concepts on different cell types, components and some novel surface receptors expressed by Treg cells, namely Neuropilin-1, CD83 and G protein-coupled receptor 83 which might represent promising targets for the modulation of Treg cell function in human disease.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antigens; Antigens, CD; Autoimmune Diseases; CD83 Antigen; Humans; Immunoglobulins; Immunotherapy; Inflammation; Membrane Glycoproteins; Neuropilin-1; Receptors, G-Protein-Coupled; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tretinoin

Protracted inflammation leading to dysregulation of effector T-cell responses represents a common feature of a wide range of autoimmune diseases. The interleukin-12 (IL-12)/T-helper 1 (Th1) pathway was thought to be responsible for the pathogenesis of multiple chronic inflammatory diseases, including psoriasis, inflammatory bowel disease, arthritis, or multiple sclerosis, mainly through their production of interferon-gamma and its effects on macrophage activation and chemokine production. However, this initial concept of T-cell-mediated chronic inflammation required an adjustment with the discovery of an IL-12-related cytokine, designated IL-23. IL-23 was rapidly recognized for its involvement in the establishment of chronic inflammation and in the development of a Th cell subset producing IL-17, designated Th17, which is distinct from the previously reported Th1 and Th2 populations. This review aims to describe the characterization of IL-23 and its receptor, its biological activities, as well as its involvement in the development of human Th17 cells and autoimmunity.

Topics: Autoimmune Diseases; Cell Differentiation; Cytokines; Humans; Inflammation; Interleukin-12; Interleukin-17; Interleukin-1beta; Interleukin-23; Signal Transduction; T-Lymphocytes, Helper-Inducer; Transcription Factors; Transforming Growth Factor beta

Fibrotic scars deposited during skin wound healing can cause disfiguration and loss of dermal function. Scar differentiation involves inputs from multiple cell types in a predictable and overlapping sequence of cellular events that includes inflammation, migration/proliferation and extracellular matrix deposition. Research into the molecular mechanisms underpinning these processes in embryonic and adult wounds has contributed to the development of a growing number of novel therapeutic approaches for improving scar appearance. This review discusses some of these emerging strategies for shifting the balance of healing from scarring to regeneration in the context of non-pathological wounds. Particular focus is given to potential therapies based on transforming growth factor (TGF)-beta signaling and recent unexpected findings involving targeting of gap junctional connexins. Lessons learned in promoting scarless healing of cutaneous injuries might provide a basis for regenerative healing in other scenarios, such as spinal cord rupture or myocardial infarction.

Topics: Adult; Cicatrix; Collagen; Connexins; Embryo, Mammalian; Extracellular Matrix; Fetus; Humans; Inflammation; Protein Engineering; Skin; Transforming Growth Factor beta; Wound Healing

Although histologic features of airway remodeling have been well characterized in asthma, the immunologic and inflammatory mechanisms that drive progression of asthma to remodeling are still incompletely understood. Conceptually, airway remodeling may be a result of persistent inflammation and/or aberrant tissue repair mechanisms. It is likely that several immune and inflammatory cell types and mediators are involved in mediating airway remodeling. In addition, different features of airway remodeling are likely mediated by different inflammatory pathways. Several important candidate mediators of remodeling have been identified, including TGF-beta and T(H)2 cytokines (including IL-5 and IL-13), as well as vascular endothelial growth factor, a disintegrin and metalloproteinase 33, and matrix metalloproteinase 9. Mouse models of airway remodeling have provided important insight into potential mechanisms by which TGF-beta activation of the Smad-2/3 signaling pathway may contribute to airway remodeling. Human studies have demonstrated that anti-IL-5 reduces levels of airway eosinophils expressing TGF-beta, as well as levels of airway remodeling as assessed by bronchial biopsies. Further such studies confirming these observations, as well as alternate studies targeting additional individual cell types, cytokines, and mediators, are needed in human subjects with asthma to determine the role of candidate mediators of inflammation on the development and progression of airway remodeling.

Topics: ADAM Proteins; Animals; Asthma; Disease Progression; Eosinophils; Humans; Inflammation; Lung; Matrix Metalloproteinase 9; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Transforming growth factor-beta (TGF-beta) and interleukin-10 (IL-10) are regulatory cytokines with pleiotropic roles in the immune system. The prominent function of TGF-beta is to maintain T cell tolerance to self or innocuous environmental antigens via its direct effects on the differentiation and homeostasis of effector and regulatory T cells. A critical route for the regulation of T cells by TGF-beta is via activation of a T cell-produced latent form of TGF-beta1 by dendritic cell-expressed avbeta8 integrin. IL-10 operates primarily as a feedback inhibitor of exuberant T cell responses to microbial antigens. T cells are also the principal producers of IL-10, the expression of which is regulated by IL-27, IL-6, and TGF-beta. The collective activity of TGF-beta and IL-10 ensures a controlled inflammatory response specifically targeting pathogens without evoking excessive immunopathology to self-tissues.

Topics: Animals; Feedback, Physiological; Humans; Infections; Inflammation; Inflammation Mediators; Interleukin-10; Mice; T-Lymphocyte Subsets; Transforming Growth Factor beta

The small leucine-rich proteoglycan (SLRP) family has significantly expanded in the past decade to now encompass five discrete classes, grouped by common structural and functional properties. Some of these gene products are not classical proteoglycans, whereas others have new and unique features. In addition to being structural proteins, SLRPs constitute a network of signal regulation: being mostly extracellular, they are upstream of multiple signaling cascades. They affect intracellular phosphorylation, a major conduit of information for cellular responses, and modulate distinct pathways, including those driven by bone morphogenetic protein/transforming growth factor beta superfamily members, receptor tyrosine kinases such as ErbB family members and the insulin-like growth factor I receptor, and Toll-like receptors. The wealth of mechanistic insights into the molecular and cellular functions of SLRPs has revealed both the sophistication of this family of regulatory proteins and the challenges that remain in uncovering the totality of their functions. This review is focused on novel biological functions of SLRPs with special emphasis on their protein cores, newly described genetic diseases, and signaling events in which SLRPs play key functions.

Topics: Animals; Bone Morphogenetic Proteins; Humans; Inflammation; Leucine; Models, Biological; Models, Genetic; Multigene Family; Phosphatidylinositol 3-Kinases; Phylogeny; Proteoglycans; Signal Transduction; Transforming Growth Factor beta

Widely heralded for depressing ongoing immune responses, renewed interest in the proficiency by which transforming growth factor beta (TGF-beta) not only engages but also might drive an over-reactive innate response highlights its bipolar nature. Although coordination of the development and function of Treg, in addition to direct inhibition of cellular activation, are prominent pathways by which TGF-beta controls adaptive immunity, paradoxically TGF-beta appears instrumental in initiation of host responses to invasion through recruitment and activation of immune cells and persuasion of Th17 lineage commitment. Nevertheless, true to its manic-depressive behavior, new evidence links TGF-beta with depression of innate cells, including NK cells, and by way of a potential bridge between mast cells and Treg. Disruption of the tenuous balance between these opposing actions of TGF-beta underlies immunopathogenicity.

Topics: Animals; CD4-Positive T-Lymphocytes; Cell Lineage; Humans; Immunity, Innate; Inflammation; Transforming Growth Factor beta

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with progressive airflow obstruction. Tobacco smoking is the main risk factor worldwide. In contrast to asthma, antiinflammatory therapies are rather ineffective in improving chronic symptoms and reducing inflammation, lung function decline, and airway remodeling. Specific drugs that are directed against the remodeling and chronic inflammation, thereby preventing lung tissue damage and progressive lung function decline, must be developed. Experimental models and expression studies suggest that anti-vascular endothelial growth factor (VEGF) receptor strategies may be of use in patients with emphysema, whereas anti-HER1-directed strategies may be more useful in patients with pulmonary mucus hypersecretion, as seen in chronic bronchitis and asthma. Growth factors and cytokines including VEGF, fibroblast growth factors, transforming growth factor-beta, tumor necrosis factor-alpha, CXCL1, CXCL8, and CCL2, and signal transduction proteins such as mitogen-activated protein kinase p38 and nuclear factor-kappaB, seem to be important pathogenetic molecules in COPD. Specific antagonists for these proteins may be effective for different inflammatory diseases. However, their efficacy for COPD therapy has not yet been demonstrated. Finally, other drugs such as retinoic acids may provide restoration of lung tissue structure. Such approaches, however, must await the first results of growth factor or cytokine antagonist therapy in chronic lung diseases.

Topics: Animals; Chemokine CCL2; Chemokine CXCL1; Cytokines; Fibroblast Growth Factors; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Interleukin-8; Macrophages; Models, Biological; Pulmonary Disease, Chronic Obstructive; Signal Transduction; Transforming Growth Factor beta; Treatment Outcome; Vascular Endothelial Growth Factor A

IL-6 plays a pivotal role in immune responses and certain oncologic conditions. The intense investigation of its biological activity and function led to the discovery of two different IL-6-driven signalling pathways. Binding to the membrane-bound IL-6 receptor (mIL-6R, CD126) causes the recruitment of two gp130 co-receptor molecules (CD130) and the activation of intracellular signalling cascades via gp130. Although this classical pathway is mainly limited to hepatocytes, neutrophils, monocytes/macrophages and certain other leukocyte populations, which express IL-6R on their surface, an alternative mechanism has also been described. Proteolytic cleavage of the mIL-6R protein or translation from alternatively spliced mRNA leads to the generation of a soluble form of the IL-6R (sIL-6R), which is likewise able to bind to IL-6. The resulting IL-6/sIL-6R complex is also capable of binding to gp130 and inducing intracellular signalling. Through this so-called 'trans-signalling' mechanism, IL-6 is able to stimulate cells that lack an endogenous mIL-6R. High levels of IL-6 and sIL-6R have been reported in several chronic inflammatory and autoimmune diseases as well as in cancer. Preclinical animal disease models have provided strong evidence that specific blockade of IL-6-regulated signalling pathways represents a promising approach for the therapy of these diseases. An optimised variant of the recently described fusion protein sgp30Fc is now heading towards its clinical evaluation.

Topics: Alternative Splicing; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Arthritis; Arthritis, Rheumatoid; Asthma; Autoimmune Diseases; Cell Line; Clinical Trials as Topic; Colitis; Colonic Neoplasms; Cytokine Receptor gp130; Disease Models, Animal; Drug Delivery Systems; Drug Evaluation, Preclinical; Humans; Inflammation; Interleukin-6; Leukocytes; Male; Mice; Neoplasms; Receptors, Interleukin-6; Recombinant Fusion Proteins; Signal Transduction; Solubility; Transforming Growth Factor beta

The genetic predisposition to deregulated mucosal immune responses and the concurrent prevalence of certain environmental triggers in developed countries are strong etiologic factors for the development of inflammatory bowel diseases in human subjects, including Crohn's disease and ulcerative colitis. Numerous clinical and experimental studies have shown that the intestinal microbes are critical for the initiation and progression of chronic intestinal inflammation. Activation of pattern recognition receptor signaling via members of the Toll-like receptor (TLR) and the nucleotide-binding oligomerization domain (NOD)-like families initiates inflammatory defense mechanisms that are required to alert and protect the host. Key inflammatory mechanisms such as nuclear transcription factor kappaB (NF-kappaB) activation and endoplasmic reticulum stress responses are controlled by a complex network of pathways that includes intrinsic feedback effectors and is targeted by immunosuppressive cytokines such as interleukin 10 (IL-10) and transforming growth factor (TGF)-beta. In the absence or after functional loss of these antiinflammatory feedback signals, physiological defense mechanisms may turn into pathological responses. The data discussed in the present review suggest that disturbances in the homeostasis between bacteria- and host-derived signals at the epithelial cell level lead to a break in the intestinal barrier function and to the development of mucosal immune disorders in genetically susceptible hosts.

Topics: Animals; Anti-Inflammatory Agents; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Epithelial Cells; Feedback, Physiological; Genetic Predisposition to Disease; Heat-Shock Proteins; Humans; Inflammation; Inflammatory Bowel Diseases; Interleukin-10; Molecular Chaperones; NF-kappa B; Protein Structure, Tertiary; Toll-Like Receptors; Transforming Growth Factor beta

The study of the cellular and molecular pathogenesis of heart valve disease is an emerging area of research made possible by the availability of cultures of valve interstitial cells (VICs) and valve endothelial cells (VECs) and by the design and use of in vitro and in vivo experimental systems that model elements of valve biological and pathobiological activity. VICs are the most common cells in the valve and are distinct from other mesenchymal cell types in other organs. We present a conceptual approach to the investigation of VICs by focusing on VIC phenotype-function relationships. Our review suggests that there are five identifiable phenotypes of VICs that define the current understanding of their cellular and molecular functions. These include embryonic progenitor endothelial/mesenchymal cells, quiescent VICs (qVICs), activated VICs (aVICs), progenitor VICs (pVICs), and osteoblastic VICs (obVICs). Although these may exhibit plasticity and may convert from one form to another, compartmentalizing VIC function into distinct phenotypes is useful in bringing clarity to our understanding of VIC pathobiology. We present a conceptual model that is useful in the design and interpretation of studies on the function of an important phenotype in disease, the activated VIC. We hope this review will inspire members of the investigative pathology community to consider valve pathobiology as an exciting new frontier exploring pathogenesis and discovering new therapeutic targets in cardiovascular diseases.

Topics: Animals; Cell Lineage; Embryonic Stem Cells; Endothelial Cells; Heart Valve Diseases; Heart Valves; Humans; Inflammation; Mesenchymal Stem Cells; Neovascularization, Pathologic; Neovascularization, Physiologic; Osteoblasts; Transforming Growth Factor beta

Effective wound healing leads to restoration of tissue integrity and occurs through a highly organized multistage process involving various cell types. Currently, methods for wound healing assessment lack a structured system for analysis of quantitative parameters. We have established a unique quantitative assessment strategy of wound healing stages based on histological criteria. Distinctive immunohistochemical parameters including re-epithelialization, epidermal differentiation, cell migration, proliferation, inflammatory response as well as dermal closure, matrix distribution, and skin remodelling were identified and followed during the timeline of wound healing progression. Assessment was based on various defined characteristics and each stage-specific parameter was independently quantified for complete wound closure. This analysis allowed a follow-up of wound healing dynamics and identified the contribution of critical and specific parameters to wound healing physiology and pathology. In this review we demonstrate our assessment strategy of crucial wound healing events and introduce a unique quantification system for each of the processes involved in wound repair. We believe that our unique method can be utilized as a diagnostic platform for standardizing assessment of wound healing progression as well as a screening tool for potential therapies.

Topics: Animals; Diabetes Mellitus, Experimental; Fibroblast Growth Factor 7; Humans; Inflammation; Mice; Platelet-Derived Growth Factor; Skin; Transforming Growth Factor beta; Wound Healing

While the cytokine IL-17 has been cloned and described more than 10 years ago [Yao Z, Fanslow WC, Seldin MF, Rousseau AM, Painter SL, Comeau MR, et al. Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 1995;3(6):811-21; Kennedy J, Rossi DL, Zurawski SM, Vega Jr F, Kastelein RA, Wagner JL, et al. Mouse IL-17: a cytokine preferentially expressed by alpha beta TCR+CD4-CD8-T cells. J Interferon Cytokine Res 1996;16(8):611-7], it was only 2 years ago that IL-17 producing T cells have been classified as a new distinct CD4 T cell subset [Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005;6(11):1123-32] and only in 2006 the molecular mechanisms underlying their differentiation were identified [Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006;24(2):179-89; Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441(7090):235-8; Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC, Elson CO, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006;441(7090):231-4]. Since then the literature on IL-17 producing cells has grown steadily and many reviews of the field are already outdated by the time they are published, a fate that no doubt will affect this review as well. In order to avoid too many repetitions we focus this review mainly on publications in 2006 and 2007 and refer to a number of reviews, which cover earlier aspects of Th17/IL-17 biology.

Topics: Animals; Autoimmunity; Cytokines; Humans; Immunity, Active; Immunity, Innate; Inflammation; Interleukin-17; T-Lymphocyte Subsets; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Upon activation, naïve CD4(+) T cells differentiate into effector T cells with specific effector functions and cytokine profiles. The Th1/Th2 paradigm has recently been reevaluated to include a third population of T helper cells, producing IL-17 and designated Th17. The differentiation of Th17 cells requires the coordinate and specific action of the proinflammatory cytokine IL-6 and the immunosuppressive cytokine TGF-beta. In addition, the IL-12 family member IL-23 is involved in the maintenance of these cells. Analogous to other T helper cell subsets, Th17 commitment is initiated by sequential involvement of STAT molecules, i.e. STAT3 downstream of cytokine receptors, and specific transcription factors, i.e. ROR-gammat. Recent data also support the existence of a complex network of cytokines regulating Th17 cells. Clearly, the specific effector functions of Th17 cells expand beyond previously described effects of Th1 and Th2 immunity, with specific roles in host defense against certain pathogens and in organ-specific autoimmunity. The potential dynamics of Th17 cell populations and their interplay with other inflammatory cells in the induction of tissue inflammation in host defense and organ-specific autoimmunity are discussed.

Topics: Animals; Autoimmunity; Cell Differentiation; Cytokines; Humans; Immunity, Innate; Inflammation; Interleukin-17; STAT3 Transcription Factor; T-Lymphocyte Subsets; T-Lymphocytes, Helper-Inducer; Transcription Factors; Transforming Growth Factor beta

T helper (TH) cells can assume different phenotypes characterized by the secretion of distinct effector molecules. Interferon-gamma producing TH1 and IL-4 producing TH2 cells have long been recognized as important mediators of host defense, whereas regulatory T cells are known to suppress T cell responses. Recently, TH17 cells were characterized as a novel CD4(+) subset that preferentially produces IL-17, IL-17F, and IL-22 as the signature cytokines. TH17 cells appear to play a critical role in sustaining the inflammatory response and their presence is closely associated with autoimmune disease, which makes them an attractive therapeutic target. In this review, we focus on the mechanisms that regulate the differentiation of naive T cells into TH17 cells and on TH17 effector cytokines, as they represent opportunities for therapeutic intervention.

Topics: Animals; CD4-Positive T-Lymphocytes; Cytokines; Humans; Inflammation; Interferon-gamma; Interleukin-17; Interleukin-23; Receptors, Cytokine; STAT3 Transcription Factor; T-Lymphocyte Subsets; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

The extracellular matrix (ECM) is composed of several families of macromolecular components: fibrous proteins such as collagens, type I collagen (COL1), type III collagen (COL3), fibronectin, elastin, and glycoconjugates such as proteoglycans and matrix glycoproteins. Their receptors on the cell membrane, most of which in the case of the ECM belong to the integrins, which are heterodimeric proteins composed of alpha and beta chains. COL1 is the major fibrous collagen of bone, tendon, and skin; while COL3 is the more pliable collagen of organs like liver. Focus will not only be given to the regulation of synthesis of several fibrogenic parameters but also modulation of their degradation during growth factor-induced tissue fibrosis and cancer development. Evidence will be provided that certain tissues, which undergo fibrosis, also become cancerous. Why does there exist a divergency between tissues, which undergo frank fibrosis as an endpoint, and those tissues that undergo fibrosis and subsequently are susceptible to carcinogenicity; resulting from the etiological factor(s) causing the initial injury? For example, why does a polyvinyl alcohol (PVA) sponge implant become encapsulated and filled with fibrous tissue then fibrosis tissue growth stops? Why does the subcutaneous injection of a fibrogenic growth factor cause a benign growth and incisional wounding results in fibrosis and ultimately scarring? There are many examples of tissues, which undergo fibrosis as a prerequisite to carcinogenesis. Is there a cause-effect relationship? If you block tissue fibrosis in these precancerous tissues, would you block cancer formation? What are the molecular targets for blocking fibrosis and ultimately carcinogenesis? How can oligo decoys may be used to attenuate carcinogenesis and which oligo decoys specifically attenuate fibrogenesis as a prelude to carcinogenesis? What are other molecular targets for oligo decoy therapy in carcinogenesis?

Topics: Animals; Cell Transformation, Neoplastic; Connective Tissue; Extracellular Matrix; Fibrosis; Gene Expression Regulation; Humans; Inflammation; Matrix Metalloproteinases; Models, Biological; Neoplasms; Oligonucleotides; Signal Transduction; Smad Proteins; Tissue Inhibitor of Metalloproteinases; Transcription Factors; Transforming Growth Factor beta

Allergic diseases are caused by the induction of T helper (Th)2 cells and IgE responses specific for common environmental antigens (allergens) in susceptible individuals. There is increasing interest in the role of both naturally occurring and induced regulatory T cell (Treg) populations in preventing these inappropriate immune responses and the underlying sensitisation to allergens. Current evidence suggests that Tregs may actively prevent Th2 responses to allergens occurring in healthy non-atopic individuals and that their function may be impaired in allergic patients. Evidence that existing therapies may act by modulating Treg function is reviewed. Future research aims to understand the mechanisms involved in the generation and function of allergen-specific Tregs. A primary aim is to promote the development of optimised therapeutic regimens with the capacity to provide long-lasting, allergen-specific, inhibitory mechanisms at the time and site of allergen challenge.

Topics: Allergens; Animals; Asthma; Humans; Hypersensitivity; Hypersensitivity, Immediate; Immunotherapy; Inflammation; Interleukin-10; Models, Biological; T-Lymphocytes; T-Lymphocytes, Regulatory; Th2 Cells; Transforming Growth Factor beta

Transforming growth factor-beta (TGF-beta) is a key regulator of immune tolerance. In this paper, we will focus on T cells and natural killer (NK) cells, which are directly regulated by TGF-beta in vivo. TGF-beta controls T-cell activation and differentiation, and is involved in the suppressive function and generation of regulatory T cells. Recently, TGF-beta has also been shown to directly inhibit NK cell activity. These studies demonstrate that TGF-beta utilizes multiple mechanisms to ensure immune tolerance, which is critical in a variety of autoimmune and inflammatory disorders. We will also discuss recent advances on the role of TGF-beta in immune-mediated diabetes, inflammatory bowel disease, arthritis, and systemic lupus erythematosus.

Topics: Animals; Autoimmune Diseases; Cell Differentiation; Humans; Immune Tolerance; Inflammation; Killer Cells, Natural; T-Lymphocytes; Transforming Growth Factor beta

A characteristic feature of chronic inflammatory reactions is their persistence and predilection for certain sites. The molecular basis for such tissue tropism (as, for example, seen with metastatic spread) has until recently remained obscure, but recent studies have strongly implicated tissue-resident, stromal cells, such as macrophages, endothelial cells and fibroblasts. These cell types make attractive therapeutic targets as they help define the three-dimensional structure of tissues and are key orchestrators of the inflammatory infiltrate. Most current anti-inflammatory therapies target immune cells in an attempt to inhibit the production of pro-inflammatory mediators; however, an equally important target is the active induction of anti-inflammatory mediators involved in the resolution of inflammation. Recent work suggests that stromal cells are an important source of these mediators. Targeting of multiple signals may be required to inhibit tissue damage associated with inflammatory disease. Cells of the monocyte lineage are present as tissue-resident cells and interact closely with other stromal populations. These cells form an ideal target for modulation of the inflammatory environment as, in some cases, they appear to induce tissue repair. Therapeutic manipulation of the stromal microenvironment has been particularly effective in treating cancer and is likely to provide a novel method to achieve improved control of chronic inflammatory disease.

Topics: Angiogenic Proteins; Animals; Anti-Inflammatory Agents; Antibodies, Monoclonal; Chronic Disease; Cytokines; Endothelial Cells; Fibroblasts; Humans; Inflammation; Monocytes; Neoplasms; Stromal Cells; Transforming Growth Factor beta

The transforming growth factor beta (TGF-beta) plays a dual role in allergic disease. It is important in suppressing T cells and also mediates repair responses that lead to unwanted remodeling of tissues. Advances in the immunology of allergy indicate that allergens cause overreactions in the lymphocyte compartment because of the lack or decreased number of suppressive, regulatory T cells. TGF-beta was shown to induce regulatory T cells and participate directly in suppression of effector T cells. Therefore, TGF-beta may help return reactivity to allergens to normal subsymptomatic activity. Whether chronic inflammatory diseases such as asthma profit from TGF-beta-mediated suppression of specific immune responses or whether the TGF-beta-mediated tissue remodeling aggravates diseases more than it helps control immune reactions is unclear. This article addresses these issues and future strategies in this field.

Topics: Humans; Hypersensitivity; Inflammation; Transforming Growth Factor beta

Healing of myocardial infarcts depends on an inflammatory cascade that ultimately results in clearance of dead cells and matrix debris and formation of a scar. Myocardial necrosis activates complement, Nuclear Factor (NF)-kappaB and Toll-like Receptor (TLR)-dependent pathways, and generates free radicals, triggering an inflammatory response. Chemokines and cytokines are markedly induced in the infarct and mediate recruitment and activation of neutrophils and mononuclear cells. Extravasation of platelets and plasma proteins, such as fibrinogen and fibronectin, results in formation of a clot, consisting of platelets embedded in a mesh of crosslinked fibrin. This provisional matrix provides a scaffold for migration of cells into the infarct. Monocytes differentiate into macrophages and secrete fibrogenic and angiogenic growth factors inducing formation of granulation tissue, containing myofibroblasts and neovessels. Repression of proinflammatory cytokine and chemokine synthesis, mediated in part through Transforming Growth Factor (TGF)-beta and Interleukin (IL)-10, is critical for resolution of the inflammatory infiltrate and transition to fibrous tissue deposition. Infarct myofibroblasts deposit extracellular matrix proteins and a collagen-based scar is formed. As the wound matures, fibroblasts undergo apoptosis and neovessels regress, resulting in formation of a scar with a low cellular content containing dense, cross-linked collagen. The pathologic and structural changes associated with infarct healing directly influence ventricular remodeling and affect prognosis in patients with myocardial infarction. Understanding the mechanisms involved in the regulation of the post-infarction inflammatory response, and the spatial and temporal parameters of wound healing is necessary in order to identify specific molecular targets for therapeutic intervention.

Topics: Chemokines; Cytokines; Extracellular Matrix; Fibroblasts; Humans; Inflammation; Interleukin-10; Macrophages; Myocardial Infarction; Myocardial Reperfusion Injury; Neovascularization, Pathologic; Neutrophils; Transforming Growth Factor beta; Wound Healing

Obstructive nephropathy is a major cause of renal failure, particularly in infants and children. Cellular and molecular mechanisms responsible for the progression of the tubular atrophy and interstitial fibrosis-processes that lead to nephron loss-have been elucidated in the past 5 years. Following urinary tract obstruction and tubular dilatation, a cascade of events results in upregulation of the intrarenal renin-angiotensin system, tubular apoptosis and macrophage infiltration of the interstitium. This is followed by accumulation of interstitial fibroblasts through proliferation of resident fibroblasts and epithelial-mesenchymal transformation of renal tubular cells. Under the influence of cytokines, chemokines and other signaling molecules produced by tubular and interstitial cells, fibroblasts undergo transformation to myofibroblasts that induce expansion of the extracellular matrix. The cellular interactions that regulate development of interstitial inflammation, tubular apoptosis and interstitial fibrosis are complex. Changes in renal gene expression and protein production afford many potential biomarkers of disease progression and targets for therapeutic manipulation. These include signaling molecules and receptors involved in macrophage recruitment and proliferation, tubular death signals and survival factors, and modulators of epithelial-mesenchymal transformation. Targeted gene deletion and various forms of gene therapy have been used in experimental obstructive nephropathy, mostly rodent models of unilateral ureteral obstruction or cell culture techniques. Further refinement of these models is needed to develop a matrix of biomarkers with clinical predictive value, as well as molecular therapies that will prevent or reverse the renal structural and functional consequences of obstructive nephropathy.

Topics: Apoptosis; Biomarkers; Chemokine CCL7; Epidermal Growth Factor; Fibrosis; Genetic Therapy; Humans; Inflammation; Kidney; Monocyte Chemoattractant Proteins; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Ureteral Obstruction

The incidence of finding evidence of both emphysema and pulmonary fibrosis in the same patient has received increased attention. Several investigators have found on biopsy the presence of emphysema of the upper zones and diffuse parenchymal disease with fibrosis of the lower zones of the lung, especially associated with current or previous heavy smokers. Believed previously to be two different disease mechanisms, there are now data to implicate some common pathways of cell and molecular activation leading to the different morphologic and physiologic outcomes. According to a current view, emphysema may originate from a protease/antiprotease imbalance, whereas a role for antiproteases has been proposed in the modulation of fibrosis. Overexpression of transforming growth factor beta (TGF-beta) in experimental rodent models leads to progressive pulmonary fibrosis, accompanied with marked up-regulation of protease inhibitors, such as tissue inhibitor of metalloproteinases (TIMP) and plasminogen activator inhibitor-1 (PAI-1) genes, along with excessive matrix accumulation. It may be that a "matrix degrading" pulmonary microenvironment, one in which metalloproteinase activities prevail, favors the development of emphysema, whereas a "matrix nondegrading" microenvironment, with enhanced presence of TIMPs, would lead to matrix accumulation and fibrosis. Surprisingly, although Smad3 null mice, deficient in TGF-beta signal transmission, are resistant to bleomycin- and TGF-beta-mediated fibrosis, they develop spontaneous age-related airspace enlargement, consistent with emphysema, with a lack of ability to repair tissue damage appropriately. A common element is tissue damage and repair, with TGF-beta and the Smad signaling pathway playing prominent molecular roles. Both changes can be followed in experimental models with noninvasive imaging and physiologic measurements.

Topics: Animals; Humans; Inflammation; Lung; Mice; Models, Animal; Pulmonary Emphysema; Pulmonary Fibrosis; Rats; Signal Transduction; Smad3 Protein; Smoking; Transforming Growth Factor beta

The beta 2 integrin family (CD11/CD18) of leukocyte adhesion molecules plays a key role in inflammation. Absence of the common chain (CD18) leads to leukocyte adhesion deficiency-1 (LAD1) in humans. We here summarize data of two genetically defined mice models of beta 2 integrin deficiency, one with a CD18 null mutation (CD18-/-), and the other one with a hypomorphic CD18 mutation (CD18hypo). Firstly, we focus on the underlying mechanism of a severely impaired wound healing in CD18-/- mice, outlining a scenario in which a defective extravasation and phagocytosis of CD18-/- neutrophils results in delayed myofibroblast-dependent wound contraction owing to a deficient transforming growth factor-beta 1 release. Based on this, we have identified a potential therapy that fully rescued the impaired wound healing in CD18-/- mice. Secondly, we expand on a CD18hyp0 PL/J mouse model closely resembling human psoriasis. Apart from common clinical and pathophysiological features, this psoriasiform dermatitis also depends on the presence of activated CD4+ T cells. We here recapitulate the influence of a reduced CD18 gene expression on T-cell function, also with regard to CD18 gene-dose effects, and its contribution to the pathogenesis of this disease. Taken together, these unique features make this model a valuable tool for investigations into the pathogenesis of human psoriasis--including its polygenic base--and future preclinical studies.

Topics: Animals; CD18 Antigens; Cell Differentiation; Fibroblasts; Humans; Inflammation; Mice; Psoriasis; Transforming Growth Factor beta; Transforming Growth Factor beta1; Wound Healing

Following injury, skin establishes a balance between too little inflammation increasing risk of infection, and excessive inflammation contributing to delayed wound healing and scarring. Mounting evidence indicates both initiation and termination of inflammation involve active mechanisms. Not only does inflammation itself seem to be a paradox because inflammatory responses are both essential and potentially detrimental, but one chronic inflammatory skin disease (e.g. psoriasis) presents additional paradoxes. While plaques share several factors with wound healing, two understudied and puzzling aspects include why do not inflamed plaques more frequently transform?; and why do not plaques result in scarring? To get at these questions, we review responses involved in wound repair. Oral mucosa was probed because, like fetal skin, wound repair is characterized by its rapidity, low inflammation, and scarless resolution. Active roles for macrophages as both initiators and terminators of inflammation are highlighted. Therapeutic implications are discussed regarding psoriasis and pyoderma gangrenosum. Based on biochemical and immunohistochemical considerations linking psoriatic plaques to hard palate, a novel metaplastic model is presented. We hypothesize saliva and chronic trauma contribute to a constitutive epithelial program where keratinocyte proliferation is more intense prior to differentiation, accompanied by keratin 16 expression in hard palate, thereby resembling plaques. Rather than viewing psoriasis as a nonspecific response to inflammation, we postulate a metaplastic switch by which prepsoriatic skin is converted to a distinct adult tissue type resembling hard palate. In summary, many lessons can be learned by focusing on complex processes involved in regulation of inflammation, tissue repair, and remodeling.

Topics: Fibrosis; Humans; Inflammation; Macrophages; Psoriasis; Skin; Skin Neoplasms; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Wound Healing

Among many molecules known to influence wound healing, transforming growth factor beta 1 (TGF beta 1) has the broadest spectrum of actions, affecting all cell types that are involved in all stages of wound healing. Both positive and negative effects of TGF beta 1 on wound healing have been reported. However, the underlying mechanisms are largely unknown. We observed that endogenous TGF beta 1 was elevated in a narrow window of time after injury, and transgenic mice constitutively overexpressing wild-type TGF beta 1 in keratinocytes (K5.TGF beta 1wt) exhibited a significant delay in full-thickness wound healing as compared to non-transgenic mice. Delayed wound healing was associated with profound inflammation throughout all stages of wound healing in K5.TGF beta 1wt mice. Our data suggest that excessive and prolonged TGF beta 1 at the wound site does not benefit wound healing, which is partially owing to its pro-inflammatory effect. Future studies need to be conducted to assess whether tightly regulated TGF beta 1 expression will benefit wound healing. To this end, we have developed a gene-switch TGF beta 1 transgenic system that allows TGF beta 1 induction in keratinocytes temporally with desired levels. These mice will provide a tool to study stage-specific effects of TGF beta 1 on cutaneous wound healing.

Topics: Animals; Humans; Inflammation; Keratinocytes; Mice; Mice, Transgenic; Skin; Transforming Growth Factor beta; Transforming Growth Factor beta1; Wound Healing

The regulation of macrophage cholesterol homoeostasis is of crucial importance in the pathogenesis of atherosclerosis, an underlying cause of heart attack and stroke. Several recent studies have revealed a critical role for the cytokine TGF-beta (transforming growth factor-beta), a key regulator of the immune and inflammatory responses, in atherogenesis. We discuss here the TGF-beta signalling pathway and its role in this disease along with the outcome of our recent studies on the action of the cytokine on the expression of key genes implicated in the uptake or efflux of cholesterol by macrophages and the molecular mechanisms underlying such regulation.

Topics: Animals; Atherosclerosis; Cholesterol; Gene Expression Regulation; Homeostasis; Humans; Inflammation; Macrophages; Signal Transduction; Transforming Growth Factor beta

Naturally occurring CD4+CD25+ regulatory T cells mediate immune suppression to limit immunopathogenesis associated with chronic inflammation, persistent infections and autoimmune diseases. Their mode of suppression is contact-dependent, antigen-nonspecific and involves a nonredundant contribution from the cytokine transforming growth factor (TGF)-beta. Not only can TGF-beta mediate cell-cell suppression between the regulatory T cells and CD4+CD25- or CD8+ T cells, but new evidence also reveals its role in the conversion of CD4+CD25- T cells, together with TCR antigen stimulation, into the regulatory phenotype. Elemental to this conversion process is induction of expression of the forkhead transcription factor, Foxp3. This context-dependent coercion of naive CD4+ T cells into a powerful subset of regulatory cells provides a window into potential manipulation of these cells to orchestrate therapeutic intervention in diseases characterized by inadequate suppression, as well as a promising means of controlling pathologic situations in which excessive suppression dominates.

Topics: Animals; Arthritis, Rheumatoid; Asthma; Autoimmune Diseases; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Clonal Anergy; Disease Models, Animal; Forkhead Transcription Factors; Gene Expression Regulation; Humans; Immune Tolerance; Immunotherapy, Adoptive; Inflammation; Lupus Erythematosus, Systemic; Mice; Mice, Knockout; Receptors, Interleukin-2; Signal Transduction; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Topics: Animals; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Humans; Inflammation; Lectins, C-Type; Ligands; Lymphocyte Activation; Models, Immunological; Transforming Growth Factor beta

Inflammation is associated with fibrosis. Angiotensin II-stimulated growth of fibroblasts and an increase in collagen type I synthesis are important component of the cardiac remodeling process in hypertension and chronic ischemia. AngII has been shown to enhance production of reactive oxygen species (ROS) via stimulation of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase. Recent studies have proposed that stimulation of ROS production by AngII may constitute a means by which this humoral factor contributes to development of tissue injury in organs such as blood vessels, kidney, and the heart. Published studies have shown that PPARgamma ligands can attenuate the expression or activity of NADPH oxidase subunits. Furthermore, it has been shown that PPARs inhibits inflammation by blocking the activation of redox-sensitive transcription factor NFkappaB. Although there is much still to learn about the link of inflammation and fibrosis, PPARs are potential therapeutic targets for treating cardiac fibrosis and perivascular fibrosis.

Topics: Adipocytes; Aldosterone; Animals; Connective Tissue Growth Factor; Fibrosis; Immediate-Early Proteins; Inflammation; Intercellular Signaling Peptides and Proteins; Mice; NADPH Oxidases; Peroxisome Proliferator-Activated Receptors; Transforming Growth Factor beta

Bone morphogenetic proteins play a key role in kidney development and postnatal function. The kidney has been identified as a major site of bone morphogenetic protein (BMP)-7 synthesis during embryonic and postnatal development, which mediates differentiation and maintenance of metanephric mesenchyme. Targeted disruption of BMP-7 gene expression in mice resulted in dysgenic kidneys with hydroureters, causing uremia within 24h after birth. Several experimental animal models of acute and chronic renal injury have all unequivocally shown beneficial effect of BMP-7 in ameliorating the severity of damage by preventing inflammation and fibrosis. Apart from the beneficial effect on kidney disease itself, BMP-7 improves important complications of chronic renal impairment such as renal osteodystrophy and vascular calcification.

Topics: Animals; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcification, Physiologic; Chronic Kidney Disease-Mineral and Bone Disorder; Fibrosis; Homeostasis; Inflammation; Kidney; Kidney Diseases; Organogenesis; Transforming Growth Factor beta

Recent evidence suggests that the progression of renal fibrosis is a reversible process, at least in experimental models. The present review summarizes the new insights concerning the mechanisms of progression and regression of renal disease and examines this novel evidence under the light of feasibility and transfer to human nephropathies. The involved mechanisms are discussed with particular emphasis on the fibrotic role of vasoactive peptides such as angiotensin II and endothelin and growth factors such as transforming growth factor (TGF)-beta. The possibility of regression is introduced by presenting the in vivo efficiency of antihypertensive treatments and of systems that antagonize the fibrogenic action of TGF-beta such as bone morphogenic protein-7 and HGF. Finally, we provide a brief description of the promising future directions and clinical considerations about the applications of the experimental data to humans.

Topics: Animals; Bone Morphogenetic Proteins; Disease Progression; Fibrosis; Humans; Inflammation; Kidney Diseases; Oxidative Stress; Peptides; Transforming Growth Factor beta

Transforming growth factor (TGF)-beta is a prototypic multifunctional cytokine whose broad modulatory mechanisms affect numerous biological functions both at the cell and organism levels. These include, but are not limited to, control of immune functions, embryogenesis, carcinogenesis, tissue responses to injury, cell proliferation, extracellular matrix (ECM) synthesis and degradation, and cell migration. The identification of Smad proteins, TGF-beta receptor kinase substrates that translocate into the cell nucleus to act as transcription factors, has increased our understanding of the molecular mechanisms underlying TGF-beta action. This introductory chapter will outline the current knowledge on how specific signals initiated by the TGF-beta receptors are brought to the nucleus to regulate gene expression, with a specific emphasis on how such signaling relates to connective tissue remodeling, repair, and fibrosis.

Topics: Animals; Cell Membrane; Cell Nucleus; Collagen; Extracellular Matrix; Fibrosis; Gene Expression Regulation; Humans; Inflammation; Models, Biological; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Signal Transduction; Transforming Growth Factor beta

The pathogenic mechanisms that lead to chronic kidney disease (CKD) converge on a common pathway that results in progressive interstitial fibrosis, peritubular capillary loss with hypoxia, and destruction of functioning nephrons because of tubular atrophy. Interstitial recruitment of inflammatory leukocytes and myofibroblasts occurs early in kidneys destined to develop fibrosis. Circulating monocytes are recruited by locally secreted chemoattractant molecules, facilitated by leukocyte adhesion molecules. Functionally heterogeneous macrophages secrete many fibrosis-promoting molecules, but under some circumstances they may also serve a protective scavenging role. Excessive extracellular matrix production occurs primarily within interstitial myofibroblasts, a population of cells that appears to have more than 1 origin, including the resident interstitial fibroblasts, trans-differentiated tubular epithelial cells, and bone marrow-derived cells. Impaired activity of the endogenous renal matrix-degrading proteases may enhance interstitial matrix accumulation, but the specific pathways that are involved remain unclear. Tubules, inflammatory cells, and myofibroblasts synthesize the molecules that activate the fibrogenic cascades, the most important of which is transforming growth factor beta (TGF-beta). TGF-beta may direct cells to assume a pro-fibrotic phenotype or it may do so indirectly after stimulating synthesis of other fibrogenic molecules such as connective tissue growth factor and plasminogen activator inhibitor-1. Reduced levels of antifibrotic factors that are normally produced in the kidney such as hepatocyte growth factor and bone morphogenic protein-7 may accelerate fibrosis and its destructive consequences. Development of new therapeutic agents for CKD looks promising, but several agents that target different components of the fibrogenic cascade will almost certainly be necessary.

Topics: Apoptosis; Child; Disease Progression; Extracellular Matrix; Fibroblasts; Fibrosis; Humans; Inflammation; Kidney; Renal Insufficiency, Chronic; Transforming Growth Factor beta

Transforming growth factor-beta (TGF-beta) family members are multifunctional molecules, which play pivotal roles in regulating cell proliferation, differentiation, migration, development, tissue remodeling and repair. These events are closely associated with host immune responses and inflammation. Despite some controversies on their function in controlling dendritic and T regulatory cell development and activity, the importance of TGF-betas in the progress of autoimmunity and inflammatory diseases has been well appreciated and new aspects of their contribution continue to be recognized. Since one of the major biological properties of TGF-betas is its capacity to potently suppress immune responses, they are considered as candidates for the development of therapeutic agents to fend off undesirable damage associated with immune and inflammatory conditions.

Topics: Alzheimer Disease; Animals; Autoimmune Diseases; Gene Expression; Humans; Immunosuppressive Agents; Inflammation; Signal Transduction; Transforming Growth Factor beta

Poor experimental design has contributed to a perceived association of ageing with delayed wound healing. Continuing research on the influence of ageing will allow more focused therapeutic strategies.

Topics: Aging; Animals; Extracellular Matrix; Hepatocyte Growth Factor; Humans; Inflammation; Neovascularization, Physiologic; Proto-Oncogene Proteins; Research Design; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Wound Healing

Topics: Animals; Critical Illness; Humans; Inflammation; Proteins; Transforming Growth Factor beta

The role of the anti-inflammatory cytokine transforming growth factor beta (TGF-beta) in atherosclerosis has been the subject of considerable debate for a decade. In the early 1990s, we postulated that TGF-beta played an important role in maintaining normal vessel wall structure and that loss of this protective effect contributed to the development of atherosclerosis. We termed this the protective cytokine hypothesis. This proposal was slow to gain broad acceptance, however, because at that time there were little data available on the role of TGF-beta during the development of atherosclerosis but much information about its role during trauma-induced neointima formation. Because TGF-beta apparently aggravates neointima formation, both by inhibiting endothelial regeneration and by promoting fibrosis, it was difficult to accept that its presence might ameliorate the superficially similar atherogenesis process. But several recent studies revealed beyond doubt the fact that TGF-beta protects against lipid lesion formation, at least in mouse models of atherosclerosis. Therefore, two important questions remain. First, is the role of TGF-beta in vascular biology similar in humans and in mice? Secondly, how important, compared with defects in thrombosis or lipoprotein metabolism, is the protective role of TGF-beta during atherogenesis?

Topics: Animals; Arteriosclerosis; Disease Models, Animal; Extracellular Matrix; Humans; Inflammation; Mice; Mice, Knockout; Models, Biological; Muscle, Smooth, Vascular; Signal Transduction; Species Specificity; T-Lymphocyte Subsets; Transforming Growth Factor beta; Tunica Intima

A set of lung diseases share the tendency for the development of progressive fibrosis ultimately leading to respiratory failure. This review examines the common pathogenetic features of these disorders in light of recent observations in both humans and animal models of disease, which reveal important pathways of lung matrix remodeling.

Topics: Animals; Collagen; Disease Models, Animal; Disease Progression; Epithelium; Fibrosis; Humans; Inflammation; Lung; Lung Diseases; Mice; Models, Anatomic; Models, Biological; Mutation; Pulmonary Fibrosis; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1

Transforming growth factor-beta (TGF-beta) family members are multifunctional peptide growth factors that regulate cell growth, differentiation, extracellular matrix production and cell migration and embryonic development. Knock-out experiments for the three mammalian isoforms of TGF-beta in mice have demonstrated their importance in regulating inflammation and tissue repair. Also, TGF-beta has been implicated in the pathogenesis of human diseases, including tissue fibrosis and carcinogenesis. In the latter case, it may exert both tumor suppressor and pro-oncogenic activities depending on the stage of the tumor. Smads proteins constitute the core components of the intracellular signaling cascade initiated by TGF-beta receptors, as they carry signals from the cell surface directly to the nucleus; where they act as transcription factors.

Topics: Animals; DNA-Binding Proteins; Humans; Inflammation; Mice; Mice, Transgenic; Signal Transduction; Smad Proteins; Trans-Activators; Transforming Growth Factor beta; Wound Healing

The renin-angiotensin system (RAS) is compartmented between circulating blood and tissue pericellular space. Whereas renin and its substrate diffuse easily from one compartment to another, the angiotensin peptides act in the compartment where there are generated: blood or pericellular space. Renin is trapped in tissues by low and high affinity receptors. In the target cells, angiotensin II/AT1 receptor interaction generates different signals including an immediate functional calcium-dependent response, secondary hypertrophy and a late proinflammatory and procoagulant response. These late pathological effects are mediated by NADPH oxydase-generated free oxygen radicals and NFkappaB activation. In vivo, the tissue binding of renin and the induction of converting enzyme are the main determinants of the involvement of the RAS in vascular remodeling. The target cells of interstitial angiotensin II are mainly the vascular smooth muscle cells and fibroblasts, whereas the endothelial cells and circulating leukocytes are the main targets of circulating angiotensin II. In vivo, angiotensin II participates in the vascular wall hypertrophy associated with hypertension. In diabetes, as in other localized fibrotic cardiovascular diseases, the tissue effects of angiotensin II are mainly dependent on its ability to induce TGF-beta expression. In experimental atherosclerosis, angiotensin II infusion induces aneurysm formation mediated by activation of circulating leucocytes. In these models, the administration of angiotensin II antagonists has beneficial effects on pathological remodeling. Such beneficial effects of angiotensin II antagonists in localized pathological remodeling have not yet been demonstrated in humans.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Animals, Genetically Modified; Arteriosclerosis; Blood Pressure; Blood Vessels; Fibrosis; Humans; Hypertension, Renovascular; Hypertrophy; Inflammation; Models, Biological; NADPH Oxidases; Reactive Oxygen Species; Receptors, Angiotensin; Renin-Angiotensin System; Transforming Growth Factor beta

Platelet-derived growth factor (PDGF) isoforms play a major role in stimulating the replication, survival, and migration of myofibroblasts during the pathogenesis of fibrotic diseases. During fibrogenesis, PDGF is secreted by a variety of cell types as a response to injury, and many pro-inflammatory cytokines mediate their mitogenic effects via the autocrine release of PDGF. PDGF action is determined by the relative expression of PDGF alpha-receptors (PDGFRalpha) and beta-receptors (PDGFRbeta) on the surface of myofibroblasts. These receptors are induced during fibrogenesis, thereby amplifying biological responses to PDGF isoforms. PDGF action is also modulated by extracellular binding proteins and matrix molecules. This review summarizes the literature on the role of PDGF and its receptors in the development of fibrosis in a variety of organ systems, including lung, liver, kidney, and skin.

Topics: Animals; Fibroblasts; Fibrosis; Gene Expression Regulation; Humans; Inflammation; Interleukin-1; Kidney; Liver; Lung; Models, Biological; Muscles; Platelet-Derived Growth Factor; Protein Isoforms; Receptor, Platelet-Derived Growth Factor alpha; Receptor, Platelet-Derived Growth Factor beta; Scleroderma, Systemic; Signal Transduction; Tissue Distribution; Transforming Growth Factor beta; Transforming Growth Factor beta1

Inflammation has been reported in numerous neurodegenerative disorders such as Parkinson's disease, stroke and Alzheimer's disease (AD). In AD, the inflammatory response is mainly located to the vicinity of amyloid plaques. Cytokines, such as Interleukin-1 (IL-1), Interleukin-6 (IL-6), Tumor Necrosis Factor alpha (TNF-alpha) and Transforminng Growth Factor beta (TGF-beta) have been clearly involved in this inflammatory process. Although their expression is induced by the presence of amyloid-beta peptide, these cytokines are also able to promote the accumulation of amyloid-beta peptide. Altogether, IL-1, IL-6, TNF-alpha and TGF-beta should be considered as key players of a vicious circle leading to the progression of the disease.

Topics: Alzheimer Disease; Brain; Cytokines; Humans; Inflammation; Models, Biological; Transforming Growth Factor beta

Mice with targeted disruptions of the transforming growth factor-beta1 (TGF-beta1) gene or TGF-beta1 intracellular signalling pathways develop intestinal inflammation. Conversely, TGF-beta1-producing regulatory T cells protect against experimental colitis. Paradoxically, however, TGF-beta1 production is high in the gut of patients with chronic inflammatory intestinal disease, and yet inflammation proceeds unchecked. Here we discuss the functional role of Smad7, an intracellular inhibitor of TGF-beta1 signalling, in the control of gut inflammation by TGF-beta1. In particular, we delineate a scenario in which the high expression of Smad7 in inflammatory cells renders them unresponsive to TGF-beta1 and propose that control of Smad7, not TGF-beta1 production, is a key determinant in understanding how TGF-beta1 negatively regulates gut inflammation.

Topics: Animals; DNA-Binding Proteins; Humans; Inflammation; Intestinal Mucosa; Intestines; Signal Transduction; Smad7 Protein; Trans-Activators; Transforming Growth Factor beta

Injury to the skin initiates a cascade of events including inflammation, new tissue formation, and tissue remodeling, that finally lead to at least partial reconstruction of the original tissue. Historically, animal models of repair have taught us much about how this repair process is orchestrated and, over recent years, the use of genetically modified mice has helped define the roles of many key molecules. Aside from conventional knockout technology, many ingenious approaches have been adopted, allowing researchers to circumvent such problems as embryonic lethality, or to affect gene function in a tissue- or temporal-specific manner. Together, these studies provide us with a growing source of information describing, to date, the in vivo function of nearly 100 proteins in the context of wound repair. This article focuses on the studies in which genetically modified mouse models have helped elucidate the roles that many soluble mediators play during wound repair, encompassing the fibroblast growth factor (FGF) and transforming growth factor-beta (TGF-beta) families and also data on cytokines and chemokines. Finally, we include a table summarizing all of the currently published data in this rapidly growing field. For a regularly updated web archive of studies, we have constructed a Compendium of Published Wound Healing Studies on Genetically Modified Mice which is avaialble at http://icbxs.ethz.ch/members/grose/woundtransgenic/home.html.

Topics: Animals; Cytokines; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Inflammation; Mice; Mice, Knockout; Mice, Transgenic; Signal Transduction; Skin; Time Factors; Transforming Growth Factor alpha; Transforming Growth Factor beta; Wound Healing

Tolerogenic antigen-presenting cells (APCs) are attractive agents for the treatment of autoimmune and inflammatory diseases that are mediated, at least in part, by antigen-specific autoreactive T cells. Transforming growth factor-beta (TGF-beta)-treated antigen-presenting cells induce a very potent form of tolerance in mice. One unique feature of this simple and elegant method of tolerance induction is that it is equally potent in both primed and naive mice, an important consideration for the development of a therapy that will be effective against an established disease. In this model, F4/80+ peritoneal exudate cells (macrophages) cultured with antigen and TGF-beta2 injected iv induce populations of regulatory T cells that mediate long-lasting antigen-specific tolerance in mice. The mechanisms that are involved in the induction of tolerance by TGF-beta-treated APCs are very complex and require the interaction of a variety of cell types, as well as soluble and membrane-bound factors. In this review, we summarize the existing data and present new data concerning the induction and effector mechanisms associated with TGF-beta-treated APC-induced tolerance. An understanding of these mechanisms will provide very important information for the design of effective strategies for the treatment of a variety of diseases that are mediated by pathogenic T cells.

Topics: Animals; Antigen-Presenting Cells; Autoimmune Diseases; Humans; Immune Tolerance; Immunotherapy, Adoptive; Inflammation; Macrophages, Peritoneal; Mice; T-Lymphocytes; Transforming Growth Factor beta

Transforming growth factor-beta (TGF-beta) is known to mediate pleiotropic functions both inside and outside the immune system. Recent progress in this field underlines the role of TGF-beta in regulatory T (Treg) cells, where it participates in both suppression and differentiation. In addition, recent information highlights the role of TGF-beta in repair responses that lead to matrix deposition and tissue remodelling. Many chronic inflammatory diseases, such as asthma, profit from the suppression of specific immune responses by TGF-beta; however, TGF-beta-mediated tissue remodelling can be a serious complication in such diseases.

Topics: Animals; Cell Differentiation; Humans; Immune Tolerance; Inflammation; Inhibin-beta Subunits; T-Lymphocytes; Transforming Growth Factor beta

Antigen-provoked polarization of CD4+ T cells along the Th1 pathway is often associated with autoimmune and chronic inflammatory diseases, whereas extreme skewing of the response toward a Th2 phenotype has been linked to atopy and allergic diseases. Intense interest in the underlying molecular mechanisms that control polarization has revealed a contingent of regulatory transcription factors, which not only help to define these pathways but also suggest potential sites for interventional tactics. Moreover, the recent identification of transcription factors specifically associated with CD4(+)CD25+ regulatory T-cells provides new clues regarding manipulation of this population in pursuit of directed immune regulation. Continued unraveling of the pathways underlying the development of deleterious immune responses and their control will guide new avenues of investigation and intervention.

Topics: Animals; Humans; Hypersensitivity; Immune System; Inflammation; T-Lymphocyte Subsets; Th2 Cells; Transcription Factors; Transforming Growth Factor beta

Genes which encode inflammatory cytokines are subject to polymorphisms in their regulatory regions that may effect both the level and ratio of cytokines produced in response to exogenous stimuli. These variant alleles are observed in a large percent of the population and are often associated with increased or decreased susceptibility or severity (modifiers) to infectious, immune or inflammatory diseases. Environmental factors can also play either a direct (i.e., causative factor) or indirect (modifying factor) role in these diseases. Thus, it would follow that gene-environment interactions would effect the expression and/or progression of the disease. In the present review, the concept that some of the common allelic variants found in cytokine genes represent modifying factors in chronic inflammatory diseases associated with occupational exposure is discussed.

Topics: Animals; Chronic Disease; Cytokines; Genetic Predisposition to Disease; Genotype; Humans; Inflammation; Interleukins; Occupational Diseases; Polymorphism, Genetic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Cytokines are regulatory proteins involved in haematopoiesis, immune cell development, inflammation and immune responses. Several cytokines have direct effects on testicular cell functions, and a number of these are produced within the testis even in the absence of inflammation or immune activation events. There is compelling evidence that cytokines, in fact, play an important regulatory role in the development and normal function of the testis. Pro-inflammatory cytokines including interleukin-1 and interleukin-6 have direct effects on spermatogenic cell differentiation and testicular steroidogenesis. Stem cell factor and leukaemia inhibitory factor, cytokines normally involved in haematopoiesis, also play a role in spermatogenesis. Anti-inflammatory cytokines of the transforming growth factor-beta family are implicated in testicular development. Consequently, local or systemic up-regulation of cytokine expression during injury, illness or infection may contribute to the disruption of testicular function and fertility that frequently accompanies these conditions. The aim of this review is to provide a very brief summary of the extensive literature dealing with cytokines in testicular biology, and to follow this with some speculation concerning the significance of these molecules in interactions between the immune system and the testis.

Topics: Animals; Colony-Stimulating Factors; Cytokines; Fas Ligand Protein; Growth Inhibitors; Humans; Inflammation; Interferons; Interleukin-1; Interleukin-6; Leukemia Inhibitory Factor; Lymphokines; Macrophage Migration-Inhibitory Factors; Male; Membrane Glycoproteins; Spermatogenesis; Stem Cell Factor; Testis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The inflammatory response to microcrystals is one of the most powerful and intriguing examples of inflammation observable in man. Although many mechanisms of this reaction are well known, some aspects need to be further clarified, in particular those related to the self-limited nature of the process. Type and duration of the inflammatory reactions are mainly influenced by crystals characteristics, including shape and size, which, in turn may involve the crystal- binding of several proteins, essential for the modulation of cellular responses. Cells most involved in the acute attacks are macrophage and neutrophils, which are responsible for the secretion of several important mediators of inflammation, such as prostaglandins and cytokines. These substances may in turn influence both intensity and duration of the acute attack. The proinflammatory effects of interleukin (IL)-1, IL-6, IL-8 and tumour necrosis factor (TNF)-alpha are counterbalanced by the anti-inflammatory activity of transforming growth factor (TGF)-beta, which may inhibit both the cell recruitment and cytokine synthesis. The role of TGF is crucial, not only by limiting acute inflammation but also by promoting formation and deposit of calcium crystals. However, the final effect of the balance between inflammatory and anti-inflammatory cytokines may also depend by other tissutal and cellular factors, not all of which are still completely understood.

Topics: Acute Disease; Arthritis; Calcium; Calcium Pyrophosphate; Crystallization; Cytokines; Humans; Inflammation; Interleukins; Macrophages; Neutrophils; Prostaglandins; Synovial Fluid; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Uric Acid

Pulmonary inflammation is a key feature in the pathogenesis of bronchopulmonary dysplasia (BPD). This inflammatory process, induced by multiple risk factors, is characterized by the presence of inflammatory cells, cytokines and an arsenal of additional humoral mediators in the airways and pulmonary tissue of preterm infants with the condition. Several mediators have a direct detrimental effect on pulmonary structures by affecting cell integrity and inducing apoptosis. An imbalance between pro-inflammatory and anti-inflammatory factors can generally be considered to be a hallmark of lung injury. Intrauterine exposure to pro-inflammatory cytokines or antenatal infection may prime the fetal lung such that minimally injurious postnatal events provoke an excessive pulmonary inflammatory response that most certainly affects normal alveolization and pulmonary vascular development in preterm infants with BPD.

Topics: Animals; Bronchopulmonary Dysplasia; Chorioamnionitis; Cytokines; Female; Humans; Infant, Newborn; Inflammation; Leukocyte Elastase; Models, Immunological; Pregnancy; Respiration, Artificial; Risk Factors; Transforming Growth Factor beta

The transforming growth factor-beta (TGF-beta) gene superfamily expresses a large set of structurally and functionally related polypeptides. Three TGF-beta isoforms are regulated by specific genes and have been identified in mammals (TGF-beta1, -beta2, and -beta3). All three-protein isoforms are observed abundantly during development and display overlapping and distinct spatial and temporal patterns of expressions. Each isoform plays a distinct role, the nature of which depends on the cell type, its state of differentiation, and growth conditions, and on the other growth factors present. TGF-beta regulates many of the processes common to both tissue repair and disease, including angiogenesis, chemotoxins, fibroblast proliferation and the controlled synthesis, and degradation of matrix proteins, such as collagen and fibronectin. This review will examine the genealogy and mode of actions of TGF-beta on the cell types involved in inflammation and repair, as well as in carcinoma.

Topics: Gene Expression Regulation; Humans; Inflammation; Neoplasms; Neovascularization, Physiologic; Receptors, Transforming Growth Factor beta; Signal Transduction; Transcription, Genetic; Transforming Growth Factor beta

Topics: Glucocorticoids; Humans; Inflammation; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Animals; Epithelium; Fibroblast Growth Factor 2; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Inflammation; Keratinocytes; Mice; Mice, Knockout; Mice, Transgenic; Models, Animal; Transforming Growth Factor beta; Transforming Growth Factor beta1; Wound Healing

A common immunopathological hallmark of many autoimmune inflammatory diseases is a T-cell invasion and accumulation at the inflamed tissue. Although the exact molecular and microenvironmental mechanisms governing such cellular invasion and tissue retention are not known, some key immunological principles must be at work. Transforming growth factor-beta (TGF-beta) is known to modulate some of these processes including homing, cellular adhesion, chemotaxis and finally T-cell activation, differentiation and apoptosis. The chronicity of such T-cell-driven inflammation probably involves an innate immunological response leading to a T-1 (Th/Tc), T-2 or T-3 (Th/Tr) T-cell adaptive immune response. Several studies suggest that the key to T-cell final destination resides on its and the antigen-presenting cell's phenotype as well as the coreceptor expression pattern and their signalling intensity. Recent observations suggest other equally important regulatory elements of T-cell inflammatory response that are sensitive to TGF-beta modulation. These include: (i) the stage of T-cell activation/differentiation; (ii) the chemotactic/adhesion molecule expression pattern; and (iii) the conditioning at the immunological synapse determining their sensitivity to known regulators such as TGF-beta. In this article, we focus on how the phenotype of the responding T cell and the T-cell receptor (TCR)-signalling intensity could drive the given inflammatory response. In particular, we discuss how TGF-beta can influence the process of T-cell migration and activation during such site-specific inflammation.

Topics: Animals; Autoimmune Diseases; Chemotaxis; Humans; Immune Tolerance; Inflammation; Mice; Protein Isoforms; Receptors, Antigen, T-Cell; Signal Transduction; T-Lymphocytes; Transforming Growth Factor beta

Transforming growth factor-beta (TGF-beta) has been considered an anti-inflammatory cytokine responsible for the bland removal of apoptotic cells. What is less established is the extent of secretion of this cytokine during the clearance of opsonized apoptotic cells via Fcgamma-mediated uptake. To date both decreased (favoring predominance of inflammation) and increased (favoring resolution of inflammation but potentially pro-fibrotic) responses have been demonstrated. IN an in vitro model of autoantibody-induced cardiac injury, we herein demonstrate that macrophages cocultured with apoptotic human fetal cardiocytes bound by anti-SSA/Ro antibodies secrete increased levels of TGF-beta. Prolonged secretion of this cytokine may contribute to the exuberant scarring seen in congenital heart block associated with maternal autoantibodies reactive with SSA/Rho and SSB/La antigens.

Topics: Antibodies, Antinuclear; Apoptosis; Coculture Techniques; Fibrosis; Heart Block; Humans; Inflammation; Macrophages; Myocardium; Transforming Growth Factor beta

Topics: Animals; Apoptosis; Humans; Inflammation; Lung Diseases, Interstitial; Models, Biological; Phagocytosis; Pulmonary Fibrosis; Transforming Growth Factor beta

The development of asthmatic inflammation involves a complex array of cytokines that promote the recruitment and activation of a number of different immune cells. While factors involved in initiating and establishing inflammation are well characterized, the process by which this pro-inflammatory cascade is regulated is less well understood. The identification and characterization of immunomodulatory cytokines in asthma has been a difficult proposition. Many of the putative regulatory factors have pleiotropic bioactivities and have been characterized as pro-inflammatory in association with certain pathologic conditions. This chapter addresses the potential role of several endogenous factors which appear to attenuate asthmatic inflammation. Understanding the integration of these factors into the regulation of the inflammatory process will likely result in novel therapeutic approaches.

Topics: Animals; Asthma; Binding Sites; Cytokines; Humans; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-16; Mice; Models, Biological; Surface-Active Agents; T-Lymphocytes; Transforming Growth Factor beta

Atherosclerosis is a vascular pathology in which inflammation plays a major role at every stage of the disease. The inflammatory process develops in response to abnormal cholesterol deposits in the intima of large arteries. The inflammatory reaction is initiated by a phase of endothelial activation induced by cytokines, oxidized low density lipoprotein (LDL) and/or changes in endothelial shear stress. This leads to the primary expression of endothelial adhesion molecules and chemokines followed by the recruitment and activation of circulating monocytes and lymphocytes. The clinical manifestations of atherosclerosis, including acute coronary syndromes, are the consequences of atherosclerotic plaque rupture/erosion that triggers thrombus formation leading to the occlusion of the vessel lumen. The local inflammatory process at the level of the atherosclerotic plaque might influence the stability of the plaque through its potential effects on the extracellular matrix, and on the plaque thrombogenicity. In humans, systemic inflammation has been recognized as a major risk factor of occurrence of acute coronary syndromes.

Topics: Arteriosclerosis; Glycoproteins; Humans; Inflammation; Inflammation Mediators; Intercellular Signaling Peptides and Proteins; Interleukin-10; Transforming Growth Factor beta

TGF-beta is a cytokine with varied properties and pleiotropic activity. It is released in an inactive form. To exhibit its biological activity, it requires binding to extracellular matrix proteins and, after that, proteolytic elimination of LAP (Latent Associated Protein) and LTBP (Latent TGF-beta Binding Protein). The process involves, among others, tissue transglutaminase, thrombin and plasmin. By stimulation of specific receptors, it influences transcription of some genes and translation of formed mRNA. Locally, it demonstrates proinflammatory properties whereas systemically, it has primarily a potent immunosuppressive effect. TGF-beta, by affecting proliferation, differentiation and migration of cells, as well as stimulation of extracellular matrix protein production, plays an important role in tissue regeneration and remodeling, but also in fibrosis. TGF-beta is also indispensable to maintain immune homeostasis of the organism. Reduced TGF-beta activity is considered to be responsible for development of autoimmune disorders in the course of several pathologic conditions. This cytokine plays an important role in the pathogenesis of chronic inflammatory processes taking place, among others, in inflammatory bowel diseases (IBD) and chronic hepatitis B and C. The paper presents a review of literature concerning diagnostic and prognostic value of TGF-beta level determinations in blood and tissue bioptates of patients with chronic non-specific enteritis and chronic hepatitis B and C.

Topics: Adult; Animals; Biomarkers; Child; Humans; Inflammation; Liver Diseases; Pediatrics; Prognosis; Protein Isoforms; Transforming Growth Factor beta

Topics: Adult; Age Factors; Aged; Alcoholism; alpha-Tocopherol; Antiviral Agents; Biopsy; Child; Cicatrix; Enzyme-Linked Immunosorbent Assay; Fatty Liver; Female; Hemochromatosis; Hepacivirus; Hepatitis C, Chronic; HIV Infections; Humans; Immunohistochemistry; Inflammation; Lipid Peroxidation; Liver; Liver Cirrhosis; Male; Necrosis; Phenotype; Risk Factors; Sex Factors; Transforming Growth Factor beta

Atherosclerosis is a disease of the arterial wall that seems to be tightly modulated by the local inflammatory balance. Transforming growth factors beta 1, 2 and 3 are cytokines/growth factors with broad activities on cells and tissues in the cardiovascular system, and have been suggested to play a role in the pathogenesis of atherosclerosis.. In the present review, we discuss recent developments in the role of transforming growth factor beta in the regulation of the immuno-inflammatory balance that modulates atherosclerosis. Such studies strongly suggest that the inhibition of endogenous transforming growth factor beta signalling favours the development of atherosclerotic lesions with an increased inflammatory component (T cells and macrophages) and decreased collagen content, features that are characteristic of unstable atherosclerotic plaques.. Transforming growth factor beta is identified as a critical modulator of the immuno-inflammatory balance in atherosclerosis, and a crucial plaque-stabilizing factor. Future studies should aim at defining the precise molecular mechanisms responsible for this protective effect, and developing immunomodulatory strategies based on the promotion of transforming growth factor beta activity (T regulatory T helper type 3 cells) to limit disease complications.

Topics: Animals; Arteriosclerosis; Humans; Inflammation; T-Lymphocytes; Transforming Growth Factor beta

Wound healing usually results in a scar. No therapy currently exists for removing scars, so treatments focus on making them less obvious. Research is investigating how to prevent scars forming, inspired by what happens to foetuses in the womb.

Topics: Adult; Chemotaxis, Leukocyte; Cicatrix; Cytokines; Fetus; Fibroblasts; Humans; Inflammation; Macrophages; Needs Assessment; Neovascularization, Physiologic; Neutrophils; Transforming Growth Factor beta; Transforming Growth Factor beta1; Wound Healing

The pathogenesis of pulmonary fibrosis remains incompletely understood. Studies of associated inflammation have led to the discovery of a number of cytokines and chemokines that are found to be important either directly or indirectly for the fibrotic process. However, the importance of inflammation in pulmonary fibrosis is unclear, and at the time of diagnosis the inflammatory component is variable and usually not responsive to anti-inflammatory therapeutic agents. Patients usually exhibit evidence of active fibrosis with increased numbers of activated fibroblasts, many of which have the phenotypic characteristics of myofibroblasts. At these sites, increased amounts of extracellular matrix deposition are evident with effacement of the normal alveolar architecture. Animal model studies show the myofibroblast to be the primary source of type I collagen gene expression in active fibrotic sites. In vitro studies show differentiation of these cells from fibroblasts under the influence of certain cytokines but indicate their susceptibility to nitric oxide-mediated apoptosis. In addition to promoting myofibroblast differentiation, transforming growth factor-beta1 provides protection against apoptosis. Thus, this well-known fibrogenic cytokine is important both for the emergence of the myofibroblast and its survival against apoptotic stimuli. This is consistent with the critical importance of this cytokine in diverse models of fibrosis in various tissues. In view of these properties, the persistence or prolonged survival of the myofibroblast may be key to understanding why certain forms of lung injury may result in progressive disease, terminating in end-stage disease.

Topics: Apoptosis; Cell Differentiation; Fibroblasts; Humans; Inflammation; Pulmonary Alveoli; Pulmonary Fibrosis; Transforming Growth Factor beta; Transforming Growth Factor beta1

Idiopathic pulmonary fibrosis (IPF) is a lung disease that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in inflammation, fibroblast proliferation, excessive extracellular matrix (ECM) deposition, and remodeling of alveolar gas exchange units. The progressive loss of lung gas exchange units in patients with IPF leads to respiratory failure and eventually to death. While the etiology of this disease is unknown, for many years studies suggested that chronic inflammation was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and fibrosis can occur independently of inflammation, suggesting that IPF is a disease caused by a mesenchymal, rather than an immune disorder. Mesenchymal growth factors, including transforming growth factor (TGF)-beta, insulin-like growth factor (IGF)-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1beta, have been shown to be exaggerated in several fibrotic lung disorders including IPF, ARDS, sarcoidosis, and bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis (scleroderma). We argue that inflammation is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in fibrotic lung diseases and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as IPF. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with IPF.

Topics: Humans; Inflammation; Insulin-Like Growth Factor I; Pulmonary Fibrosis; Respiratory Mucosa; Transforming Growth Factor beta

Topics: Animals; Cytokines; Disease Models, Animal; High Mobility Group Proteins; Humans; Inflammation; Interferon-gamma; Interleukins; Macrophage Migration-Inhibitory Factors; Mice; Mice, Knockout; Shock, Septic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Knowledge regarding putative inflammatory component(s) participating in Alzheimer's disease (AD) and in vascular dementia (VAD) remains scarce. Recently, we have demonstrated the presence of inflammatory components, such as cytokines, in the CSF of demented patients. Although the initial events triggering the neurodegenerative processes in AD versus VAD may be different and thus lead to different neuropathological outcome, they may initiate a similar cascade of cytokine production in response to neuronal injury. The cytokines released in the CNS may in turn, act in a similar manner in both diseases, amplifying certain pathological changes such as amyloidogenesis and amyloid accumulation in the blood vessels, white matter lesions and angiogenesis. This hypothesis is supported by clinical studies demonstrating the presence of white matter infarcts and cerebrovascular pathology in patients with AD as well as the presence of senile plaques in patients with VAD. This review will focus on the production of pro-inflammatory and anti-inflammatory cytokines in dementia, and their putative role for glia cell activation, amyloidogenesis, vascular changes, white matter damage and neurodegeneration.

Topics: Adjuvants, Immunologic; Alzheimer Disease; Central Nervous System; Cytokines; Dementia; Humans; Inflammation; Neovascularization, Pathologic; Receptor Cross-Talk; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Inflammation and genetics are both prominent mechanisms in the pathogenesis of atherosclerosis and arterial thrombosis. Accordingly, a number of population studies have explored the association of ischaemic heart disease with gene polymorphisms of the inflammatory molecules tumour necrosis factors (TNF) alpha and beta, transforming growth factors (TGF) beta1 and 2, interleukin (IL) 1 and its receptor antagonist (IL 1ra), CD14 (the receptor for lipopolysaccharide), P and E selectins, and platelet endothelial cell adhesion molecule (PECAM) 1. Although they are very preliminary and partly conflicting, the data provide some evidence that alterations in the genetics of the inflammatory system may modify the risk of ischaemic heart disease.

Topics: Adult; E-Selectin; Female; Humans; Inflammation; Interleukin-1; Lipopolysaccharide Receptors; Male; Middle Aged; Myocardial Ischemia; P-Selectin; Phenotype; Platelet Endothelial Cell Adhesion Molecule-1; Polymorphism, Genetic; Risk Factors; Transforming Growth Factor alpha; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Topics: Animals; Apoptosis; Autoimmune Diseases; Autoimmunity; Cell Differentiation; Cell Division; Clonal Anergy; Disease Models, Animal; DNA-Binding Proteins; Gene Expression Regulation; Humans; Immune Tolerance; Inflammation; Lymphocyte Activation; Mammals; Mice; Mice, Knockout; Phagocytosis; Phosphorylation; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Signal Transduction; T-Lymphocyte Subsets; Trans-Activators; Transforming Growth Factor beta

Topics: Angiotensin II; Animals; Anti-Inflammatory Agents, Non-Steroidal; Fibrosis; Humans; Inflammation; Inflammation Mediators; Kidney Diseases; Models, Biological; Mycophenolic Acid; Nephritis; Renin-Angiotensin System; Transforming Growth Factor beta

In this article, the authors review current and latest evidence linking helminth infections and the development of atopy. Although there is intense ongoing investigation and debate on this issue, the review of experimental, clinical and epidemiological data apparently shows that helminth infections can have beneficial aspects in regard to the pathogenesis of atopy and allergic diseases. Despite the fact that simplistic views are not recommended, it seems that polyclonal IgE production and mainly the stimulation of host immunoregulatory networks leading to synthesis of anti-inflammatory cytokines (IL-10, TGF-beta and others) can provide new insights into how mechanisms that helminths have developed throughout their evolution and that are useful for parasite evasion and persistence, could also be used in humans in order to provide new approaches in atopy prevention.

Topics: Animals; Disease Susceptibility; Eosinophilia; Helminthiasis; Host-Parasite Interactions; Humans; Hypersensitivity, Immediate; Immunity, Cellular; Immunoglobulin E; Inflammation; Interleukin-10; Interleukins; Mast Cells; Mice; Mice, Knockout; Models, Immunological; Signal Transduction; Th2 Cells; Transforming Growth Factor beta

The erosion of lean body mass resulting from protracted critical illness remains a significant risk factor for increased morbidity and mortality in this patient population. Previous studies have documented the well known impairment in nitrogen balance results from both an increase in muscle protein degradation as well as a decreased rate of both myofibrillar and sacroplasmic protein synthesis. This protein imbalance may be caused by an increased presence or activity of various catabolic agents, such as tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6 or glucocorticoids, or may be mediated via a decreased concentration or responsiveness to various anabolic hormones, such as growth hormone or insulin-like growth factor-I. This review focuses on recent developments pertaining to the importance of alterations in the growth hormone-insulin-like growth factor-I axis as a mechanism for the observed defects in muscle protein balance.

Topics: Critical Illness; Growth Hormone; Humans; Inflammation; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Muscle Proteins; Myostatin; Transforming Growth Factor beta; Wounds and Injuries

Heart failure is not a simple defect in the pumping function of cardiac muscle, but rather a complex systemic inflammatory disease affecting many organ systems. Recognition of this fact has led to new therapeutic interventions such as angiotensin-converting enzyme inhibitors and beta-blockers, which have a significant impact on the quality of life and survival of patients with heart failure. During the course of heart failure, the steps involved in the activation of inflammation are now better understood. As a result, new therapies will develop that block, modify, or prevent these inflammatory changes, and supplement our armamentarium for providing better and longer lives for patients.

Topics: Adrenergic beta-Antagonists; Algorithms; Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Heart Failure; Humans; Inflammation; Interleukin-1; Interleukin-6; Quality of Life; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) to reduce serum cholesterol is well described. However, the recent finding that statins have direct effects on bone was unexpected. A number of epidemiological studies have recently been published that explore the effects of statins on bone mineral density and risk of fracture in humans. Statins may act by directly stimulating the expression of bone morphogenetic protein-2 and increasing osteoblast differentiation or, like nitrogen-containing bisphosphonates, may have effects on the mevalonate pathway that leads to inhibition of osteoclast activity and osteoblast apoptosis. In addition, the demonstration that statins can inhibit inflammation and encourage angiogenesis offers other possibilities for action.

Topics: Bone and Bones; Bone Density; Bone Development; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Female; Fractures, Bone; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Male; Neovascularization, Pathologic; Osteoblasts; Transforming Growth Factor beta

Chronic obstructive pulmonary disease (COPD) is characterized by chronic obstruction of expiratory flow affecting peripheral airways, associated with chronic bronchitis (mucus hypersecretion with goblet cell and submucosal gland hyperplasia) and emphysema (destruction of airway parenchyma), together with fibrosis and tissue damage, and inflammation of the small airways. Cytokines are extracellular signalling proteins. Increased levels of interleukin (IL)-6, IL-1beta, tumour necrosis factor-alpha (TNF-alpha) and IL-8 have been measured in sputum, with further increases during exacerbations, and the bronchiolar epithelium over-expresses monocyte chemotactic protein (MCP)-1 and IL-8. IL-8 can account for some chemotactic activity of sputum, and sputum IL-8 levels correlate with airway bacterial load and blood myeloperoxidase levels. The expression of chemokines such as regulated on activation, normal T-cell expressed and secreted (RANTES) may underlie the airway eosinophilia observed in some COPD patients. Cytokines may be involved in tissue remodelling. TNF-alpha and IL-1beta stimulate macrophages to produced matrix metalloproteinase-9 (MMP-9), and bronchial epithelial cells to produce extracellular matrix glycoproteins such as tenascin. Increased expression of transforming growth factor-beta (TGFbeta) and of epidermal growth factor (EGF) occurs in the epithelium and submucosal cells of patients with chronic bronchitis. TGFbeta and EGF activate proliferation of fibroblasts, while activation of the EGF receptor leads to mucin gene expression. The cytokine profile seen in chronic obstructive pulmonary disease is different from that observed in asthma. The role of these cytokines needs to be defined and there is a potential for anticytokine therapy in chronic obstructive pulmonary disease.

Topics: Cytokines; Eosinophils; Epidermal Growth Factor; Female; Humans; Inflammation; Interleukin-1; Interleukin-8; Male; Prognosis; Pulmonary Disease, Chronic Obstructive; Sensitivity and Specificity; Severity of Illness Index; Transforming Growth Factor beta

Inflammatory demyelinating diseases comprise a heterogeneous group of disorders that affect the peripheral and central nervous system. Multiple sclerosis (MS) is the most common disease affecting the CNS white matter. Close similarities between MS and the animal model of the disease, experimental allergic encephalitis (EAE), have suggested that MS might be an autoimmune disease, which is triggered by an infectious agent. Our laboratory has directed its effort in identifying and designing therapies that interfere with key signaling pathways that mediate CNS inflammation in experimental allergic encephalitis. These have included naturally occurring cytokines such as TGFbeta and synthetic small molecules, lysofyline and tyrphostin, which inhibit the inflammatory response and prevent the development of EAE.

Topics: Adult; Animals; Anti-Inflammatory Agents, Non-Steroidal; CD4-Positive T-Lymphocytes; Cerebrospinal Fluid; Chlamydia Infections; Chlamydophila pneumoniae; Cytokines; Demyelinating Autoimmune Diseases, CNS; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Enzyme Inhibitors; Glatiramer Acetate; Humans; Immunotherapy; Inflammation; Interleukin-12; Mice; Multiple Sclerosis; Pentoxifylline; Peptides; Protein Kinase Inhibitors; Protein Kinases; Signal Transduction; Transforming Growth Factor beta

Topics: Animals; Cell Division; Chemokines; Cytokines; Disease Progression; Extracellular Matrix; Humans; Inflammation; Interferons; Lung; Matrix Metalloproteinase 7; Matrix Metalloproteinases; Pulmonary Fibrosis; Transforming Growth Factor beta; Transforming Growth Factor beta1

The uptake and removal of necrotic or lysed cells involves inflammation and an immune response, due in part to processes that involve members of the collectin family, surface calreticulin and CD91. Clearance of apoptotic cells, by contrast, does not induce either inflammation or immunity. Could the phosphatidylserine receptor be the molecular switch that determines what the outcome will be?

Topics: Animals; Antigen Presentation; Apoptosis; Calcium-Binding Proteins; Calreticulin; Carrier Proteins; Cell Adhesion; Cell Death; Cellular Senescence; Collectins; Dendritic Cells; Endopeptidases; Humans; Inflammation; Inflammation Mediators; Jumonji Domain-Containing Histone Demethylases; Low Density Lipoprotein Receptor-Related Protein-1; Membrane Lipids; Models, Biological; Necrosis; Phagocytosis; Phosphatidylserines; Receptors, Cell Surface; Receptors, Immunologic; Ribonucleoproteins; Transforming Growth Factor beta

Neuroinflammation occuring after traumatic brain injury (TBI) is a complex phenomenon comprising distinct cellular and molecular events involving the injured as well as the healthy cerebral tissue. Although immunoactivation only represents a one of the many cascades initiated in the pathophysiology of TBI, the exact function of each mediator, activated cell types or pathophysiological mechanism, needs to be further elucidated. It is widely accepted that inflammatory events display dual and opposing roles promoting, on the one hand, the repair of the injured tissue and, on the other hand, causing additional brain damage mediated by the numerous neurotoxic substances released. Most of the data supporting these hypotheses derive from experimental work based on both animal models and cultured neuronal cells. More recently, evidence has been provided that a complete elimination of selected inflammatory mediators is rather detrimental as shown by the attenuation of neurological recovery. However, there are conflicting results reported on this issue which strongly depend on the experimental setting used. The history of immunoactivation in neurotrauma is the subject of this review article, giving particular emphasis to the comparison of clinical versus experimental studies performed over the last 10 years. These results also are evaluated with respect to other neuropathologies, which are years ahead as compared to the research in TBI. The possible reciprocal influence of peripheral and intrathecal activation of the immune system will also be discussed. To conclude, the future directions of research in the field of neurotrauma is considered.

Topics: Animals; Brain; Brain Injuries; Cell Death; Complement C3; Cytokines; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Transforming Growth Factor beta

Regulatory T(Treg)-cell populations have been identified in a number of disease models. In this review we focus on the role of naturally occurring Treg cells in the control of intestinal inflammation. Specifically, we discuss their mechanism of action with particular emphasis on the role of anti-inflammatory cytokines and cell surface molecules.

Topics: Animals; CD4-Positive T-Lymphocytes; Humans; Immunity, Mucosal; Inflammation; Interleukin-10; Intestines; Mice; T-Lymphocyte Subsets; Transforming Growth Factor beta

Rheumatoid arthritis (RA) is a common, frequently severe, chronic inflammatory disease. Although the cause of RA remains unknown, recent advances in understanding its pathogenesis have been substantial. Despite the use of a variety of medications, particularly methotrexate, treatment of RA is not fully effective in most patients. Until recently, insights into inflammatory mechanisms in RA had not been successfully translated into novel classes of therapeutic agents. This gap now will likely be bridged in the form of a new strategy for treating RA-cytokine blockade. Although a variety of cytokines are important in the pathogenesis of RA, tumor necrosis factor (TNF) seems to play a pivotal role. Neutralizing TNF in patients with RA, by means of soluble TNF receptors or anti-TNF monoclonal antibodies, has proven to be a powerful means of controlling disease activity. Studies are in progress to obtain additional information regarding long-term safety of TNF blockade and its effects on disease progression.

Topics: Acute Disease; Animals; Antibodies, Monoclonal; Arthritis, Rheumatoid; Chronic Disease; Cytokines; Disease Progression; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Inflammation; Interferon-gamma; Interleukins; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Inflammatory stimuli cause plasma leakage and leukocyte adhesion in venules but not in capillaries or arterioles. The specific response of venules is governed by phenotypic specialization of the venular endothelial cells. What regulates this specialized phenotype? Several recent developments have shed new light on this question and may challenge our thinking about regulation of the venular endothelial cell phenotype. In this review, we consider some of the molecular markers of venular endothelial cells, the hemodynamic and molecular factors that may regulate the phenotype of venular endothelial cells, and abnormalities in endothelial cell phenotype in disease-related angiogenesis and microvascular remodeling. The expanding list of molecular markers may help clarify the physiologic and molecular factors that regulate the phenotype of venular endothelial cells in normal development and disease.

Topics: Angiopoietin-1; Animals; Biomarkers; Blood Flow Velocity; Blood Pressure; Capillary Leak Syndrome; Capillary Permeability; Cell Adhesion; Cytokines; Endothelium, Vascular; Glycoconjugates; Humans; Inflammation; Leukocytes; Male; Membrane Glycoproteins; Mice; Mice, Transgenic; Neovascularization, Pathologic; Neovascularization, Physiologic; Organ Specificity; Phenotype; Rats; Receptor Protein-Tyrosine Kinases; Receptor, EphB4; Receptor, TIE-2; Receptors, Cell Surface; Receptors, Eph Family; Signal Transduction; Transforming Growth Factor beta; Venules

CD36 has been associated with diverse normal and pathologic processes. These include scavenger receptor functions (uptake of apoptotic cells and modified lipid), lipid metabolism and fatty acid transport, adhesion, angiogenesis, modulation of inflammation, transforming growth factor-beta activation, atherosclerosis, diabetes and cardiomyopathy. Although CD36 was identified more than 25 years ago, it is only with the advent of recent genetic technology that in-vivo evidence has emerged for its physiologic and pathologic relevance. As these in-vivo studies are expanded, we will gain further insight into the mechanism(s) by which CD36 transmits a cellular signal, and this will allow the design of specific therapeutics that impact on a particular function of CD36.

Topics: Animals; Arteriosclerosis; CD36 Antigens; Cell Adhesion; Humans; Inflammation; Lipid Metabolism; Membrane Proteins; Neovascularization, Pathologic; Receptors, Immunologic; Receptors, Lipoprotein; Receptors, Scavenger; Scavenger Receptors, Class B; Signal Transduction; Transforming Growth Factor beta

Topics: Animals; Humans; Immunity; Inflammation; Transforming Growth Factor beta

Defining the mechanisms whereby transforming growth factor-beta (TGF-beta) controls physiologic inflammation and the immune response and how it contributes to pathology when it is dysregulated is critical to our ability to manipulate the levels and activity of this potent cytokine for therapeutic benefit. In keeping with its dichotomous nature, recent evidence suggests that overproduction and/or activation contribute to persistent inflammation and that antagonists of TGF-beta delivered locally can break the cycle of leukocyte recruitment and fibrotic sequelae. On the other hand, systemic routing of TGF-beta can also inhibit inflammatory pathogenesis by multiple mechanisms as exemplified by systemic injections of the protein and by recent gene transfer studies. In addition, enhanced levels of circulating endogenous TGF-beta appear to be an instrument of suppression during the development of oral tolerance, cyclosporin treatment, and following administration of retinoic acid. Although treatment of autoimmune and chronic inflammatory diseases is an important goal, the multiplicity of actions of TGF-beta and the nearly ubiquitous expression of TGF-beta and its receptors dictate a cautious approach to the use of this powerful cytokine as a therapeutic agent.

Topics: Animals; Autoimmune Diseases; Genetic Therapy; Inflammation; Transforming Growth Factor beta

The TGF-beta family of cytokines are ubiquitous, multifunctional and essential to survival. They play important roles in growth and development, inflammation and repair and host immunity. The mammalian TGF-beta isoforms (TGF-beta 1, beta 2 and beta 3) are secreted as latent precursors and have multiple cell surface receptors of which at least two mediate signal transduction. Autocrine and paracrine effects of TGF-beta's can be modified by extracellular matrix, neighbouring cells and other cytokines. The vital role of the TGF-beta family is illustrated by the fact that approximately 50% of TGF-beta 1 gene knockout mice die in utero and the remainder succumb to uncontrolled inflammation after birth. TGF-beta 2 and TGF-beta 3 gene knockout mice are not yet described. More recently, novel TGF-beta-like molecules have been described which share some of the properties of the mammalian TGF-beta isoforms. The role of TGF-beta in homeostatic and pathogenic processes suggests numerous applications in the diagnosis and treatment of various diseases characterised by inflammation and fibrosis.

Topics: Animals; Embryonic and Fetal Development; Female; Growth; Humans; Immunity; Inflammation; Mice; Mice, Knockout; Pregnancy; Recombinant Proteins; Signal Transduction; Transforming Growth Factor beta

Topics: Cell Division; Conjunctiva; Dry Eye Syndromes; Epidermal Growth Factor; Epithelial Cells; Epithelium; Humans; Inflammation; Lacrimal Apparatus; Metaplasia; Models, Biological; Surface Properties; Tears; Transforming Growth Factor beta

Topics: Animals; Arachidonate 5-Lipoxygenase; Endothelial Growth Factors; Endothelins; Humans; Hypertension, Pulmonary; Inflammation; Insulin-Like Growth Factor I; Lymphokines; Platelet Activating Factor; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Scarring of superficial tissues and chronic fibroses of major organs present major medical problems ranging from disfigurement to progressive disability and death. Growing understanding of the cellular and molecular events, which are common to these intractable disorders, now provides a favourable basis for the development of effective drug therapies. Much attention is focussed on the roles of the many cytokines and growth factors, which contribute to the fibrogenic process. The transforming growth factor (TGF)-beta 1 and 2 isoforms are among the most significant of these and approaches to control their activity include blocking the activation of latent TGF-beta, preventing the ligand-receptor interactions and the inhibition of down-stream signal transduction. Concerns regarding possible risks of the long-term suppression of TGF-beta function point to connective tissue growth factor (CTGF) as a possible alternative target. CTGF is induced by and appears to mediate at least some of the fibrogenic actions of TGF-beta, although not its important antimitogenic activity on epithelial cells. The fibrogenic effects of endothelins and angiotensin II have aroused considerable interest in the anti-fibrotic potential of antihypertensive agents designed primarily to limit the vasoconstrictive activities of these peptides. Polypeptides including interferons alpha and gamma, relaxin, TGF-beta 3 and hepatocyte growth factor, all show an ability to limit fibrogenesis in either clinical or experimental situations. Finally, inhibitors of the enzymes required for the post-translational processing of collagens, including prolyl 4-hydroxylase, C-proteinase and lysyl oxidase provide a more direct means of reducing the deposition of fibrillar collagens into the extracellular matrix although the potentially adverse effects of sustained manipulation of collagen metabolism remain to be investigated.

Topics: Animals; Collagen; Cytokines; Extracellular Matrix; Fibroblasts; Fibrosis; Humans; Inflammation; Transforming Growth Factor beta

Asthma is a chronic inflammatory disease of the airways, with associated repair processes. Both inflammatory and repair processes appear to be strictly related, and can lead to several histopathological alterations of the bronchial mucosa, such as the shedding of epithelium and increased thickness of the basement membrane. The integrity as well as the alterations of the bronchial structure are the consequence of several biological events, such as cell proliferation and death, cell activation and inhibition, and extracellular matrix (ECM) production and degradation. These events are critically regulated by polypeptides called growth factors (GFs), which are able, functioning in an autocrine and paracrine fashion, to affect and modulate cell functions and ECM turnover. Although the importance of GFs has been widely demonstrated in other pulmonary conditions, such as lung fibrotic diseases, their possible involvement in the pathogenesis of inflammatory and postinflammatory processes in asthma is still not completely clear. The aim of the present review was to discuss the biological evidence concerning the role of several growth factors, such as transforming growth factor-beta (TGF-beta), epidermal growth factor (EGF), granulocyte/macrophage colony-stimulating factor (GM-CSF), platelet-derived growth factor (PDGF) and endothelin, in asthma and chronic bronchitis.

Topics: Asthma; Bronchi; Endothelial Growth Factors; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Humans; Hyperplasia; Inflammation; Lung; Platelet-Derived Growth Factor; Respiratory System; Transforming Growth Factor beta

Topics: Adjuvants, Immunologic; Animals; Autoimmune Diseases; Humans; Inflammation; Lymphocytes; Mice; Transforming Growth Factor beta

An increased interest in mucosal immunity has stemmed from the identification of novel T-cell populations and developments in oral vaccines and oral tolerance. The development of physiological inflammation is antigen driven. Upon recognition of antigen, the lamina propria (LP) is populated with lymphocytes and activated peripheral cells acquire the capacity to home to the gut. Antigen entry to the gut is via follicle-associated epithelium or M cells. The antigen now interacts with macrophages or CD4+ cells, and go on to the Peyer's patch where B cells undergo a transforming growth factor beta (TGF-beta)-mediated isotope switch to immunoglobulin (Ig) A. TGF-beta may also play a role in the development of oral tolerance. The intestinal epithelium is seen as the site for the activation of CD8+ suppressor cells. Controlled inflammation is therefore explained by the interaction of LP lymphocytes and intra-epithelial cells (IEC). IECs are capable of extending processes that express regulatory surface molecules coupled with antigen processed from luminal uptake. CD8+ T-cell activation is favoured over CD4+ T-cell activation due to the size of the antigenic binding peptide. The result is suppressed inflammation. Other antigen-presenting cells (APCs) and dendritic cells may also contribute to local immunosuppression.

Topics: Animals; Antigen Presentation; B-Lymphocytes; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Epithelial Cells; Epithelium; Humans; Immunoglobulin A, Secretory; Inflammation; Intestinal Mucosa; Lymphocyte Activation; Peyer's Patches; Transforming Growth Factor beta

Topics: Animals; Disease Models, Animal; Inflammation; Mice; Mice, Knockout; Phenotype; Transforming Growth Factor beta

Renal hypertrophy (an increase in cellular protein content and cellularity as well as an accumulation of extracellular matrix) is due to the imbalance between protein synthesis and degradation. Proteolytic activity in the kidney plays an important role in maintaining this balance. Impaired renal proteolytic activity caused by such factors as high protein intake, metabolic acidosis, angiotensin II and transforming growth factor-beta 1 in vivo and in vitro may result in decreased protein degradation and subsequent induction of cellular hypertrophy, even in the absence of increased protein synthesis.

Topics: Acidosis; Ammonia; Angiotensin II; Animals; Diabetes Mellitus, Experimental; Dietary Proteins; Endopeptidases; Glomerulonephritis; Humans; Hypertrophy; Inflammation; Insulin-Like Growth Factor I; Kidney; Kidney Diseases; Proteins; Transforming Growth Factor beta

Chronic lung disease of prematurity (CLD) is a common respiratory disorder of preterm infants. At autopsy, fibroblast proliferation, and components of the extracellular matrix, including collagen and fibronectin, are markedly increased in the lungs of infants who die from CLD. Examination of broncho-alveolar fluid suggests that the persistence of neutrophils is associated with the development of CLD. In our studies, the pro-inflammatory cytokines, interleukin-1 beta (IL-1 beta) and interleukin-6, (IL-6) and mediators which reflect neutrophil recruitment and activation, including soluble intercellular adhesion molecule, interleukin-8 (IL-8) and neutrophil elastase, were increased in lavage fluid obtained from infants who developed CLD when compared to infants who did not. Furthermore, semiquantitative reverse transcriptase-polymerase chain reaction of mRNA extracted from lavage cells suggested that luminal cells may be the source of IL-6 detected in lavage fluid but non-luminal cells may be the sources of IL-1 beta and IL-8. Fibrosis is thought to be mediated by the pro-fibrotic cytokines including transforming growth factor-beta1 (TGF-beta 1). Both active and total TGF-beta 1 were increased in lavage fluid from infants who developed CLD. Furthermore, both type I procollagen and TGF-beta were increased qualitatively in lung tissue obtained at autopsy from infants who died from respiratory failure. The increase in inflammatory mediators was maximal at 10 days of age. By contrast, the increase in TGF-beta 1 was maximal at 4 days of age. This suggests that the interaction between inflammation and fibrosis in CLD is complex, and that prenatal factors may be important in the pathogenesis of CLD.

Topics: Cytokines; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Inflammation; Lung; Lung Diseases; Pulmonary Fibrosis; Transforming Growth Factor beta

Three isoforms of Transforming Growth Factor-beta (TGF-beta 1, beta 2 and beta 3) exist in mammals. They play critical roles in growth regulation and development. Each isoform is encoded by a unique gene on different chromosomes. All three of these growth factors are secreted by most cell types, generally in a latent form, requiring activation before they can exert biological activity. This activation of latent TGF-beta, which may involve plasmin, thrombospondin and possibly acidic microenvironments, appears to be a crucial regulatory step in controlling their effects. The TGF-betas possess three major activities: they inhibit proliferation of most cells, but can stimulate the growth of some mesenchymal cells; they exert immunosuppressive effects; and they enhance the formation of extracellular matrix. Two types of membrane receptors (type I and type II) possessing a serine/threonine kinase activity within their cytoplasmic domains are involved in signal transduction. Inhibition of growth by the TGF-betas stems from a blockage of the cell cycle in late G1 phase. Among the molecular participants concerned in G1-arrest are the Retinoblastoma (Rb) protein and members of the Cyclin/Cyclin-dependent kinase/Cyclin dependent kinase inhibitor families. In the intact organism the TGF-betas are involved in wound repair processes and in starting inflammatory reactions and then in their resolution. The latter effects of the TGF-betas derive in part from their chemotactic attraction of inflammatory cells and of fibroblasts. From gene knockout and from overexpression studies it has been shown that precise regulation of each isoform is essential for survival, at least in the long term. Several clinical applications for certain isoforms have already shown their efficacy and they have been implicated in numerous other pathological situations.

Topics: Animals; Cell Differentiation; Cell Division; CHO Cells; Cricetinae; Humans; Inflammation; Mice; Mice, Knockout; Neoplasms; Rats; Receptors, Transforming Growth Factor beta; Recombinant Proteins; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta; Wound Healing

Topics: Animals; Cell Division; Chemokines; Cytokines; Extracellular Matrix; Fibrosis; Humans; Inflammation; Renal Insufficiency; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Topics: Cytokines; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-10; Receptors, Cytokine; Receptors, Interleukin-1; Sialoglycoproteins; Solubility; Transforming Growth Factor beta

Topics: Animals; Humans; Immunity; Inflammation; Transforming Growth Factor beta

In recent years increasing evidence has been accumulated on the role of cytokines in mediating glomerular and renal damage. Many such cytokines are released in the inflamed glomeruli by leukocytes and intrinsic glomerular cells. Cytokines not only recruit inflammatory cells into the injured glomeruli, but also induce a variety of responses on glomerular cells that range from a direct toxic effect to shape changes, proliferation, and induction of the release of inflammatory mediators and extracellular matrix, and could promote further glomerular damage. Moreover, exogenous administration of cytokines has induced glomerular injury in healthy animals and has enhanced renal damage in animals with glomerulonephritis. Anti-cytokine strategies have proved to be effective therapeutical alternatives in experimental models of glomerular diseases and may provide a more specific approach to the management of human glomerulonephritis.

Topics: Animals; Cytokines; Glomerular Mesangium; Glomerulonephritis; Humans; Inflammation; Interleukin-1; Interleukin-6; Kidney Glomerulus; Platelet-Derived Growth Factor; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

A modern approach of Pathology, using immunohistochemistry, electron microscopy and image analysis, was made to describe the matrix profile of the non reversible fibrosis observed in the cutaneous lesion of Chromomycosis. The distribution pattern of cell populations in dense inflammatory infiltrate, sometimes organized in granulomas, has been identified concurrently with the in situ demonstration of the pro-fibrotic cytokine TGF-beta. The professional phagocytes (polymorphonuclear neutrophils and macrophages) seem unable to fully eliminate the fungi. We suppose it is this persistence which explains the exuberant cell immune response.

Topics: Biopsy; Chromoblastomycosis; Fibrosis; Humans; Immunohistochemistry; Inflammation; Macrophages; Neutrophils; Transforming Growth Factor beta

TGF-beta 1 mRNA and protein were recently found to increase in animal brains after experimental lesions that cause local deafferentation or neuron death. Elevations of TGF-beta 1 mRNA after lesions are prominent in microglia but are also observed in neurons and astrocytes. Moreover, TGF-beta 1 mRNA autoinduces its own mRNA in the brain. These responses provide models for studying the increases of TGF-beta 1 protein observed in beta A/amyloid-containing extracellular plaques of Alzheimer's disease (AD) and Down's syndrome (DS) and in brain cells of AIDS victims. Involvement of TGF-beta 1 in these human brain disorders is discussed in relation to the potent effects of TGF-beta 1 on wound healing and inflammatory responses in peripheral tissues. We hypothesize that TGF-beta 1 and possibly other TGF-beta peptides have organizing roles in responses to neurodegeneration and brain injury that are similar to those observed in non-neural tissues. Work from many laboratories has shown that activities of TGF-beta peptides on brain cells include chemotaxis, modification of extracellular matrix, and regulation of cytoskeletal gene expression and of neurotrophins. Similar activities of the TGF-beta's are well established in other tissues.

Topics: Animals; Brain Diseases; Humans; Immunity; Inflammation; Nerve Degeneration; RNA, Messenger; Transforming Growth Factor beta

Topics: Animals; Chimera; Female; Gene Expression Regulation; Inflammation; Male; Mice; Mice, Mutant Strains; Mutation; Phenotype; Transforming Growth Factor beta

It is now apparent that the TGF-beta has potent immunoregulatory properties. Although most reports have described the immunosuppressive activities of TGF-beta, recent evidence supports the concept that TGF-beta can have both inhibitory and stimulatory actions. The delivery of sufficient quantities of TGF-beta has proven beneficial in several disease models such as allograft rejection and autoimmunity. Moreover, the increased levels of TGF-beta found in several disease states associated with immunosuppression suggests that inhibitors of TGF-beta may be clinically useful in some diseases. Thus, TGF-beta or antagonists to TGF-beta have exciting potential for use in treating or preventing several diseases (Table 6).

Topics: Animals; Autoimmune Diseases; Cytotoxicity, Immunologic; Graft Rejection; Hematopoiesis; Humans; Immune System; Immune Tolerance; Inflammation; Lymphocytes; Monocytes; Transforming Growth Factor beta

Topics: Animals; Bone and Bones; Humans; Immunity; Inflammation; Ischemia; Neoplasms; Transforming Growth Factor beta

Topics: Bone Remodeling; Endocrine Glands; Hematopoiesis; Humans; Immune System; Inflammation; Receptors, Cell Surface; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta; Wound Healing

As we continue to explore the biology of TGF-beta in the network of cells and mediators contributing to host defense, the mechanisms controlling whether the pro- or antiinflammatory effects of this peptide prevail will be unraveled. Understanding these basic mechanisms may offer new approaches for identifying agonists and/or antagonists and in which circumstances their use might be appropriate. The striking differences between local and systemic administration of this cytokine reaffirm that the functional consequences of any biologic mediator must be considered in context (9) and, furthermore, suggest avenues of therapeutic application (Table III). In summary, the central role of TGF-beta in normal and aberrant host defense has become indisputable.

Topics: Acquired Immunodeficiency Syndrome; Animals; Disease Models, Animal; Fibrosis; Humans; Immune Tolerance; Immunosuppression Therapy; Inflammation; Monocytes; Receptors, Cell Surface; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta; Wound Healing

Topics: Animals; Colony-Stimulating Factors; Fibroblast Growth Factors; Growth Substances; Hematopoiesis; Humans; Inflammation; Interleukins; Macrophages; Nerve Regeneration; Platelet-Derived Growth Factor; Somatomedins; Transforming Growth Factor alpha; Transforming Growth Factor beta; Wound Healing

It is now apparent that the transforming growth factor beta (TGF-beta) family of proteins has potent immunoregulatory properties ranging from effects on the growth and differentiation of primitive stem cells to the differentiated functions of immune effector cells. Although most reports have described the immunosuppressive activities of TGF-beta, recent evidence supports the concept that TGF-beta can have both inhibitory and stimulatory actions on these systems. Recently, it has been found that TGF-beta can have autocrine as well as paracrine effects on the immune system, indicating that immune cells can activate the inactive secreted form of TGF-beta. Furthermore, TGF-beta has differential intracellular effects on cell surface receptor modulation, tyrosine phosphorylation, and cytokine gene transcription as well as cell-mediated cytotoxicity. Importantly, the administration of TGF-beta has proven beneficial in several animal disease models such as septic shock, allograft rejection, and autoimmunity. Moreover, the increased levels of TGF-beta found in several disease states associated with immunosuppression such as different forms of malignancy, chronic degenerative diseases, and AIDS implicate the involvement of TGF-beta in the pathogenesis of some diseases. Ultimately, well designed clinical trials will determine whether the exciting potential of TGF-beta can be used to treat or prevent disease.

Topics: Animals; Autoimmunity; Humans; Immune Tolerance; Immunity; Inflammation; Lymphoma; Neoplasms; Receptors, Cell Surface; Receptors, Transforming Growth Factor beta; Retroviridae Infections; Transforming Growth Factor beta

Topics: Animals; Arthritis; Disease Models, Animal; Humans; Immune Tolerance; Inflammation; Monocytes; T-Lymphocytes; Transforming Growth Factor beta

Topics: Animals; Extracellular Matrix; Granulation Tissue; Humans; Inflammation; Pulmonary Fibrosis; Transforming Growth Factor beta; Wound Healing

This experiment investigated the protective effect of resveratrol (RES) on the hepatic antioxidant status and systemic inflammation in yellow-feathered broilers challenged with lipopolysaccharide (LPS). A total of 240 healthy 1-day-old yellow-feathered broilers were randomly divided into 4 groups (control, LPS, RES, and RES+LPS), with 5 replicates of 12 chickens per replicate. The experiment lasted 21 d. The broilers were fed with either the basal diet or the basal diet supplemented with 400 mg/kg RES followed by intraperitoneal challenge with LPS (1 mg/kg body weight) or the same amount of saline at d 16, 18, and 20. The results showed that dietary RES supplementation could improve the activities of total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) in the liver of yellow-feathered broilers challenged with LPS (P < 0.05). Furthermore, LPS challenge increased the plasma interleukin-17 (IL-17) concentration, the hepatic interleukin-6 (IL-6) and interleukin-1β (IL-1β) concentrations, as well as the concentrations of tumor necrosis factor (TNF-α), IL-6, and IL-1β in the spleen (P < 0.05), and decreased the transforming growth factor-β (TGF-β) concentrations in the plasma, liver, and spleen (P < 0.05). However, dietary RES supplementation could reduce the increased TNF-α levels in the plasma, liver, and spleen induced by LPS, and increased TGF-β level in the liver and spleen (P < 0.05). Collectively, these results suggest that dietary RES supplementation could effectively improve the hepatic antioxidant capacity and attenuate LPS-induced inflammation in yellow-feathered broilers during the starter stage.

Topics: Animal Feed; Animals; Antioxidants; Chickens; Diet; Dietary Supplements; Inflammation; Interleukin-6; Lipopolysaccharides; Liver; Resveratrol; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Ankylosing spondylitis (AS) is an inflammatory rheumatic disease with increased bone mass in the main sites of inflammation. Regulatory T (Treg) cells have been reported to involve in pathology of AS. This study designed at investigating the effects of nanocurcumin on Treg cell responses in peripheral blood (PB) of AS patients.. Test group including 12 AS patients received nanocurcumin daily for 4 months and control group including 12 patients received placebo. The frequency of Treg was measured by flow cytometry. The expression levels of FoxP3 and several associated microRNAs (miRNAs; miR-27, miR-17, and miR-146a) and cytokines including Interleukin-10 (IL-10), TGF-β, and IL-6 were assessed by real-time polymerase chain reaction. Furthermore, enzyme-linked immunosorbent assay was done to determine the secretion levels of cytokines.. After treatment with nanocurcumin the frequency of Treg cells in AS patients increased significantly. The RT-PCR data indicated that the expression of miR-17 and miR-27 were significantly decreased following nanocurcumin treatment while miR-146a and FoxP3 were significantly increased. Moreover, nanocurcumin-treated group had high levels of IL-10 and TGF-β and low levels of IL-6 production than control group.. The findings suggested that dysregulation of Treg cells in PB influences the AS development and nanocurcumin therapy could regulate the Treg cells, and so could be useful in the treatment of AS and may be other autoimmune diseases. This study is registered with IRCT.ir, number IRCT2017052927520N7.

Topics: Adult; Curcumin; Double-Blind Method; Female; Forkhead Transcription Factors; Humans; Inflammation; Interleukin-10; Interleukin-6; Leukocytes, Mononuclear; Male; MicroRNAs; Middle Aged; Nanoparticles; Spondylitis, Ankylosing; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Young Adult

Because molecular memories of past inflammatory events can persist in epidermal cells, we evaluated the long-term epidermal protein expression landscapes after dermal regeneration and in psoriatic inflammation. We first characterized the effects of two dermal regeneration strategies on transplants of indicator split-thickness skin grafts (STSGs) in ten adult patients with deep burns covering more than 20% of their body surface area. After fascial excision, three adjacent areas within the wound were randomized to receive a permanent dermal matrix, a temporary granulation-tissue-inducing dressing or no dermal component as control. Control areas were covered with STSG immediately, and treated areas after two-weeks of dermis formation. Epidermis-dermis-targeted proteomics of one-year-follow-up samples were performed for protein expression profiling. Epidermal expression of axonemal dynein heavy chain 10 (DNAH10) was increased 20-fold in samples having had regenerating dermis vs control. Given the dermal inflammatory component found in our dermal regeneration samples as well as in early psoriatic lesions, we hypothesized that DNAH10 protein expression also would be affected in psoriatic skin samples. We discovered increased DNAH10 expression in inflammatory lesions when compared to unaffected skin. Our results associate DNAH10 expression with cell proliferation and inflammation as well as with the epidermal memory resulting from the previous regenerative signals of dermis. This study (ISRCTN14499986) was funded by the Finnish Ministry of Defense and by government subsidies for medical research.

Topics: Adult; Burns; Cell Proliferation; Dermis; Dyneins; Epidermis; Female; Humans; Immunohistochemistry; Inflammation; Keratinocytes; Male; Middle Aged; Psoriasis; Regeneration; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Wound Healing; Young Adult

Pressure ulcers (PU) are wounds located mainly on bone surfaces where the tissue under pressure suffers ischemia leading to cellular lesion and necrosis , its causes and the healing process depend on several factors. The aim of this study was evaluating the gene expression of inflammatory/reparative factors: IL6, TNF, VEGF, and TGF, which take part in the tissue healing process under effects of low-level laser therapy (LLLT). In order to perform lesion area analysis, PUs were photographed and computer analyzed. Biochemical analysis was performed sa.mpling ulcer border tissue obtained through biopsy before and after laser therapy and quantitative real-time PCR (qRT-PCR) analysis. The study comprised eight individuals, mean age sixty-two years old, and sacroiliac and calcaneous PU, classified as degree III and IV according to the National Pressure Ulcer Advisory Panel (NPUAP). PUs were irradiated with low-level laser (InGaAIP, 100 mW, 660 nm), energy density 2 J/cm

Topics: Biomarkers; Diabetes Mellitus; Female; Gene Expression Regulation; Granulation Tissue; Humans; Inflammation; Interleukin-6; Low-Level Light Therapy; Male; Middle Aged; Pressure Ulcer; Real-Time Polymerase Chain Reaction; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Wound Healing

Inflammation affects tumor immune surveillance and resistance to therapy. Here, we show that production of IL1β in primary breast cancer tumors is linked with advanced disease and originates from tumor-infiltrating CD11c

Topics: Animals; Breast Neoplasms; Capecitabine; CD11c Antigen; Cell Line, Tumor; Cell Membrane; Female; Furans; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Ketones; Leukocytes, Mononuclear; Macrophages; Mice; Mice, SCID; Myeloid Cells; Neoplasm Metastasis; Neoplasm Transplantation; Paclitaxel; Pilot Projects; Transcription, Genetic; Transforming Growth Factor beta

Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease of central nervous system and recent studies show that inflammatory processes are highly associated with neurodegeneration in the brain. The purpose of this study was to investigate the effect of coenzyme Q10 supplementation on inflammatory and anti-inflammatory markers in patients with MS.. This randomized, double-blind, placebo-controlled clinical study was performed among 48 patients with relapsing-remitting MS. Subjects were randomly assigned to a placebo group (n = 24) or coenzyme Q10 (CoQ10)-supplemented group (500 mg/day, n = 24). The intervention was administered for 12 weeks. Peripheral blood samples were collected at baseline and after 12-week intervention, to measure inflammatory (tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and matrix metalloproteinase (MMP)-9) and anti-inflammatory (IL-4 and TGF-β) markers.. Forty-five patients completed the study. After 12 weeks of intervention, the TNF-α levels (P = 0.003) decreased significantly in the CoQ10 group. Subjects in the CoQ10 group had significantly lower IL-6 levels (P = 0.037), compared to the placebo group. CoQ10 supplementation also resulted in decreased serum levels of MMP-9 as compared to the placebo group (P = 0.011). However, CoQ10 supplementation did not alter the IL-4 and TGF-β levels (P = 0.16 and P = 0.81, respectively).. CoQ10 supplementation at a dosage of 500 mg appears to decrease the inflammatory markers (TNF-α, IL-6, and MMP-9) in patients with MS.

Topics: Adult; Biomarkers; Dietary Supplements; Double-Blind Method; Female; Humans; Inflammation; Interleukin-4; Interleukin-6; Male; Matrix Metalloproteinases; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Ubiquinone

Although histology data favour the view of a degenerative nature of tendinopathy, indirect support for inflammatory reactions to loading in affected tendons exists. The purpose of the present study was to elucidate whether inflammatory signalling responses after acute mechanical loading were more pronounced in tendinopathic versus healthy regions of human tendon and if treatment with non-steroidal anti-inflammatory medications (NSAID's) reduces this response. Twenty-seven tendinopathy patients (>6 months) were randomly assigned to a placebo (n = 14) or NSAID (Ibumetin NYCOMED GmbH Plant Oranienburg Germany (600 mg) × 3/day/1 week) group (n = 13) in a double-blinded-fashion. Tendon biopsies were taken from the painful and a healthy region of the same tendon 2 h after 1 h running. Gene-expression of several targets was analysed in the sampled Achilles tendon biopsies. The mRNA for TGF-β, collagen-I and collagen-III were significantly higher expressed, and decorin, CTGF, IL-6 and IL-10 were significantly lower expressed in the tendinopathic versus healthy tendon area. Only IL-10 was lower in expression in experiments with NSAID administration, while all other determined parameters were unaffected by NSAID. All ultrasonographic outcomes were unchanged in response to acute exercise and not influenced by NSAID. The signalling for collagen and TGF-beta was upregulated after acute loading in tendinopathic tendon. In contrast to the hypothesis, inflammatory signalling was not exaggerated in tendinopathic tendon 2 h after acute mechanical loading.

Topics: Achilles Tendon; Adult; Anti-Inflammatory Agents, Non-Steroidal; Collagen Type I; Collagen Type III; Connective Tissue Growth Factor; Decorin; Exercise; Female; Humans; Ibuprofen; Inflammation; Interleukin-10; Interleukin-6; Male; Middle Aged; Tendinopathy; Transcription, Genetic; Transforming Growth Factor beta; Ultrasonography

After anterior cruciate ligament (ACL) reconstruction, there is significant atrophy of the quadriceps muscles that can limit full recovery and place athletes at risk for recurrent injuries with return to play. The cause of this muscle atrophy is not fully understood.. Circulating levels of proatrophy, proinflammatory, and cartilage turnover cytokines and biomarkers would increase after ACL reconstruction.. Descriptive laboratory study.. Patients (N = 18; mean age, 28 ± 2.4 years) underwent surgical reconstruction of the ACL after a noncontact athletic injury. Circulating levels of biomarkers were measured along with Short Form-12, International Knee Documentation Committee, and objective knee strength measures preoperatively and at 6 postoperative visits. Differences were tested using repeated-measures 1-way analysis of variance.. Myostatin, TGF-β, and C-reactive protein levels were significantly increased in the early postoperative period and returned to baseline. Cartilage oligomeric matrix protein levels decreased immediately after surgery and then returned to baseline. CCL2, CCL3, CCL4, CCL5, EGF, FGF-2, IGF-1, IL-10, IL-1α, IL-1β, IL-1ra, IL-6, myoglobin, and TNF-α were not different over the course of the study.. An increase in potent atrophy-inducing cytokines and corresponding changes in knee strength and functional scores were observed after ACL reconstruction.. Although further studies are necessary, the therapeutic inhibition of myostatin may help prevent the muscle atrophy that occurs after ACL reconstruction and provide an accelerated return of patients to sport.

Topics: Adolescent; Adult; Anterior Cruciate Ligament Injuries; Anterior Cruciate Ligament Reconstruction; Biomarkers; C-Reactive Protein; Cartilage Oligomeric Matrix Protein; Chondrogenesis; Cytokines; Extracellular Matrix Proteins; Female; Follow-Up Studies; Glycoproteins; Humans; Inflammation; Insulin-Like Growth Factor I; Knee Injuries; Male; Matrilin Proteins; Middle Aged; Muscular Atrophy; Myostatin; Postoperative Complications; Postoperative Period; Preoperative Period; Transforming Growth Factor beta; Treatment Outcome; Young Adult

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by both a chronic inflammation and tissue remodelling; as indicated by extracellular matrix protein deposition, basement membrane thickening, goblet cell hyperplasia and subepithelial edema, with reduced vessels and glands. Although remodelling is generally considered to be consequence of persistent inflammation, the chronological order and relationship between inflammation and remodelling in polyp development is still not clear. The aim of our study was therefore to investigate the pathological features prevalent in the development of nasal polyps and to elucidate the chronological order and relationship between inflammation and remodelling, by comparing specific markers of inflammation and remodelling in early stage nasal polyps confined to the middle turbinate (refer to as middle turbinate CRSwNP) obtained from 5 CRSwNP patients with bilateral polyposis, mature ethmoidal polyps from 6 CRSwNP patients, and normal nasal mucosal tissue from 6 control subjects. Middle turbinate CRSwNP demonstrated significantly more severe epithelial loss compared to mature ethmoidal polyps and normal nasal mucosa. The epithelial cell junction molecules E-cadherin, ZO-1 and occludin were also expressed in significantly lower amounts in mature ethmoidal polyps compared to healthy mucosa. Middle turbinate CRSwNP were further characterized by significantly increased numbers of subepithelial eosinophils and M2 type macrophages, with a distinct lack of collagen and deposition of fibronectin in polyp part. In contrast, the turbinate area of the middle turbinate CRSwNP was characterized by an increase in TGF-β activated myofibroblasts expressing α-SMA and vimentin, an increase in the number of pSmad2 positive cells, as well as increased deposition of collagen. These findings suggest a complex network of processes in the formation of CRSwNP; including gross epithelial damage and repair reactions, eosinophil and macrophage cell infiltration, and tissue remodelling. Furthermore, remodelling appears to occur in parallel, rather than subsequent to inflammation.

Topics: Adult; Biomarkers; Cadherins; Collagen; Female; Humans; Inflammation; Macrophages; Male; Nasal Mucosa; Nasal Polyps; Smad2 Protein; Transforming Growth Factor beta; Vimentin; Zonula Occludens-1 Protein

Flavanol-rich lychee fruit extract (FRLFE) is a processed lychee fruit extract that is higher in flavanols (monomers, dimers and trimers) than its unprocessed counterpart. FRLFE exerts antioxidant activities in vitro and is expected to protect against inflammation and tissue damage. However, the physiological effects of FRLFE intake have not been explored in vivo. The aim of this study was to examine the effects of FRLFE supplementation on inflammation and tissue damage in young athletes during intense physical training. Twenty healthy male long-distance runners at a university were randomly assigned to receive FRLFE or placebo in a double-blind manner. Blood and serum parameters associated with inflammation, tissue damage and oxidative stress were evaluated before (pre-training), during (mid-training) and after (post-training) a 2-month training period. Some parameters, including the white blood cell count, were significantly modified by FRLFE supplementation. Compared with the placebo group, the change in the serum interleukin-6 level between pre- and mid-training were significantly lower in the FRLFE group, while the change in the transforming growth factor-β level between pre- and post-training was significantly greater in the FRLFE group. These findings suggest that FRLFE supplementation may suppress inflammation or tissue damage caused by high-intensity exercise training.

Topics: Adult; Anti-Inflammatory Agents; Dietary Supplements; Double-Blind Method; Flavonoids; Fruit; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Leukocyte Count; Leukocytes; Litchi; Male; Physical Education and Training; Phytotherapy; Plant Extracts; Running; Transforming Growth Factor beta; Young Adult

The aim of the study was to analyze the acute inflammatory response after implantation of a heavyweight mesh of polypropylene (PP) compared with a composite mesh of light PP and polyglactin 910 (PG) in patients undergoing inguinal hernioplasty. A total of 30 male patients with inguinal hernia were included in the study and divided into 2 groups (PP and PP-PG) according to the mesh used. Changes of leukocytes, cytokines, growth factors, and acute phase proteins were evaluated in the sera. Leukocytes and acute phase proteins were significantly increased postoperatively in both groups, and the values were slightly higher in the PP group. Cytokine levels were significantly increased postoperatively in both groups; a slight increase was observed in the PP-PG group, especially for the proinflammatory cytokine. Growth factors decreased significantly in both groups immediately after surgery. The authors found that the use of the mesh is a stimulator of inflammatory response, and the 2 types of mesh induce a similar inflammatory response.

Topics: Adult; Aged; Biocompatible Materials; C-Reactive Protein; Fibroblast Growth Factors; Hernia, Inguinal; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-6; Male; Middle Aged; Polyglactin 910; Polypropylenes; Surgical Mesh; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Bacillus clausii has been demonstrated to exert some immunomodulatory activities and to be safe. Allergic subjetcs show Th2 polarization and defect of T regulatory cells. Aim of the study was to investigate whether Bacillus clausii administration in allergic subjects might modulate cytokine pattern. Ten subjects (mean age 22.3 years) suffering from allergic rhinitis were enrolled. Bacillus clausii spores (Enterogermina: 2 billions spores/vial) were administered at the dosage schedule of 3 vials a day for 4 weeks. Nasal lavage was performed in all subjects before and after the treatment. A panel of cytokines, including IL4, IL10, IFNgamma, and TGFbeta, was measured by immunoassay in the fluid recovered from nasal lavage, before and after the treatment.. Bacillus clausii treatment showed a significant decrease of IL4 levels (p=0.004) and a significant increase of IFNgamma (p=0.038), TGFbeta (p=0.039), and IL10 (p=0.009) levels. In conclusion, this study shows that the Bacillus clausii may exert immuno-modulating activity by affecting cytokine pattern in allergic subjects and confirms previous study conducted in allergic children.

Topics: Adolescent; Adult; Bacillus; Body Fluids; Cytokines; Female; Humans; Immunologic Factors; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-4; Intestinal Mucosa; Male; Models, Immunological; Nasal Cavity; Pilot Projects; Probiotics; Rhinitis, Allergic, Perennial; Single-Blind Method; Spores, Bacterial; Th2 Cells; Therapeutic Irrigation; Transforming Growth Factor beta

Treatment of hypertrophic scars can be difficult for both patients and physicians. Silicone-containing gel dressings have been reported to be an effective alternative treatment for hypertrophic scars, yet the mechanism of action of these dressings is unknown.. To determine whether silicone is an essential factor in the treatment of hypertrophic scars and investigate the effects of occlusive dressing therapy on the expression of key wound healing mediators.. A pilot paired comparison, nonrandomized study was conducted comparing a silicone gel sheeting (Silastic [SGS]) with a hydrogel dressing (ClearSite). The effects of the dressings were compared side by side in the treatment of 15 hypertrophic scars at both the clinical and molecular levels through the use of reverse transcriptase/polymerase chain reaction to evaluate effects on the expression of interleukin 8 (IL-8), basic fibroblast growth factor (bFGF), granulocyte-macrophage colony-stimulating factor (GMCSF), epidermal growth factor (EGF), transforming growth factor beta (TGF-beta), and fibronectin.. Comparable clinical improvement of the hypertrophic scars was obtained with both dressings. Treatment of hypertrophic scars resulted in increased mean levels of IL-8, bFGF, and GMCSF mRNA; while mean TGF beta and fibronectin mRNAs decreased after treatment with both dressings. Comparison between the two dressings revealed significant changes in IL-8 and fibronectin mRNA levels after treatment with ClearSite, while only fibronectin changes were significant after treatment with SGS with respect to normal skin. Only ClearSite induced significant changes in IL-8 and bFGF levels when untreated scars were compared with posttreatment lesions, suggesting that the hydrogel augments collagenolysis via promotion of inflammation.. This study demonstrates that silicone is not a necessary component of occlusive dressings in the treatment of hypertrophic scars. The pathogenesis of hypertrophic scars is further elucidated by demonstrating that there is molecular evidence for extensive connective tissue remodeling occurring during occlusive dressing therapy.

Topics: Adult; Aged; Cicatrix, Hypertrophic; Collagen; Connective Tissue; Cytokines; Epidermal Growth Factor; Fibroblast Growth Factor 2; Fibronectins; Gels; Gene Expression Regulation; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Inflammation; Interleukin-8; Middle Aged; Occlusive Dressings; Pilot Projects; Polyethylene Glycols; Polymerase Chain Reaction; Polyurethanes; RNA, Messenger; Silicone Elastomers; Silicones; Skin; Transforming Growth Factor beta; Wound Healing

We investigated the effect of propofol (0.5, 5, and 50 μM) on the gene expression of inflammatory cytokines [ IL-1β , IL-6 , transforming growth factor β ( TGF-β ), and LIF ] and apoptosis process ( BCL-2 and Bax ) in corneal activated keratocytes (CAKs).. CAKs (10 6 cells/10 cm 2 ) were exposed to propofol at a concentration of 0.5, 5, and 50 μM for 24 hours at 37°C. The control group did not receive propofol at the same time or under the same condition. Ribonucleic acid (RNA) extraction, complementary DNA (cDNA) synthesis, and real-time polymerase chain reaction (PCR) were performed to quantify the relative expression of IL-1β , IL-6 , TGF-β , LIF , BCL-2 , and Bax expression in the treated versus control cells.. The results of this study showed that propofol treatment (0.5 and 5 μM) led to the downregulation of IL-1β and IL-6 gene expression in CAKs. TGF-β (with a role in fibrogenesis) was not changed in 0.5 and 5 μM propofol-treated CAKs, whereas CAKs treated with 50 μM propofol showed upregulation of the TGF-β gene. LIF (with a role in regeneration) was upregulated in 0.5 and 5 μM propofol-treated CAKs. The BCL-2/Bax ratio (as the antiapoptosis index) was increased in CAKs treated with 0.5 μM propofol and indicated the induction of an antiapoptotic effect.. We showed that CAKs treatment with propofol, at concentrations of 0.5 and 5 μM, could decrease the expression of genes related to inflammation and enhance the genes associated with cell regeneration. While 50 μM propofol treatment might induce CAK fibrogenesis. This proof-of-concept study could preserve a groundwork for future drug design for the treatment of corneal stromal diseases and ocular regenerative medicine.

Topics: Apoptosis; bcl-2-Associated X Protein; Cells, Cultured; Corneal Keratocytes; Humans; Inflammation; Interleukin-6; Propofol; Proto-Oncogene Proteins c-bcl-2; Transforming Growth Factor beta

Pulmonary injury and fibrosis can be caused by various factors because of their inflammatory nature, both can lead to serious clinical consequences. Inula japonica Thunb. is used in traditional Chinese medicine for the treatment of lung diseases. However, the effect and mechanism of action of the essential oil of I. japonica (EOI) on pulmonary injury and fibrosis are not well understood.. To investigate the therapeutic effects of EOI on mice with bleomycin (BLM)-induced acute pulmonary injury and chronic fibrosis formation, as well as its potential mechanism.. A short-term mouse model of pulmonary injury was established by intratracheal injection of BLM to investigate the anti-inflammatory effect of EOI, and a long-term model of pulmonary fibrosis was used to explore the anti-fibrosis effect of EOI. High-dose EOI (200 mg/kg) was administered intragastrically, and low-dose (50 mg/kg) was administered by intratracheal injection. Gas chromatography-mass spectrometry (GC-MS) was used to identify the ingredients in EOI, and high-performance liquid chromatography (HPLC) was performed for the preparation of EOI compounds. Western blot and real-time qPCR were used to verify the effects of EOI and its active composition on inflammation, oxidative stress and fibrosis signaling pathway.. Treatment with EOI significantly reduced the inflammation and oxidative stress by reducing the levels of inflammatory and oxidative cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and malondialdehyde in BLM-treated mice with acute pulmonary injury. EOI treatment could also suppress the formation of fibrous tissue in mice with BLM-induced pulmonary fibrosis through inhibiting TGF-β/Smad and PI3K/Akt pathways. Chromatographic analysis and preparation suggested that fatty acid and phenol derivatives are present in EOI. Based on cellular inflammation and fibrosis models, the phenolic compounds in EOI can represent the anti-inflammatory and anti-fibrotic effects of EOI by regulating pro-inflammatory and pro-fibrotic cytokines such as NO, TNF-α, IL-6, TGF-β1, and α-SMA.. EOI ameliorated BLM-induced pulmonary injury and fibrosis in mice by inhibiting the inflammatory response and regulating the redox equilibrium, as well as by mediating TGFβ/Smad and PI3K/Akt, which suggested that EOI has potential to treat pulmonary diseases.

Topics: Animals; Anti-Inflammatory Agents; Bleomycin; Cytokines; Fibrosis; Inflammation; Interleukin-6; Inula; Lung; Lung Injury; Mice; Oils, Volatile; Phenols; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pulmonary Fibrosis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The mechanism by which neutrophil extracellular traps (NETs) may cause intestinal barrier dysfunction in response to trauma/hemorrhagic shock (T/HS) remains unclear. In this study, the roles and mechanisms of NETs in macrophage polarization were examined to determine whether this process plays a role in tissue damage associated with T/HS. Rat models of T/HS and macrophage polarization were developed and the levels of NETs formation in the intestinal tissue of T/HS rats were assessed. NET formation was inhibited in models of T/HS to examine the effect on intestinal inflammation and barrier injury. The proportions of pro-inflammatory and anti-inflammatory macrophages in the damaged intestinal tissues were measured. Finally, high-throughput sequencing was performed to investigate the underlying mechanisms involved in this process. The study revealed that the level of NETs formation was increased and that inhibition of NETs formation alleviated the intestinal inflammation and barrier injury. Moreover, the number of pro-inflammatory macrophages increased and the number of anti-inflammatory macrophages decreased. RNA sequencing analysis indicated that NETs formation decreased the expression of transforming growth factor-beta receptor 2 (TGFBR2), bioinformatic analyses revealed that TGFBR2 was significantly enriched in the transforming growth factor-beta (TGF-β) signaling pathway. Verification experiments showed that NETs impeded macrophage differentiation into the anti-inflammatory/M2 phenotype and inhibited TGFBR2 and TGF-β expression in macrophages. However, treatment with DNase I and overexpression of TGFBR2, and inhibition of TGF-β promoted and prevented this process, respectively. NETs may regulate the macrophage polarization process by promoting intestinal barrier dysfunction in T/HS rats through the TGFBR2-mediated TGF-β signaling pathway.

Topics: Animals; Anti-Inflammatory Agents; Extracellular Traps; Inflammation; Macrophages; Rats; Receptor, Transforming Growth Factor-beta Type II; Shock, Hemorrhagic; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factors

This study aimed at exploring the expression level of LTBP1 in the mouse model of epilepsy. The mechanism of LTBP1 in epileptic cerebral neural stem cells was deeply investigated to control the occurrence of epilepsy with neuroprotection.. qRT-PCR was conducted for the expression levels of LTBP1 in clinical human epileptic tissues and neural stem cells, as well as normal cerebral tissues and neural stem cells. The mouse model of postischemic stroke epilepsy (PSE) was established by the middle cerebral artery occlusion (MCAO). Then, qRT-PCR was conducted again for the expression levels of LTBP1 in mouse epileptic tissues and neural stem cells as well as normal cerebral tissues and neural stem cells. The activation and inhibitory vectors of LTBP1 were constructed to detect the effects of LTBP1 on the proliferation of cerebral neural stem cells in the PSE model combined with CCK-8. Finally, Western blot was conducted for the specific mechanism of LTBP1 affecting the development of epileptic cells.. Racine score and epilepsy index of 15 mice showed epilepsy symptoms after the determination with MCAO, showing a successful establishment of the PSE model. LTBP1 expression in both diseased epileptic tissues and cells was higher than that in normal clinical epileptic tissues and cells. Meanwhile, qRT-PCR showed higher LTBP1 expression in both mouse epileptic tissues and their neural stem cells compared to that in normal tissues and cells. CCK-8 showed that the activation of LTBP1 stimulated the increased proliferative capacity of epileptic cells, while the inhibition of LTBP1 expression controlled the proliferation of epileptic cells. Western blot showed an elevated expression of TGFβ/SMAD signaling pathway-associated protein SMAD1/5/8 after activating LTBP1. The expression of molecular MMP-13 associated with the occurrence of inflammation was also activated.. LTBP1 can affect the changes in inflammation-related pathways by activating the TGFβ/SMAD signaling pathway and stimulate the development of epilepsy, and the inhibition of LTBP1 expression can control the occurrence of epilepsy with neuroprotection.

Topics: Animals; Cerebral Cortex; Disease Models, Animal; Epilepsy; Gene Expression; Humans; Inflammation; Latent TGF-beta Binding Proteins; Mice; Neuroprotection; Sincalide; Stroke; Transforming Growth Factor beta

After myocardial infarction (MI), cardiac cells work together to regulate wound healing of the infarct. The pathological response to MI yields cardiac remodelling comprising inflammatory and fibrosis phases, and the interplay of cellular dynamics that underlies these phases has not been elucidated. This study developed a computational model to identify cytokine and cellular dynamics post-MI to predict mechanisms driving post-MI inflammation, resolution of inflammation, and scar formation. Additionally, this study evaluated the interdependence between inflammation and fibrosis. Our model bypassed limitations of in vivo approaches in achieving cellular specificity and performing specific perturbations such as global knockouts of chemical factors. The model predicted that inflammation is a graded response to initial infarct size that is amplified by a positive feedback loop between neutrophils and interleukin 1β (IL-1β). Resolution of inflammation was driven by degradation of IL-1β, matrix metalloproteinase 9, and transforming growth factor β (TGF-β), as well as apoptosis of neutrophils. Inflammation regulated TGFβ secretion directly through immune cell recruitment and indirectly through upregulation of macrophage phagocytosis. Lastly, we found that mature collagen deposition was an ultrasensitive switch in response to inflammation, which was amplified primarily by cardiac fibroblast proliferation. These findings describe the relationship between inflammation and fibrosis and highlight how the two responses work together post-MI. This model revealed that post-MI inflammation and fibrosis are dynamically coupled, which provides rationale for designing novel anti-inflammatory, pro-resolving or anti-fibrotic therapies that may improve the response to MI. KEY POINTS: Inflammation and matrix remodelling are two processes involved in wound healing after a heart attack. Cardiac cells work together to facilitate these processes; this is done by secreting cytokines that then regulate the cells themselves or other cells surrounding them. This study developed a computational model of the dynamics of cardiac cells and cytokines to predict mechanisms through which inflammation and matrix remodelling is regulated. We show the roles of various cytokines and signalling motifs in driving inflammation, resolution of inflammation and fibrosis. The novel concept of inflammation-fibrosis coupling, based on the model prediction that inflammation and fibrosis are dynamically coupl

Topics: Animals; Cytokines; Fibrosis; Heart; Inflammation; Mice; Mice, Inbred C57BL; Myocardial Infarction; Transforming Growth Factor beta; Ventricular Remodeling

Topics: HIV Infections; Humans; Inflammation; Phosphorylation; Signal Transduction; Smad2 Protein; T-Lymphocytes; Transforming Growth Factor beta

Topics: Antigens, CD; Asthma; Dendritic Cells; GPI-Linked Proteins; Humans; Hypersensitivity; Inflammation; Neoplasm Proteins; Transforming Growth Factor beta

Topics: Animals; Brain-Derived Neurotrophic Factor; Calcitriol; Choroid Plexus; Inflammation; Lupus Erythematosus, Systemic; Mice; Mice, Inbred MRL lpr; NF-kappa B; PPAR gamma; Smad Proteins; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Patients suffering from inflammatory bowel diseases (IBDs) express increased mucosal levels of transforming growth factor (TGF)-β compared with non-IBD controls. SMAD7 negatively regulates TGF-β signaling. An earlier study aiming to target Smad7 showed a lack of clinical benefit. It remains unknown whether inhibition of SMAD7 is beneficial in specific settings of IBD. We evaluated the effect of Smad7 deficiency on inflammation, fibrogenesis, and wound healing.. For the initiation of fibrosis in Smad7-/- (Smad7Δex-I) CD-1 mice, the dextran sodium sulfate-induced chronic colitis model and the heterotopic transplantation model of fibrosis were used. Wound closure of fibroblasts from Smad7-/- mice was determined using culture inserts and electric cell-substrate impedance sensing in vitro.. In dextran sodium sulfate-induced chronic colitis, Smad7 deficiency was associated with ameliorated inflammation, as evidenced by decreased clinical score, histological score, and myeloperoxidase activity. Absence of SMAD7 decreased T-cell accumulation in colonic tissue and tumor necrosis factor (TNF) mRNA expression levels. Smad7-/- mice showed a significant increase in hydroxyproline and collagen content, as well as ColIVa1 mRNA expression. Wild type mice transplanted with terminal ileum from Smad7-/- mice in the heterotopic animal model for intestinal fibrosis showed a significant increase in collagen content and protein expression of α-smooth muscle actin.. Smad7 deficiency is associated with a decrease in intestinal inflammation and an increase in fibrosis. Targeting SMAD7 constitutes a potential new treatment option for IBD; progression of disease-associated fibrosis should be considered.. We evaluated the effect of Smad7 deficiency on inflammation and fibrogenesis. Smad7 deficiency was associated with ameliorated inflammation and increased collagen deposition. When targeting Smad7 as therapeutic strategy in IBD, potential initiation or aggravation of fibrosis should be considered.

Topics: Animals; Colitis; Collagen; Dextrans; Fibrosis; Inflammation; Mice; Mice, Inbred C57BL; RNA, Messenger; Smad7 Protein; Transforming Growth Factor beta

Our study aimed to elucidate the correlation of macrophage (mø) with the inflammatory reaction in ulcerative colitis (UC) and the influence of curcumin (Cur) on mø chemotaxis in mice with UC.. A total of 49 patients with UC (research group; RG) admitted between June 2020 and October 2021 and 56 healthy individuals (control group; CG) who visited concurrently were selected as the study participants. The peripheral blood mononuclear cells (PBMCs) were analyzed, and M1-type/M2-type mø and inflammatory factors (IFs) interleukin (IL)-1, IL-6, IL-10, tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β) were detected. In addition, 15 BALB/c mice were purchased and divided into the normal group fed normally, the UC model group established with sodium dextran sulfate (DSS) and the Cur group induced by DSS + Cur feeding. Colon tissue mø was collected from mice to measure mø activity via CCK-8 and to quantify levels of IFs and chemokine CCL2 by polymer chain reaction (PCR)c and Western blotting.. The RG had a higher percentage of peripheral blood M1-type mø and a lower percentage of M2-type mø and M1/M2 mø ratio than the CG (P < .05). In the RG, IL-1, IL-6 and TNF-α all increased and were inversely correlated with the ratio of M1/M2 mø, while IL-10 and TGF-β decreased, with a positive connection with the M1/M2 mø ratio. In the UC model mice, mø activity increased, but the apoptosis rate decreased. mø activity was lower in the Cur group than in the model and normal groups; mø apoptosis in the Cur group was higher than in the model group but lower than in the normal group. In addition, proIFs increased and anti-IFs decreased in the model group, and Cur also ameliorated this process. Finally, CCL2 and MCP-1 levels in the model group were also increased, while those in the Cur group were lower compared with the model group.. In UC, the M1/M2 mø ratio is severely misadjusted, activation of M1-type mø is enhanced and pro-IFs are released in large quantities. Cur can ameliorate the abnormal activation of mø in mice with UC, inhibit mø chemotaxis and alleviate the inflammatory reaction, which may make it a new option for UC treatment in the future.

Topics: Animals; Chemotaxis; Colitis, Ulcerative; Curcumin; Disease Models, Animal; Inflammation; Interleukin-10; Interleukin-6; Leukocytes, Mononuclear; Macrophages; Mice; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Tuberculosis (TB) disease is usually marked by inflammation which is closely linked to haemostasis both in health and disease. Close monitoring of haemostatic response to inflammatory changes during treatment is important to improve TB management. Here we studied associations between haemostatic markers and inflammatory cytokines in 60 TB-infected individuals, aged 18-65 years who received anti-TB therapy. They were recruited before commencement of therapy and followed up till completion of therapy after 6-months. The TNF-α, IL-6, IL-2 (pro-inflammatory cytokines) and P-selectin, GP IIb/IIIa, thrombopoietin (haemostatic variables) were significantly increased at 2 month into therapy compared to pre-treatment values and decreased at 6 month into therapy. Also at 6 month into therapy in comparison to 2-month into therapy, there were significant increase in IL-10 and TGF-β (anti-inflammatory cytokines) as well as a significant decline in PF-4. There were significant positive correlations between GP IIb/IIIa and TNF-α, IL-6 and PSEL, IL-6 and TPO, PF4 and TGF-β. Conclusively, the changes in the TNF-α, IL-6, IL-2 aligned with changes in the levels of P-selectin, GP IIb/IIIa, and TPO in the course of TB therapy. This may suggest that the levels of inflammatory cytokines are linked to the levels of these haemostatic variables in TB individuals.

Topics: Cytokines; Hemostasis; Hemostatics; Humans; Inflammation; Interleukin-2; Interleukin-6; Mycobacterium tuberculosis; P-Selectin; Platelet Membrane Glycoprotein IIb; Transforming Growth Factor beta; Tuberculosis; Tuberculosis, Pulmonary; Tumor Necrosis Factor-alpha

To determine the changes of Porphyromonas gingivalis (P. gingivalis) growth and metabolism and identify whether the vascular epithelium change could be induced in diabetic periodontitis.. Maintaining favourable vascular function is a precondition for periodontal regeneration. In diabetic periodontitis, high glucose levels could enhance the metabolism of pathogens, and a complex condition involving inflammation and high glucose levels would disrupt homeostasis of the epithelium and promote fibrosis by endothelial-to-mesenchymal transition (EndMT).. Porphyromonas gingivalis was cultured with glucose to judge its metabolic activity. Human umbilical vein endothelial cells (HUVECs) were treated with P. gingivalis-lipopolysaccharide (LPS) (10 μg/ml) and/or high glucose concentrations (25 mM), and transforming growth factor (TGF)-β inhibitor was used to block EndMT. Inflammation level was assessed by flow cytometry. Multiple biological functions including EndMT, angiopoiesis, and cell migration were analysed. Additionally, gene expressions and protein levels were determined with qPCR and western blot, respectively. Finally, blood vessels were cultured ex vivo, and EndMT and fibrosis markers were detected by immunohistochemistry.. Glucose could promote P. gingivalis growth and biofilm formation as well as the expression of virulence factor genes including FimA, RgpA, RgpB, and Kgp. P. gingivalis-LPS and glucose could increase intracellular reactive oxygen species (ROS) and promote fibrosis via EndMT in HUVECs, along with attenuating angiopoiesis and cell migration, which could be resumed by blocking EndMT with TGF-β inhibitor. Vascular fibrosis was observed after the addition of glucose via EndMT regulation.. Glucose augmented the growth and metabolism of P. gingivalis and promoted fibrosis by the activation of EndMT, as well as the inhibition of angiopoiesis and cell migration.

Topics: Cells, Cultured; Fibrosis; Glucose; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Lipopolysaccharides; Periodontitis; Signal Transduction; Transforming Growth Factor beta

Microglial activation is a key event in neuroinflammation, which, in turn, is a central process in neurological disorders. In this study, we investigated the protective effects of D-beta-hydroxybutyrate (BHB) against microglial activation in lipopolysaccharide (LPS)-treated mice and BV-2 cells. The effects of BHB in mice were assessed using behavioral testing, morphological analysis and immunofluorescence labeling for the microglial marker ionizing calcium-binding adaptor molecule 1 (IBA-1) and the inflammatory cytokine interleukin-6 (IL-6) in the hippocampus. Moreover, we examined the levels of the inflammatory IL-6 and tumor necrosis factor-α (TNF-α), as well as those of the neuroprotective brain-derived neurotrophic factor (BDNF) and transforming growth factor-β (TGF-β) in the brain. In addition, we examined the effects of BHB on IL-6, TNF-α, BDNF, TGF-β, reactive oxygen species (ROS) level and cell viability in LPS-stimulated BV-2 cells. BHB treatments attenuated behavioral abnormalities, reduced the number of IBA-1-positive cells and the intensity of IL-6 fluorescence in the hippocampus, with amelioration of microglia morphological changes in the LPS-treated mice. Furthermore, BHB inhibited IL-6 and TNF-α generation, but promoted BDNF and TGF-β production in the brain of LPS-treated mice. In vitro, BHB inhibited IL-6 and TNF-α generation, increased BDNF and TGF-β production, reduced ROS level, ameliorated morphological changes and elevated cell viability of LPS-stimulated BV-2 cells. Together, our findings suggest that BHB exerts protective effects against microglial activation in vitro and in vivo, thereby reducing neuroinflammation.

Topics: 3-Hydroxybutyric Acid; Animals; Brain-Derived Neurotrophic Factor; Inflammation; Interleukin-6; Lipopolysaccharides; Mice; Microglia; Neuroinflammatory Diseases; Reactive Oxygen Species; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Idiopathic pulmonary fibrosis is a terminal lung ailment that shares several pathological and genetic mechanisms with severe COVID-19. Thymol (THY) is a dietary compound found in thyme species that showed therapeutic effects against various diseases. However, the effect of THY against bleomycin (BLM)-induced lung fibrosis was not previously investigated. The current study investigated the ability of THY to modulate oxidative stress, inflammation, miR-29a/TGF-β expression, and PI3K/phospho-Akt signaling in lung fibrosis. Mice were divided into Normal, THY (100 mg/kg, p.o.), BLM (15 mg/kg, i.p.), BLM + THY (50 mg/kg, p.o.), and BLM + THY (100 mg/kg, p.o.) groups and treated for four weeks. The obtained results showed that BLM + THY (50 mg/kg) and BLM + THY (100 mg/kg) reduced fibrotic markers; α-SMA and fibronectin, inflammatory mediators; TNF-α, IL-1β, IL-6, and NF-kB and oxidative stress biomarkers; MDA, GSH, and SOD, relative to BLM group. Lung histopathological examination by H&E and Masson's trichrome stains confirmed the obtained results. Remarkably, expression levels of TGF-β, PI3K, and phospho-Akt were decreased while miR-29a expression was elevated. In conclusion, THY effectively prevented BLM-induced pulmonary fibrosis by exerting significant anti-oxidant and anti-inflammatory effects. Our novel findings that THY upregulated lung miR-29a expression while decreased TGF-β and PI3K/Akt signaling are worthy of further investigation as a possible molecular mechanism for THY's anti-fibrotic actions.

Topics: Animals; Bleomycin; COVID-19; Fibrosis; Inflammation; Lung; Mice; MicroRNAs; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pulmonary Fibrosis; Thymol; Transforming Growth Factor beta

This study aimed to assess levels of biomarkers associated with inflammation and tissue destruction in peri-implant crevicular fluid (PICF) of implants provided with customized or standard healing abutments during early implant healing.. Thirty implants were placed in 22 patients with partial posterior edentulism. Subsequently, test group implants (n=15) received one-piece titanium abutments that were fabricated using computer-aided design/computer-aided manufacturing (CAD/CAM). Control group implants (n=15) were provided with standard abutments. PICF collection and standardized periapical radiographs were carried out at suture removal one week later, following crown delivery after 3 months and at 6 months. Expression of C-reactive protein (CRP), interferon-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12A, IL-17A, macrophage inflammatory protein (MIP)-1α, matrix metalloproteinase (MMP)-13, osteopontin, osteoactivin, Receptor Activator of NF-κB (RANK), and TGF-β were analyzed using a multiplex ELISA kit.. Both groups showed a significant decrease in protein expression of CRP, IL-1β, IL-6, IL-8, MIP-1α, osteopontin, osteoactivin, and TGF-β, while MMP-13 levels increased during the observation period. A rise in OPG and RANK levels was detected among customized abutments. Expression of CRP was higher, whereas IL-1β, IL-1α, and MIP-1α were decreased in control compared to test group implants after 6 months. Marginal bone loss did not depend on abutment modality.. Both abutment types showed distinctive temporal expression of inflammatory biomarkers during 6 months following implant placement.. ISRCTN98477184, registration date 18/05/2022 CLINICAL RELEVANCE: Customized healing abutments exert similar effects on inflammation during early implant healing compared to standard healing abutments.

Topics: Chemokine CCL3; Computer-Aided Design; Dental Abutments; Dental Implants; Humans; Inflammation; Interleukin-1alpha; Interleukin-6; Interleukin-8; Osteopontin; Pilot Projects; Titanium; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Pathological conditions associated with dysfunctional wound healing are characterized by impaired remodelling of extracellular matrix (ECM), increased macrophage infiltration, and chronic inflammation. Macrophages also play an important role in wound healing as they drive wound closure by secretion of molecules like transforming growth factor beta-1 (TGF-β). As the functions of macrophages are regulated by their metabolism, local administration of small molecules that alter this might be a novel approach for treatment of wound-healing disorders. Itaconate is a tricarboxylic acid (TCA) cycle-derived metabolite that has been associated with resolution of macrophage-mediated inflammation. However, its effects on macrophage wound healing functions are unknown. In this study, we investigated the effects of the membrane-permeable 4-octyl itaconate (4-OI) derivative on ECM scavenging by cultured human blood monocyte-derived macrophages (hMDM). We found that 4-OI reduced signalling of p38 mitogen-activated protein kinase (MAPK) induced by the canonical immune stimulus lipopolysaccharide (LPS). Likely as a consequence of this, the production of the inflammatory mediators like tumor necrosis factor (TNF)-α and cyclooxygenase (COX)-2 were also reduced. On the transcriptional level, 4-OI increased expression of the gene coding for TGF-β (TGFB1), whereas expression of the collagenase matrix metalloprotease-8 (MMP8) was reduced. Furthermore, surface levels of the anti-inflammatory marker CD36, but not CD206 and CD11c, were increased in these cells. To directly investigate the effect of 4-OI on scavenging of ECM by macrophages, we developed an assay to measure uptake of fibrous collagen. We observed that LPS promoted collagen uptake and that this was reversed by 4-OI-induced signaling of nuclear factor erythroid 2-related factor 2 (NRF2), a regulator of cellular resistance to oxidative stress and the reduced glycolytic capacity of the macrophage. These results indicate that 4-OI lowers macrophage inflammation, likely promoting a more wound-resolving phenotype.

Topics: Collagen; Cyclooxygenase 2; Humans; Inflammation; Lipopolysaccharides; Macrophages; Phenotype; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Chronic hyperammonemia, a main contributor to hepatic encephalopathy (HE), leads to neuroinflammation which alters neurotransmission leading to cognitive impairment. There are no specific treatments for the neurological alterations in HE. Extracellular vesicles (EVs) from mesenchymal stem cells (MSCs) reduce neuroinflammation in some pathological conditions. The aims were to assess if treatment of hyperammonemic rats with EVs from MSCs restores cognitive function and analyze the underlying mechanisms. EVs injected in vivo reach the hippocampus and restore performance of hyperammonemic rats in object location, object recognition, short-term memory in the Y-maze and reference memory in the radial maze. Hyperammonemic rats show reduced TGFβ levels and membrane expression of TGFβ receptors in hippocampus. This leads to microglia activation and reduced Smad7-IkB pathway, which induces NF-κB nuclear translocation in neurons, increasing IL-1β which alters AMPA and NMDA receptors membrane expression, leading to cognitive impairment. These effects are reversed by TGFβ in the EVs from MSCs, which activates TGFβ receptors, reducing microglia activation and NF-κB nuclear translocation in neurons by normalizing the Smad7-IkB pathway. This normalizes IL-1β, AMPA and NMDA receptors membrane expression and, therefore, cognitive function. EVs from MSCs may be useful to improve cognitive function in patients with hyperammonemia and minimal HE.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Cognition; Extracellular Vesicles; Hippocampus; Hyperammonemia; Inflammation; Mesenchymal Stem Cells; Neuroinflammatory Diseases; NF-kappa B; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Transforming Growth Factor beta

Septic arthritis is a joint disease caused by Staphylococcus aureus. Different macrophage populations contribute in various ways to control blood-borne infections and induce inflammatory responses. Macrophage tissue-resident niche is necessary for the suppression of chronic inflammation and may contribute to the pathogenesis of septic arthritis. Thus, to obtain a resolution of the disease and restoration of synovial homeostasis, it needs the activation of macrophages that further regulate the inflammatory consequences. The aim of this study was to find out the mechanism by which neutralization of transforming growth factor-beta (TGF-β) and/or interleukin (IL)-6 after induction of septic arthritis could alter the specific macrophage responses in spleen and synovial joints via different cytokines (osteoprotegerin (OPG), osteopontin (OPN), IL-10, IL-12 and CXCL8) cross-talking, and how the response could be modulated by reactive oxygen species vs antioxidant enzyme activities. Dual neutralization of TGF-β and IL-6 is notably effective in eliciting splenic and synovial tissue-resident macrophage responses. Synovial macrophage-derived IL-10 can elicit protection against septic arthritis via regulating receptor-activated nuclear factor Kappa-B ligand (RANKL)/OPG interaction. They also reduced oxidative stress by increasing the activity of antioxidant enzymes including SOD and catalase. Histopathological analysis revealed that dual neutralization of TGF-β and IL-6 prevented bone destruction and osteoclastic activity in septic arthritis by promoting the differential functional response of the splenic and synovial macrophages. Additionally, the macrophage-derived IL-10 can elicit protection against S. aureus-induced septic arthritis via regulating RANKL/OPG interaction. Further studies on STAT3 and STAT4 are needed for the understanding of such cross-talking in resident macrophages of arthritic mice.

Topics: Animals; Antioxidants; Arthritis, Infectious; Inflammation; Interleukin-10; Interleukin-6; Macrophages; Mice; Spleen; Staphylococcus aureus; Transforming Growth Factor beta

Neuroinflammation is a hallmark of hypoxic-ischemic injury and can be characterized by the activation of glial cells and the expression of inflammatory cytokines and chemokines. Interleukin (IL)-1β and tumor necrosis factor (TNF)α are among the best-characterized early response cytokines and are often expressed concurrently. Several types of central nervous system cells secrete IL-1β and TNFα, including microglia, astrocytes, and neurons, and these cytokines convey potent pro-inflammatory actions. Chemokines also play a central role in neuroinflammation by controlling inflammatory cell trafficking. Our aim was to characterise the evolution of early neuroinflammation in the neonatal piglet model of hypoxic-ischemic encephalopathy (HIE). Piglets (< 24 h old) were exposed to HI insult, and recovered to 2, 4, 8, 12 or 24H post-insult. Brain tissue from the frontal cortex and basal ganglia was harvested for assessment of glial cell activation profiles and transcription levels of inflammatory markers in HI piglets with comparison to a control group of newborn piglets. Fluorescence microscopy was used to observe microglia, astrocytes, neurons, degenerating neurons and possibly apoptotic cells, and quantitative polymerase chain reaction was used to measure gene expression of several cytokines and chemokines. HI injury was associated with microglial activation and morphological changes to astrocytes at all time points examined. Gene expression analyses of inflammation-related markers revealed significantly higher expression of pro-inflammatory cytokines tumor necrosis factor-α (TNFα) and interleukin 1 beta (IL-1β), chemokines cxc-chemokine motif ligand (CXCL)8 and CXCL10, and anti-inflammatory cytokine transforming growth factor (TGF)β in every HI group, with some region-specific differences noted. No significant difference was observed in the level of C-X-C chemokine receptor (CCR)5 over time. This high degree of neuroinflammation was associated with a reduction in the number of neurons in piglets at 12H and 24H in the frontal cortex, and the putamen at 12H. This reduction of neurons was not associated with increased numbers of degenerating neurons or potentially apoptotic cells. HI injury triggered a robust early neuroinflammatory response associated with a reduction in neurons in cortical and subcortical regions in our piglet model of HIE. This neuroinflammatory response may be targeted using novel therapeutics to reduce neuropathology in our piglet model of ne

Topics: Animals; Animals, Newborn; Brain; Cytokines; Hypoxia; Hypoxia-Ischemia, Brain; Inflammation; Microglia; Neuroglia; Neuroinflammatory Diseases; Swine; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Asthma is a chronic airway disease. Allergic reactions and T helper (h)2 immune response play a key role in asthma occurrence. Cell therapy can control inflammation and remodeling responses in allergic asthma, and cytokines can change this effect. Therefore, in this study, the effect of treated cell therapy with IL-2 to control allergic asthma was studied. Bone marrow cells were extracted and co-cultured with IL-2 and the cells were used via intra-tracheal administration in allergic asthma mice. Levels of IL-4, IL-5, IL-13, Leukotriene B4 and C4, and remodeling factors were measured. At least, a histopathology test of lung tissue was done. Type2 cytokines, leukotrienes, remodeling factors, mucus secretion, goblet cell hyperplasia, peri-bronchial and peri-vascular inflammation were significantly (p˂0.05) decreased by treating with bone marrow-derived mononuclear cells (BMDMCs) and IL-2-BMDMCs. Treatment with IL-2-BMDMCs could significantly decrease IL-13, transforming growth factor (TGF)-β, HP levels, and mucus secretion (p˂0.05) compared to BMDMCs treatment. In this study, BMDMCs and IL-2-BMDMCs therapy could decrease inflammation, allergic, and remodeling factors in allergic asthma. Cell therapy with BMDMCs had a strong and notable effect on the control of allergic asthma pathophysiology when co-cultured and used with IL-2.

Topics: Animals; Asthma; Bone Marrow; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Hypersensitivity; Inflammation; Interleukin-13; Interleukin-2; Leukocytes, Mononuclear; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Transforming Growth Factor beta

Although the beneficial role of training and the use of some antioxidants in physiological and psychological disorders in autoimmune diseases has been reported, the simultaneous effect of aerobic training (AT) and royal jelly (RJ) with different doses is not well understood. The present study aimed to investigate the impact of AT and RJ on inflammatory factors in the hippocampus, as well as depression and anxiety in the experimental autoimmune encephalomyelitis (EAE).. Sprague-Dawley rats with EAE were assigned to seven groups: (1) EAE without any other intervention (EAE); (2) sham, receiving normal saline (Sh); (3) 50 mg/kg RJ (RJ50); (4) 100 mg/kg RJ (RJ100); (5) AT; (6) AT + RJ50; and (7) AT + RJ100. In addition, a healthy control group was assessed.. EAE significantly increased interleukin 17 (IL-17), transforming growth factor-β (TGF-β) gene expression and immobilization time as well as anxiety and depression indices, and significantly decreased interleukin 10 (IL-10), compared to the control group. AT decreased significantly IL-17, TGF-β gene expression and immobilization time as well as anxiety and depression indices, while it significantly increased IL-10, compared to the EAE group. RJ50 and RJ100 decreased significantly IL-17, IL-23 gene expression, anxiety and depression indices, and significantly increased IL-10 compared to the EAE group. AT + RJ50 and AT + RJ100 significantly decreased IL-17, IL-23, and TGF-β and as well as anxiety and depression indices while significantly increasing IL-10 compared to the EAE group. The effects of AT + RJ100 on significant decreasing IL-17, IL-23, anxiety and depression and increasing TGF-β, IL-10 were more favorable than RJ50.. AT and RJ improved inflammatory and regulatory factors of autoimmunity and reduced anxiety and depression. The RJ combined with AT induced additive effects while using RJ100 was more favorable than RJ50.

Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Hippocampus; Inflammation; Interleukin-10; Interleukin-17; Interleukin-23; Mice; Mice, Inbred C57BL; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta

Regulatory T cell (Treg) activity and differentiation in visceral adipose tissue (VAT) play an important role in inhibiting chronic inflammation and insulin resistance. Whether JAZF-1 and PPAR-γ mediate VAT Treg differentiation to promote the inhibition of chronic inflammation and insulin resistance remains unclear. Here, we investigated the roles of JAZF-1 and PPAR-γ in VAT Treg differentiation, inflammation and insulin resistance using a transgenic mouse model. First, we determined that the levels of glucose and insulin biochemical markers in the JAZF-1 transgenic general feeding or high-fat groups were lower than those in the wild-type general feeding or high-fat groups. Second, the levels of CD4

Topics: Animals; Cell Differentiation; Forkhead Transcription Factors; Inflammation; Insulin Resistance; Interleukin-10; Interleukin-6; Intra-Abdominal Fat; Mice; Mice, Transgenic; PPAR gamma; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Increasing evidence shows that tRNA-derived small RNAs (tsRNAs) are not only by-products of transfer RNAs, but they participate in numerous cellular metabolic processes. However, the role of tsRNAs in skeletal muscle regeneration remains unknown.. Small RNA sequencing revealed the relationship between tsRNAs and skeletal muscle injury. The dynamic expression level of 5'tiRNA-Gly after muscle injury was confirmed by real-time quantitative PCR (q-PCR). In addition, q-PCR, flow cytometry, the 5-ethynyl-2'-deoxyuridine (Edu), cell counting kit-8, western blotting and immunofluorescence were used to explore the biological function of 5'tiRNA-Gly. Bioinformatics analysis and dual-luciferase reporter assay were used to further explore the mechanism of action under the biological function of 5'tiRNA-Gly.. Transcriptome analysis revealed that tsRNAs were significantly enriched during inflammatory response immediately after muscle injury. Interestingly, we found that 5'tiRNA-Gly was significantly up-regulated after muscle injury (P < 0.0001) and had a strong positive correlation with inflammation in vivo. In vitro experiments showed that 5'tiRNA-Gly promoted the mRNA expression of proinflammatory cytokines (IL-1β, P = 0.0468; IL-6, P = 0.0369) and the macrophages of M1 markers (TNF-α, P = 0.0102; CD80, P = 0.0056; MCP-1, P = 0.0002). On the contrary, 5'tiRNA-Gly inhibited the mRNA expression of anti-inflammatory cytokines (IL-4, P = 0.0009; IL-10, P = 0.0007; IL-13, P = 0.0008) and the mRNA expression of M2 markers (TGF-β1, P = 0.0016; ARG1, P = 0.0083). Flow cytometry showed that 5'tiRNA-Gly promoted the percentage of CD86. These results reveal that 5'tiRNA-Gly potentially regulated skeletal muscle regeneration by inducing inflammation via the TGF-β signalling pathway. The findings of this study uncover a new potential target for skeletal muscle regeneration treatment.

Topics: Cytokines; Humans; Inflammation; Muscle, Skeletal; Receptor, Transforming Growth Factor-beta Type I; Regeneration; RNA; RNA, Messenger; RNA, Transfer; Transforming Growth Factor beta

Lung injury is the most common secondary complication of pancreatitis and pancreatic malignancy. Around 60-70% of pancreatitis-related deaths are caused by lung injury; however, there is no animal model of the inflammation-mediated progressive pulmonary pathological events that contribute to acute lung injury in chronic pancreatitis (CP). Hence, we developed an inflammation-mediated mouse model and studied the pathological events that have a critical role in promoting the pathogenesis of lung injury. Our proteomic analysis of lung tissue revealed neutrophil-associated induction of neutrophil gelatinase-associated lipocalin (NGAL) and myeloperoxidase enzyme, further supporting a role for neutrophils in promoting IL-18-associated lung injury. We show that neutrophils released IL-18-induced p-NF-κB along with profibrotic and oncogenic proteins like TTF1, PDX1, and SOX9 in lung tissues of a mouse model of chronic pancreatitis. We also show that neutrophil infiltration induces TGF-β and SMAD4 and activates epithelial cells to produce other profibrotic proteins like ZO-1 and MUC2, along with the fibroblast markers FGF-1 and αSMA, that cause mesenchymal transition and accumulation of extracellular matrix collagen. Most importantly, we present evidence that IL-18 inhibition significantly alleviates CP-induced lung injury. This was further established by the finding that IL-18 gene-deficient mice showed improved lung injury by inhibition of TGF-β and fibroblast to mesenchymal transition and reduced collagen accumulation. The present study suggests that inhibition of IL-18 may be a novel treatment for CP-associated induced acute lung injury.

Topics: Acute Lung Injury; Animals; Collagen; Inflammation; Interleukin-18; Lung; Mice; Neutrophil Infiltration; Pancreatitis, Chronic; Proteomics; Transforming Growth Factor beta

Chronic kidney disease stage 5 on dialysis (CKD-5D) remains a global health problem associated with an increased risk of morbidity and mortality owing to cardiovascular disease. This condition is associated with chronic inflammation, which is characterized by an increase in cytokines, including tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β). Superoxide dismutase (SOD) is a first-line endogenous enzymatic antioxidant capable of neutralizing the effects of inflammation and oxidative stress. Therefore, the main aim of this study was to determine the effect of SOD supplementation on serum TNF-α and TGF-β levels in patients undergoing hemodialysis (CKD-5D).. A quasi-experimental study with a pretest-posttest design was conducted from October to December 2021 in the Hemodialysis Unit of Dr. Hasan Sadikin Hospital, Bandung. Patients with CKD-5D who routinely underwent hemodialysis therapy twice a week were included in the study. All participants received SOD-gliadin 250 IU twice a day for 4 weeks. Serum TNF-α and TGF-β levels were assessed before and after the intervention, and statistical analyses were performed.. This study enrolled 28 patients undergoing hemodialysis. The median age of the patients was 42 ± 11 years, with a male-to-female ratio of 1:1. The average duration of hemodialysis in the participants was 24 (5-72) months. A statistically significant decrease in serum TNF-α and TGF-β levels from 0.109 (0.087-0.223) to 0.099 (0.083-0.149) pg/mL (p=0.036) and 15.38 ± 3.64 to 13.47 ± 3.07 pg/mL (p=0.031), respectively, after SOD administration was noted.. Exogenous SOD supplementation decreased serum TNF-α and TGF-β levels in patients with CKD-5D. Further randomized controlled trials are required to confirm these findings.

Topics: Adult; Antioxidants; Dietary Supplements; Female; Hemodialysis Units, Hospital; Humans; Inflammation; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Superoxide Dismutase; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Allergen-specific sublingual immunotherapy (SLIT) was considered an interesting needle-free alternative for subcutaneous immunotherapy (SCIT). Mesenchymal stem cell (MSC)-derived exosomes were introduced as potent nanoscale delivery systems with immunomodulatory potentials. The current study investigated the therapeutic efficacy of SLIT using ovalbumin (OVA)-enriched MSC-derived exosomes formulation in a murine model of allergic asthma.. MSCs were harvested from mice adipose tissues. Then, exosomes were isolated, and OVA-loaded exosomes were prepared. Following sensitization, Balb/c mice received therapeutic formulation (10 μg/dose OVA-containing MSC-derived exosomes) twice a week for two months. Serum OVA-specific IgE levels as well as IFN-γ, IL-4, and TGF-β secretions by cultured splenocytes were measured by ELISA. Also, lung tissue underwent histopathologic analysis, and the numbers of inflammatory cells and eosinophils in nasopharyngeal lavage fluid (NALF) were examined.. SLIT using OVA-enriched exosomes significantly reduced IgE levels and IL-4 production, while the secretion of IFN-γ and TGF-β were significantly elevated. Also, a decrease was observed in the numbers of total cells and eosinophils in the NALF, and lower levels of perivascular and peribronchiolar inflammation and cellular infiltrations were observed in the lung tissue.. SLIT using OVA-loaded exosomes improved immunomodulatory responses and efficiently alleviated allergic inflammation.

Topics: Allergens; Animals; Cytokines; Disease Models, Animal; Exosomes; Immunity; Immunoglobulin E; Inflammation; Interleukin-4; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Ovalbumin; Sublingual Immunotherapy; Transforming Growth Factor beta

Long-term peritoneal dialysis (PD) is often associated with peritoneal dysfunction leading to withdrawal from PD. The characteristic pathologic features of peritoneal dysfunction are widely attributed to peritoneal fibrosis and angiogenesis. The detailed mechanisms remain unclear, and treatment targets in clinical settings have yet to be identified. We investigated transglutaminase 2 (TG2) as a possible novel therapeutic target for peritoneal injury. TG2 and fibrosis, inflammation, and angiogenesis were investigated in a chlorhexidine gluconate (CG)-induced model of peritoneal inflammation and fibrosis, representing a noninfectious model of PD-related peritonitis. Transforming growth factor (TGF)-β type I receptor (TGFβR-I) inhibitor and TG2-knockout mice were used for TGF-β and TG2 inhibition studies, respectively. Double immunostaining was performed to identify cells expressing TG2 and endothelial-mesenchymal transition (EndMT). In the rat CG model of peritoneal fibrosis, in situ TG2 activity and protein expression increased during the development of peritoneal fibrosis, as well as increases in peritoneal thickness and numbers of blood vessels and macrophages. TGFβR-I inhibitor suppressed TG2 activity and protein expression, as well as peritoneal fibrosis and angiogenesis. TGF-β1 expression, peritoneal fibrosis, and angiogenesis were suppressed in TG2-knockout mice. TG2 activity was detected by α-smooth muscle actin-positive myofibroblasts, CD31-positive endothelial cells, and ED-1-positive macrophages. CD31-positive endothelial cells in the CG model were α-smooth muscle actin-positive, vimentin-positive, and vascular endothelial-cadherin-negative, suggesting EndMT. In the CG model, EndMT was suppressed in TG2-knockout mice. TG2 was involved in the interactive regulation of TGF-β. As inhibition of TG2 reduced peritoneal fibrosis, angiogenesis, and inflammation associated with TGF-β and vascular endothelial growth factor-A suppression, TG2 may provide a new therapeutic target for ameliorating peritoneal injuries in PD.

Topics: Actins; Animals; Chlorhexidine; Endothelial Cells; Fibrosis; Inflammation; Mice; Mice, Knockout; Peritoneal Fibrosis; Peritoneum; Protein Glutamine gamma Glutamyltransferase 2; Rats; Transforming Growth Factor beta; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

Pulmonary fibrosis (PF) is a progressive pulmonary disease with no effective treatment and high mortality. Resveratrol has shown promising benefits in the treatment of PF. However, the probable efficacy and underlying mechanism of resveratrol in PF treatment remain unclear. This study investigates the intervention effects and potential mechanisms underpinning the treatment of PF with resveratrol. The histopathological analysis of lung tissues in PF rats showed that resveratrol improved collagen deposition and reduced inflammation. Resveratrol decreased the levels of collagen, glutathione, superoxide dismutase, myeloperoxidase, and hydroxyproline, lowered total anti-oxidant capacity, and suppressed the migration of TGF-[Formula: see text]1 and LPS-induced 3T6 fibroblasts. With resveratrol intervention, the protein and RNA expressions of TGF-[Formula: see text]1, a-SMA, Smad3/4, p-Smad3/4, CTGF, and p-ERK1/2 were markedly downregulated. Similarly, the protein and RNA expression levels of Col-1 and Col-3 were significantly downregulated. However, Smad7 and ERK1/2 were evidently upregulated. The protein and mRNA expression levels of TGF-[Formula: see text], Smad, and p-ERK correlated positively with the lung index, while the protein and mRNA expression levels of ERK correlated negatively with the lung index. These results reveal that resveratrol may have therapeutic effects on PF by reducing collagen deposition, oxidation, and inflammation. The mechanism is associated with the regulation of the TGF-[Formula: see text]/Smad/ERK signaling pathway.

Topics: Animals; Inflammation; Pulmonary Fibrosis; Rats; Resveratrol; RNA; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta

Kidney-derived thrombopoietin (TPO) increases myeloid cell and platelet production during antibody-mediated chronic kidney disease (AMCKD) in a mouse model, exacerbating chronic thromobinflammation in microvessels. The effect is mirrored in patients with extracapillary glomerulonephritis associated with thromboinflammation, TGF β -dependent glomerulosclerosis, and increased bioavailability of TPO. Neutralization of TPO in mice normalized hematopoiesis, reduced chronic thromboinflammation, and ameliorated renal disease. The findings suggest that TPO is a relevant biomarker and a promising therapeutic target for patients with CKD and other chronic thromboinflammatory diseases.Neutralization of TPO in mice normalized hematopoiesis, reduced chronic thromboinflammation, and ameliorated renal disease. The findings suggest that TPO is a relevant biomarker and a promising therapeutic target for patients with CKD and other chronic thromboinflammatory diseases.. Chronic thromboinflammation provokes microvascular alterations and rarefaction, promoting organ dysfunction in individuals with various life-threatening diseases. Hematopoietic growth factors (HGFs) released by the affected organ may sustain emergency hematopoiesis and fuel the thromboinflammatory process.. Using a murine model of antibody-mediated chronic kidney disease (AMCKD) and pharmacological interventions, we comprehensively monitored the response to injury in the circulating blood, urine, bone marrow, and kidney.. Experimental AMCKD was associated with chronic thromboinflammation and the production of HGFs, especially thrombopoietin (TPO), by the injured kidney, which stimulated and skewed hematopoiesis toward myelo-megakaryopoiesis. AMCKD was characterized by vascular and kidney dysfunction, TGF β -dependent glomerulosclerosis, and microvascular rarefaction. In humans, extracapillary glomerulonephritis is associated with thromboinflammation, TGF β -dependent glomerulosclerosis, and increased bioavailability of TPO. Analysis of albumin, HGF, and inflammatory cytokine levels in sera from patients with extracapillary glomerulonephritis allowed us to identify treatment responders. Strikingly, TPO neutralization in the experimental AMCKD model normalized hematopoiesis, reduced chronic thromboinflammation, and ameliorated renal disease.. TPO-skewed hematopoiesis exacerbates chronic thromboinflammation in microvessels and worsens AMCKD. TPO is both a relevant biomarker and a promising therapeutic target in humans with CKD and other chronic thromboinflammatory diseases.

Topics: Animals; Antibodies; Glomerulonephritis; Hematopoiesis; Humans; Inflammation; Kidney; Mice; Receptors, Thrombopoietin; Renal Insufficiency, Chronic; Thromboinflammation; Thrombopoietin; Thrombosis; Transforming Growth Factor beta

Heart failure (HF) is the end stage of the progression of many cardiovascular diseases. Cardiac remodeling is the main pathophysiological process of cardiac function deterioration in HF patients. Inflammation is a key factor that stimulates cardiomyocyte hypertrophy, fibroblast proliferation, and transformation leading to myocardial remodeling, which severity is significantly related to the prognosis of patients. SAA1 (Serum amyloid A1) is a lipid-binding protein that was an important regulator involved in inflammation, whose biological functions in the heart remain rarely known. In this research, we intended to test the role of SAA1 in SAA1-deficient (SAA1

Topics: Animals; Cardiomegaly; Cardiomyopathies; Disease Models, Animal; Fibrosis; Heart Failure; Inflammation; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; NF-kappa B; Transforming Growth Factor beta; Ventricular Remodeling

Topics: Animals; Antioxidants; Apoptosis; Cadmium; Cadmium Poisoning; Caspase 3; Collagen; Creatine Kinase, MB Form; Fibrosis; Inflammation; Oxidative Stress; Rats; Transforming Growth Factor beta

Chronic low-grade inflammation and ovarian germline stem cells (OGSCs) aging are important reasons for the decline of ovarian reserve function, resulting in ovarian aging and infertility. Regulation of chronic inflammation is expected to promote the proliferation and differentiation of OGSCs, which will become a key means for maintaining and remodeling ovarian function. Our previous study demonstrated that Chitosan Oligosaccharides (Cos) promoted the OGSCs proliferation and remodelled the ovarian function through improving the secretion of immune related factors,but the mechanism remains unclear, and the role of macrophages, the important source of various inflammatory mediators in the ovary needs to be further studied. In this study, we used the method of macrophages and OGSCs co-culture to observe the effect and mechanism of Cos on OGSCs, and explore what contribution macrophages give during this process. Our finding provides new drug treatment options and methods for the prevention and treatment of premature ovarian failure and infertility.. We used the method of macrophages and OGSCs co-culture to observe the effect and mechanism of Cos on OGSCs, and explore the important contribution of macrophages in it. The immunohistochemical staining was used to locate the OGSCs in the mouse ovary. Immunofluorescent staining, RT-qPCR and ALP staining were used to identify the OGSCs. CCK-8 and western blot were used to evaluate the OGSCs proliferation. β-galactosidase(SA-β-Gal) staining and western blot were used to detect the changing of cyclin-dependent kinase inhibitor 1A(P21), P53, Recombinant Sirtuin 1(SIRT1) and Recombinant Sirtuin 3(SIRT3). The levels of immune factors IL-2, IL-10, TNF-α and TGF-β were explored by using Western blot and ELISA.. We found that Cos promoted OGSCs proliferation in a dose-and time-dependent manner, accompanied by IL-2, TNF-α increase and IL-10, TGF-β decrease. Mouse monocyte-macrophages Leukemia cells(RAW) can also produce the same effect as Cos. When combined with Cos, it can enhance the proliferative effect of Cos in OGSCs, and further increase IL-2, TNF-α and further decrease IL-10, TGF-β. The macrophages can enhance the proliferative effect of Cos in OGSCs is also associated with the further increase in IL-2, TNF-α and the further decrease in IL-10, TGF-β. In this study, we determined that the anti-aging genes SIRT-1 and SIRT-3 protein levels were increased by Cos and RAW respectively, whereas the senescence-associated SA-β-Gal and aging genes P21 and P53 were decreased. Cos and RAW had a protective effect on OGSCs delaying aging. Furthermore, RAW can further decrease the SA-β-Gal and aging genes P21 and P53 by Cos, and further increase SIRT1 and SIRT3 protein levels in OGSCs by Cos.. In conclusion, Cos and macrophages have synergistic effects on improving OGSCs function and delaying ovarian aging by regulating inflammatory factors.

Topics: Animals; Female; Inflammation; Interleukin-10; Interleukin-2; Macrophages; Mice; Oligosaccharides; Ovary; Sirtuin 1; Sirtuin 3; Stem Cells; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by chronic eosinophilic inflammation and new bone formation (NBF). These processes may be associated with each other in the pathogenesis and influence the severity and prognosis of the disease. However, it is still unclear how eosinophilic inflammation is involved in the NBF.. Sinus bone cells were isolated from ethmoid bone tissues of patients with CRSwNP and controls. Transforming growth factor beta 1 (TGFβ1) and alkaline phosphatase (ALP) expression in sinus bone cells was determined using quantitative RT-PCR, immunoblotting, and immunohistochemistry. The co-localization of TGFβ1 with eosinophils was assessed by immunofluorescence staining. Sinus bone cells were co-cultured with eosinophils (Eol-1 cell line), which were differentiated with butyrate, to measure the osteoblast differentiation activity of sinus bone cells.. TGFβ1 expression was increased in sinus bone tissues and correlated with CT scores in CRSwNP. TGFβ1 was also increased in the submucosa of CRSwNP and co-localized predominantly with eosinophils compared with neutrophils Differentiated Eol-1 cells-derived TGFβ1 increased ALP expression in sinus bone cells. Treatment with a TGFβ inhibitor attenuated TGFβ1-induced ALP expression and staining in sinus bone cells of CRSwNP, leading to loss of bone formation.. Eosinophil-derived TGFβ1 was enriched in the submucosa of CRSwNP, which induced ALP expression in sinus bone cells and NBF. Therefore, eosinophil-derived TGFβ1 may mediate aberrant bone remodeling in CRSwNP.

Topics: Chronic Disease; Eosinophils; Humans; Inflammation; Nasal Polyps; Osteogenesis; Rhinitis; Sinusitis; Transforming Growth Factor beta

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Aberrant lipid metabolism and accumulation of extracellular matrix proteins are hallmarks of the disease, but the underlying mechanisms are largely unknown. This study aims to elucidate the key role of sine oculis homeobox homologue 1 (SIX1) in the development of NAFLD.. Alb-Cre mice were administered the AAV9 vector for SIX1 liver-specific overexpression or knockdown. Metabolic disorders, hepatic steatosis, and inflammation were monitored in mice fed with HFHC or MCD diet. High throughput CUT&Tag analysis was employed to investigate the mechanism of SIX1 in diet-induced steatohepatitis.. Here, we found increased SIX1 expression in the livers of NAFLD patients and animal models. Liver-specific overexpression of SIX1 using adeno-associated virus serotype 9 (AAV9) provoked more severe inflammation, metabolic disorders, and hepatic steatosis in the HFHC or MCD-induced mice model. Mechanistically, we demonstrated that SIX1 directly activated the expression of liver X receptor α (LXRα) and liver X receptor β (LXRβ), thus inducing de novo lipogenesis (DNL). In addition, our results also illustrated a critical role of SIX1 in regulating the TGF-β pathway by increasing the levels of type I and II TGF-β receptor (TGFβRI/TGFβRII) in hepatic stellate cells (HSCs). Finally, we found that liver-specific SIX1 deficiency could ameliorate diet-induced NAFLD pathogenesis.. Our findings suggest a detrimental function of SIX1 in the progression of NAFLD. The direct regulation of LXRα/β and TGF-β signalling by SIX1 provides a new regulatory mechanism in hepatic steatosis and fibrosis.

Topics: Animals; Diet, High-Fat; Fibrosis; Inflammation; Lipogenesis; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Transforming Growth Factor beta

Atopic Dermatitis (AD) is a multifactorial cutaneous disorder associated with chronic inflammation of the skin. Growing evidence points to TGF-β/SMAD signaling as a key player in mediating inflammation and the subsequent tissue remodeling, often resulting in fibrosis. This study investigates the role of a core transcription factor involved in TGF-β signaling i.e., SMAD3 genetic variants (rs4147358) in AD predisposition and its association with SMAD3 mRNA expression, serum IgE levels, and sensitization to various allergens in AD patients.. A total of 246 subjects including 134 AD cases and 112 matched healthy controls were genotyped for SMAD3 intronic SNP by PCR-RFLP. mRNA expression of SMAD3 was determined by quantitative Real-Time PCR (qRT-PCR), Vitamin-D levels by chemiluminescence, and total serum IgE levels by ELISA. In-vivo allergy testing was performed for the evaluation of allergic reactions to house dust mites (HDM) and food allergens.. A significantly higher frequency of mutant genotype AA (cases: 19.4% vs controls: 8.9%) (OR = 2.8, CI = 1.2 - 6.7, p = 0.01) was observed in AD cases. The mutant allele 'A' also showed a 1.9-fold higher risk for AD compared to the wild allele 'C' indicating that the carriers of the A allele have a higher risk for AD predisposition (OR-1.9, CI = 1.3-2.8, p < 0.001). In addition, quantitative analysis of SMAD3 mRNA in peripheral blood showed 2.8-fold increased expression in AD cases as compared to healthy controls. Stratification analysis revealed the association of the mutant AA genotype with deficient serum Vitamin D levels (p = 0.02) and SMAD3 mRNA overexpression with HDM sensitization (p = 0.03). Furthermore, no significant association of genotypes with SMAD3 mRNA expression was observed.. Our study indicates that SMAD3 intronic SNP bears a significant risk of AD development. Moreover, overexpression of SMAD3 mRNA and its association with HDM sensitization highlights the possible role of this gene in AD pathogenesis.

Topics: Allergens; Animals; Case-Control Studies; Dermatitis, Atopic; Food Hypersensitivity; Humans; Immunoglobulin E; Inflammation; Pyroglyphidae; Smad3 Protein; Transforming Growth Factor beta

Cognitive function is negatively impacted by schistosomiasis and might be caused by systemic inflammation which has been hypothesized to be one of the mechanisms driving cognitive decline, This study explored the association of systemic inflammatory biomarkers; interleukin (IL)-10, IL-6, IL-17, transforming growth factor (TGF-β), tumor necrosis factor (TNF-α), C-reactive protein (CRP) and hematological parameters with cognitive performance of preschool-aged children (PSAC) from an Schistosoma haematobium endemic area.. The Griffith III tool was used to measure the cognitive performance of 136 PSAC. Whole blood and sera were collected and used to quantify levels of IL-10, TNF-α, IL-6, TGF-β, IL-17 A and CRP using the enzyme-linked immunosorbent assay and hematological parameters using the hematology analyzer. Spearman correlation analysis was used to determine the relationship between each inflammatory biomarker and cognitive performance. Multivariate logistic regression analysis was used to determine whether systemic inflammation due to S. haematobium infection affected cognitive performance in PSAC.. Higher levels of TNF-α and IL-6, were correlated with lower performance in the Foundations of Learning domain (r = -0.30; p < 0.001 and r = -0.26; p < 0.001), respectively. Low cognitive performance in the Eye-Hand-Coordination Domain was observed in PSAC with high levels of the following inflammatory biomarkers that showed negative correlations to performance; TNF-α (r = -0.26; p < 0.001), IL-6 (r = -0.29; p < 0.001), IL-10 (r = -0.18; p < 0.04), WBC (r = -0.29; p < 0.001), neutrophils (r = -0.21; p = 0.01) and lymphocytes (r = -0.25; p = 0.003) The General Development Domain correlated with TNF-α (r = -0.28; p < 0.001) and IL-6 (r = -0.30; p < 0.001). TGF-β, L-17A and MXD had no significant correlations to performance in any of the cognitive domains. The overall general development of PSAC was negatively impacted by S. haematobium infections (OR = 7.6; p = 0.008) and (OR = 5.6; p = 0.03) where the PSAC had higher levels of TNF-α and IL-6 respectively.. Systemic inflammation and S. haematobium infections are negatively associated with cognitive function. We recommend the inclusion of PSAC into mass drug treatment programs.

Topics: Animals; Biomarkers; C-Reactive Protein; Child; Child, Preschool; Cognition; Humans; Inflammation; Interleukin-10; Interleukin-17; Interleukin-6; Schistosoma haematobium; Schistosomiasis haematobia; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Zimbabwe

The evidence shows that obesity is associated with chronic inflammation in obese subjects. Polyphenols are a complex group of plant secondary metabolites that may play a role in reducing the risk of obesity and obesity-related diseases. Given the scarcity of evidence on the association between inflammatory markers and dietary polyphenols intake in overweight/obese Iranian women, the current study aims to investigate this link.. The present cross-sectional study was conducted on 391 overweight and obese Iranian women aged 18-48 years (body mass index (BMI) ≥ 25 kg/m. The findings revealed a significant negative association between flavonoids intake and MCP-1 (P = 0.024), lignans intake and MCP-1 (P = 0.017), and Gal-3 (P = 0.032). These significant associations were observed between other polyphenols intake and IL_1β (P = 0.014). There was also a significant positive association between other polyphenol intake and TGF-β (P = 0.008) and between phenolic acid intake and TGF-β (P = 0.014).. Our findings suggest that a high polyphenol intake may help individuals to reduce systemic inflammation. Further large studies involving participants of different ages and genders are highly warranted.

Topics: Biomarkers; Body Mass Index; Cholesterol; Cross-Sectional Studies; Female; Humans; Inflammation; Iran; Male; Obesity; Overweight; Polyphenols; Transforming Growth Factor beta

Chronic graft-versus-host disease (cGVHD) presents with dermal inflammation and fibrosis. We investigated the characteristics of extracellular vesicles (EVs) obtained from cGVHD patients, and their potential effects on human dermal fibroblast (NHDF) cells. The anti-inflammatory and anti-fibrotic effects of placental EVs were also explored given their known anti-inflammatory properties. Fourteen cGVHD patients' EVs contained higher levels of fibrosis-related proteins, TGFβ and α-smooth muscle actin (αSMA), compared to EVs from thirteen healthy subjects. The exposure of NHDF cells to the patients' EVs increased the NHDF cells' TGFβ and αSMA expressions. Placental EVs derived from placental-expanded cells (PLX) (Pluri Inc.) and human villous trophoblast (HVT) cells expressing the mesenchymal markers CD29, CD73, and CD105, penetrated into both the epidermal keratinocytes (HACATs) and NHDF cells. Stimulation of the HACAT cells with cytokine TNFα/INFγ (0.01-0.1 ng/µL) reduced cell proliferation, while the addition of placental EVs attenuated this effect, increasing and normalizing cell proliferation. The treatment of NHDF cells with a combination of TGFβ and placental HVT EVs reduced the stimulatory effects of TGFβ on αSMA production by over 40% (

Topics: Extracellular Vesicles; Female; Fibrosis; Graft vs Host Disease; Humans; Inflammation; Placenta; Pregnancy; Transforming Growth Factor beta

Transforming growth factor-beta (TGF-β) exists in three isoforms TGF-β1, -β2, and -β3. TGF-β1 has been suggested to be important for maintaining plaque stability, yet the role of TGF-β2 and -β3 in atherosclerosis remains to be investigated.This study explores the association of the three isoforms of TGF-β with plaque stability in the human atherosclerotic disease.. TGF-β1, -β2, and -β3 proteins were quantified in 223 human carotid plaques by immunoassays. Indications for the endarterectomy were: symptomatic carotid plaque with stenosis >70% or without symptoms and >80% stenosis. Plaque mRNA levels were assessed by RNA sequencing. Plaque components and extracellular matrix were measured histologically and biochemically. Matrix metalloproteinases and monocyte chemoattractant protein-1 (MCP-1) was measured with immunoassays. The effect of TGF-β2 on inflammation and protease activity was investigated in vitro using THP-1 and RAW264.7 macrophages. Patients were followed longitudinally for cardiovascular (CV) events.TGF-β2 was the most abundant isoform and was increased at both protein and mRNA levels in asymptomatic plaques. TGF-β2 was the main determinant separating asymptomatic plaques in an Orthogonal Projections to Latent Structures Discriminant Analysis. TGF-β2 correlated positively to features of plaque stability and inversely to markers of plaque vulnerability. TGF-β2 was the only isoform inversely correlated to the matrix-degrading matrix metalloproteinase-9 and inflammation in the plaque tissue. In vitro, TGF-β2 pre-treatment reduced MCP-1 gene and protein levels as well as matrix metalloproteinase-9 gene levels and activity. Patients with plaques with high TGF-β2 levels had a lower risk to suffer from future CV events.. TGF-β2 is the most abundant TGF-β isoform in human plaques and may maintain plaque stability by decreasing inflammation and matrix degradation.

Topics: Cardiovascular Diseases; Constriction, Pathologic; Humans; Inflammation; Matrix Metalloproteinase 9; Plaque, Atherosclerotic; Protein Isoforms; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Transforming Growth Factors

Fibrosis development in ulcerative colitis is associated directly with the severity of mucosal inflammation, which increases the risk of colorectal cancer. The transforming growth factor-β (TGF-β) signaling pathway is an important source of tissue fibrogenesis, which is stimulated directly by reactive oxygen species produced from nicotinamide adenine dinucleotide phosphate oxidases (NOX). Among members of the NOX family, NOX4 expression is up-regulated in patients with fibrostenotic Crohn's disease (CD) and in dextran sulfate sodium (DSS)-induced murine colitis. The aim of this study was to determine whether NOX4 plays a role in fibrogenesis during inflammation in the colon using a mouse model.. Acute and recovery models of colonic inflammation were performed by DSS administration to newly generated Nox4. Nox4. Nox4 protects against injury and plays a crucial role in fibrogenesis in DSS-induced colitis through canonical TGF-β signaling regulation, highlighting a new treatment target.

Topics: Animals; Colitis; Dextran Sulfate; Fibrosis; Inflammation; Mice; NADPH Oxidase 4; Reactive Oxygen Species; Transforming Growth Factor beta

Sepsis-induced intensive care unit-acquired weakness (ICUAW) features profound muscle atrophy and attenuated muscle regeneration related to malfunctioning satellite cells. Transforming growth factor beta (TGF-β) is involved in both processes. We uncovered an increased expression of the TGF-β receptor II (TβRII)-inhibitor SPRY domain-containing and SOCS-box protein 1 (SPSB1) in skeletal muscle of septic mice. We hypothesized that SPSB1-mediated inhibition of TβRII signalling impairs myogenic differentiation in response to inflammation.. We performed gene expression analyses in skeletal muscle of cecal ligation and puncture- (CLP) and sham-operated mice, as well as vastus lateralis of critically ill and control patients. Pro-inflammatory cytokines and specific pathway inhibitors were used to quantitate Spsb1 expression in myocytes. Retroviral expression plasmids were used to investigate the effects of SPSB1 on TGF-β/TβRII signalling and myogenesis in primary and immortalized myoblasts and differentiated myotubes. For mechanistical analyses we used coimmunoprecipitation, ubiquitination, protein half-life, and protein synthesis assays. Differentiation and fusion indices were determined by immunocytochemistry, and differentiation factors were quantified by qRT-PCR and Western blot analyses.. SPSB1 expression was increased in skeletal muscle of ICUAW patients and septic mice. Tumour necrosis factor (TNF), interleukin-1β (IL-1β), and IL-6 increased the Spsb1 expression in C2C12 myotubes. TNF- and IL-1β-induced Spsb1 expression was mediated by NF-κB, whereas IL-6 increased the Spsb1 expression via the glycoprotein 130/JAK2/STAT3 pathway. All cytokines reduced myogenic differentiation. SPSB1 avidly interacted with TβRII, resulting in TβRII ubiquitination and destabilization. SPSB1 impaired TβRII-Akt-Myogenin signalling and diminished protein synthesis in myocytes. Overexpression of SPSB1 decreased the expression of early (Myog, Mymk, Mymx) and late (Myh1, 3, 7) differentiation-markers. As a result, myoblast fusion and myogenic differentiation were impaired. These effects were mediated by the SPRY- and SOCS-box domains of SPSB1. Co-expression of SPSB1 with Akt or Myogenin reversed the inhibitory effects of SPSB1 on protein synthesis and myogenic differentiation. Downregulation of Spsb1 by AAV9-mediated shRNA attenuated muscle weight loss and atrophy gene expression in skeletal muscle of septic mice.. Inflammatory cytokines via their respective signalling pathways cause an increase in SPSB1 expression in myocytes and attenuate myogenic differentiation. SPSB1-mediated inhibition of TβRII-Akt-Myogenin signalling and protein synthesis contributes to a disturbed myocyte homeostasis and myogenic differentiation that occurs during inflammation.

Topics: Animals; Cytokines; Inflammation; Interleukin-6; Mice; Muscle Development; Muscle, Skeletal; Myogenin; Proto-Oncogene Proteins c-akt; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

As a part of natural disease progression, acute kidney injury (AKI) can develop into chronic kidney disease via renal fibrosis and inflammation. LTBP4 (latent transforming growth factor beta binding protein 4) regulates transforming growth factor beta, which plays a role in renal fibrosis pathogenesis. We previously investigated the role of LTBP4 in chronic kidney disease. Here, we examined the role of LTBP4 in AKI.. LTBP4 expression was upregulated in the renal tissues of patients with AKI.. Our study is the first to demonstrate that LTBP4 deficiency increases AKI severity, consequently leading to chronic kidney disease. Potential therapies focusing on LTBP4-associated angiogenesis and LTBP4-regulated DRP1-dependent mitochondrial division are relevant to renal injury.

Topics: Acute Kidney Injury; Animals; Endothelial Cells; Fibrosis; Humans; Inflammation; Kidney; Latent TGF-beta Binding Proteins; Mice; Mice, Inbred C57BL; Mitochondria; Renal Insufficiency, Chronic; Reperfusion Injury; Transforming Growth Factor beta

In idiopathic pulmonary fibrosis (IPF), excessive collagen deposition predisposes to irreversible lung function decline, respiratory failure, and ultimately death. Due to the limited therapeutic efficacy of FDA-approved medications, novel drugs are warranted for better treatment outcomes. Dehydrozingerone (DHZ) is an analogue of curcumin that has been investigated against pulmonary fibrosis using a bleomycin-induced pulmonary fibrosis model in rats. In in vitro, TGF-β-induced differentiation models (using NHLF, LL29, DHLF and A549 cells) were adopted to assess fibrotic markers expression and explored the mechanism of action. DHZ administration attenuated the bleomycin-induced elevation of lung index, inflammatory cell infiltrations, and hydroxyproline levels in lung tissues. Furthermore, treatment with DHZ mitigated the bleomycin-mediated elevation of extracellular matrix (ECM), epithelial-to-mesenchymal-transition (EMT), and collagen deposition markers and improved lung mechanics. In addition, treatment with DHZ significantly suppressed the BLM-induced apoptosis and rescued the BLM-induced pathological abnormalities in lung tissues. In vitro assays revealed that DHZ suppressed the expression of TGF-β-elevated collagen deposition, EMT and ECM markers in both mRNA/protein levels. Our findings showed that DHZ has anti-fibrotic effect against pulmonary fibrosis by modulating Wnt/β-catenin signaling, suggesting that DHZ may serve as a potential treatment option for IPF.

Topics: Animals; beta Catenin; Bleomycin; Collagen; Epithelial-Mesenchymal Transition; Idiopathic Pulmonary Fibrosis; Inflammation; Lung; Rats; Transforming Growth Factor beta; Transforming Growth Factor beta1

Ginseng, when used as a food and nutritional supplement, has the ability to regulate human immunity. Here, the potential anti-hepatic fibrosis effect of ginsenoside Rd (Rd), one of the protopanaxadiol types of ginsenoside, was investigated. We established a hepatic fibrosis model using intraperitoneal injection of thioacetamide (TAA) for five weeks in mice. In addition, an

Topics: Animals; ERRalpha Estrogen-Related Receptor; Ginsenosides; Hepatic Stellate Cells; Humans; Inflammasomes; Inflammation; Liver; Liver Cirrhosis; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Thioacetamide; Transforming Growth Factor beta

Cell‒cell communication following spinal cord injury (SCI) plays a key role in remyelination and neurological recovery. Although communication between neuron-neural stem cells (NSCs) affects remyelination, its precise mechanism remains unclear. The present study investigated the biological effects of extracellular vesicles (EVs) derived from neurons on the differentiation of NSCs and the remyelination of axons in a rat model for SCI. We found that that EVs derived from neurons promoted the differentiation of NSCs into oligodendrocytes and the remyelination of axons in SCI rats. However, neuron-derived EVs lost their biological effects after inflammatory stimulation of these neurons from which they originate. Further analysis demonstrated that the inflammatory stimulation on neurons upregulated miR-21 within EVs, which targeted SMAD 7 and upregulated the TGF-β/SMAD2 signaling pathway, resulting in an excess of astrocytic scar boundaries and in remyelination failure. Moreover, these effects could be abolished by miR-21 inhibitors/antagomirs. Considered together, these results indicate that inflammatory stimulation of neurons prevents remyelination following SCI via the upregulation of miR-21 expression within neuron-derived EVs, and this takes place through SMAD 7-mediated activation of the TGF-β/SMAD2 signaling pathway. Graphical Astract.

Topics: Animals; Extracellular Vesicles; Inflammation; MicroRNAs; Neurons; Rats; Remyelination; Spinal Cord Injuries; Transforming Growth Factor beta

Topics: Animals; Carcinogenesis; Cell Transformation, Neoplastic; Colitis; Colitis-Associated Neoplasms; Dextran Sulfate; Inflammation; Intestinal Mucosa; Mice; Transforming Growth Factor beta; Transforming Growth Factor beta1

Ulcerative colitis (UC) is a chronic mucosal inflammation of the large intestine that mostly affects the rectum and colon. The absence of safe and effective therapeutic agents encourages the discovery of novel therapeutic agents to effectively treat UC and its complications. The purpose of this research was to examine the protective impact of Eicosapentaenoic acid (EPA) in rats with UC induced by acetic acid (AA).. AA (2 ml, 3 % v/v) was injected intrarectally to cause UC. Before administering AA, EPA (300 and 1000 mg/kg) was given orally for 28 days.. EPA inhibited AA-induced UC by enhancing colonic histopathological changes like inflammation, goblet cell loss, glandular hyperplasia and mucosal ulceration, concomitant with a reduction in colon weight, colon weight/length ratio, C-reactive protein (CRP), and serum lactate dehydrogenase (LDH). EPA also effectively restored the imbalance between oxidants and antioxidants caused by AA. In addition, EPA increased the levels of trefoil factor-3 (TFF-3) and glucagon-like peptide-1 (GLP-1), while significantly reducing the expression of nuclear factor kappa B (NF-κB), interferon-γ (IFN-γ), and interleukin-6 (IL-6), transforming growth factor-1(TGF-β1), and phosphorylated epidermal growth factor receptor (P-EGFR), phosphatidylinositol-3-kinase (PI3K) and protein kinase B (AKT) expression in colonic tissues.. EPA inhibited AA-induced UC in rats by modulating the TGF-β/P-EGFR and NF-κB inflammatory pathways, regulating the oxidant/antioxidant balance, and enhancing the colon barrier integrity.

Topics: Acetic Acid; Animals; Antioxidants; Colitis, Ulcerative; Colon; Eicosapentaenoic Acid; ErbB Receptors; Inflammation; NF-kappa B; Rats; Signal Transduction; Transforming Growth Factor beta

Excessive TGF-β signaling and mitochondrial dysfunction fuel chronic kidney disease (CKD) progression. However, inhibiting TGF-β failed to impede CKD in humans. The proximal tubule (PT), the most vulnerable renal segment, is packed with giant mitochondria and injured PT is pivotal in CKD progression. How TGF-β signaling affects PT mitochondria in CKD remained unknown. Here, we combine spatial transcriptomics and bulk RNAseq with biochemical analyses to depict the role of TGF-β signaling on PT mitochondrial homeostasis and tubulo-interstitial interactions in CKD. Male mice carrying specific deletion of Tgfbr2 in the PT have increased mitochondrial injury and exacerbated Th1 immune response in the aristolochic acid model of CKD, partly, through impaired complex I expression and mitochondrial quality control associated with a metabolic rewiring toward aerobic glycolysis in the PT cells. Injured S3T2 PT cells are identified as the main mediators of the maladaptive macrophage/dendritic cell activation in the absence of Tgfbr2. snRNAseq database analyses confirm decreased TGF-β receptors and a metabolic deregulation in the PT of CKD patients. This study describes the role of TGF-β signaling in PT mitochondrial homeostasis and inflammation in CKD, suggesting potential therapeutic targets that might be used to mitigate CKD progression.

Topics: Animals; Fibrosis; Humans; Inflammation; Kidney; Male; Mice; Mitochondria; Receptor, Transforming Growth Factor-beta Type II; Renal Insufficiency, Chronic; Signal Transduction; Transforming Growth Factor beta

Peritoneal adhesion is a common abdominal surgical complication that induces abdominal haemorrhage, intestinal obstruction, infertility, and so forth. The high morbidity and recurrence rate of this disease indicate the need for novel therapeutic approaches. Here, we revealed the protective roles of tetrahydroberberrubine (THBru), a novel derivative of berberine (BBR), in preventing peritoneal adhesion and identified its underlying mechanism in vivo and in vitro. Abrasive surgery was used to create a peritoneal adhesion rat model. We found that THBru administration markedly ameliorated peritoneal adhesion, as indicated by a lowered adhesion score and ameliorated caecal tissue damage. By comparison, THBru exhibited more potent anti-adhesion effects than BBR at the same dose. Mechanistically, THBru inhibited inflammation and extracellular matrix (ECM) accumulation in the microenvironment of adhesion tissue. THBru suppressed the expression of inflammatory cytokines including interleukin-1β (IL-1β), IL-6, transforming growth factor β (TGF-β), tumor necrosis factor-α (TNF-α) and intercellular adhesion molecule-1 (ICAM-1), by regulating the transforming growth factor beta-activated kinase 1 (TAK1)/c-Jun N-terminal kinase (JNK) and TAK1/nuclear factor κB (NF-κB) signaling pathways. However, THBru promoted the activation of MMP-3 by directly blocking the TIMP-1 activation core and subsequently decreased collagen deposition. Taken together, this study identifies THBru as an effective anti-adhesion agent that regulates diverse mechanisms, thereby outlining its potential therapeutic implications for the treatment of peritoneal adhesion.

Topics: Animals; Berberine; Extracellular Matrix; Inflammation; Intercellular Adhesion Molecule-1; NF-kappa B; Rats; Transforming Growth Factor beta

Mesenchymal stromal cells (MSC) show promise as cellular therapeutics. Psoriasis is a chronic inflammatory disease affecting the skin and the joints. Injury, trauma, infection and medications can trigger psoriasis by disrupting epidermal keratinocyte proliferation and differentiation, which activates the innate immune system. Pro-inflammatory cytokine secretion drives a T helper 17 response and an imbalance of regulatory T cells. We hypothesized that MSC adoptive cellular therapy could immunomodulate and suppress the effector T cell hyperactivation that underlies the disease. We used the imiquimod-induced psoriasis-like skin inflammation model to study the therapeutic potential of bone marrow and adipose tissue-derived MSC in vivo. We compared the secretome and the in vivo therapeutic potential of MSC with and without cytokine pre-challenge ("licensing"). The infusion of both unlicensed and licensed MSC accelerated the healing of psoriatic lesions, and reduced epidermal thickness and CD3

Topics: Animals; Cytokines; Dermatitis; Inflammation; Interleukin-17; Interleukin-6; Mesenchymal Stem Cells; Mice; Psoriasis; Skin; Transforming Growth Factor beta

Fibrosis is a response to ongoing cellular injury, disruption, and tissue remodeling, the pathogenesis of which is unknown, and is characterized by extracellular matrix deposition. The antifibrotic effect of Geranylgeranylacetone (GGA), as an inducer of Heat shock protein 70 (HSP70), in liver, kidney and pulmonary fibrosis has been supported by multiple preclinical evidence. However, despite advances in our understanding, the precise roles of HSP70 in fibrosis require further investigation. The purpose of this study was to investigate whether GGA could participate in the progression of pulmonary fibrosis in mice through apoptosis, oxidative stress and inflammation.. B-cell lymphoma-2(Bcl-2) and Bcl2-Associated X (Bax) are two proteins related to apoptosis. Anti-apoptotic factor Bcl-2 and pro-apoptotic factor Bax are often involved in the apoptotic process in the form of dimer. Immunofluorescence and Western blot results showed that bleomycin (BLM) and transforming growth factor-β (TGF-β) inhibited Bcl-2 expression and promoted Bax expression in vitro and in vivo, respectively. In contrast, GGA treatment reverses this change. Reactive oxygen species (ROS), Malondialdehyde (MDA) and superoxide dismutase (SOD) are markers of oxidative stress, which often reflect oxidative injury of cells. The detection of ROS, MDA and SOD expression showed that TGF-β and BLM treatment could significantly promote oxidative stress, while GGA treatment could alleviate oxidative stress damage. In addition, BLM significantly elevated Tumor necrosis factor-α(TNF-α), Interleukin1β (IL-1β) and Interleukin 6 (IL-6), while scutellarin reversed the above alterations except for that of GGA.. Taken together, GGA suppressed apoptotic, oxidative stress and inflammation in BLM-induced pulmonary fibrosis.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Bleomycin; Fibrosis; Inflammation; Lung; Mice; Oxidative Stress; Pneumonia; Pulmonary Fibrosis; Reactive Oxygen Species; Superoxide Dismutase; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Studies have demonstrated increased morbidity and mortality with platelet transfusions in the neonatal period. Platelets are as important for host immunity and inflammation as for hemostasis. Increased inflammation may explain the dose-associated increase in mortality, bleeding, and lung disease.. This study aims to assess if there are any changes in inflammatory cytokines post-platelet transfusion in babies in NICU.. This prospective observational study recruited babies due to receive a non-emergency platelet transfusion. Dried whole blood samples were collected prior to and 2 h post-transfusion. Samples were processed using multiplex immunoassay to enable analysis of tiny blood volumes. Statistical analysis was performed using R.. The increase in the cytokines CXCL5, CD40 and TGF-β after platelet transfusion in babies in NICU could potentiate existing inflammation, NEC, lung, or white matter injury. This could potentially explain long-term harm from platelet transfusion in babies.. There is a change in levels of immunomodulatory proteins CXCL5, CD40, and TGF-β after platelet transfusion in babies in NICU. Murine neonatal models have demonstrated an increase in cytokine levels after platelet transfusions. This is the first time that this has been demonstrated in human neonates. The increase in proinflammatory cytokines could potentially explain the long-term harm from platelet transfusion in babies, as they could potentiate existing inflammation, NEC, lung injury, or white matter injury.

Topics: Animals; Blood Platelets; Cytokines; Humans; Infant, Newborn; Inflammation; Mice; Platelet Transfusion; Transforming Growth Factor beta

Liver fibrosis is a worldwide challenge of health issue. Developing effective new drugs for treating liver fibrosis is of great importance. In recent years, chemically synthesized drugs have significant advantages in treating liver fibrosis. Small molecule pyrazole derivatives as activin receptor-like kinase 5 (ALK5) inhibitors have also shown anti-fibrotic and tumor growth inhibitory effects. To develop the candidate with anti-fibrotic effect, we synthesized a novel pyrazole derivative, J-1048. The inhibitory effect of J-1048 on ALK5 and p38α mitogen-activated protein (MAP) kinase activity was assessed by enzymatic assays. We established an in vivo liver fibrosis model by injecting thioacetamide (TAA) into mice and in vitro model of TGF-β stimulated hepatic stellated cells to explore the inhibition mechanisms and therapeutic potential of J-1048 as an ALK5 inhibitor in liver fibrosis. Our data showed that J-1048 inhibited TAA-induced liver fibrosis in mice by explicitly blocking the TGF-β/Smad signaling pathway. Additionally, J-1048 inhibited the production of inflammatory cytokine Interleukin-1β (IL-1β) by inhibiting the purinergic ligand-gated ion channel 7 receptor (P2X7r) -Nucleotide-binding domain-(NOD-)like receptor protein 3 (NLRP3) axis, thereby alleviating liver fibrosis. Our findings demonstrated that a novel small molecule ALK5 inhibitor, J-1048, exhibited strong potential as a clinical therapeutic candidate for liver fibrosis.

Topics: Animals; Fibrosis; Hepatitis; Inflammation; Liver Cirrhosis; Mice; Mice, Inbred NOD; Protein Serine-Threonine Kinases; Pyrazoles; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta

In pulmonary hypertension (PH), pulmonary arterial remodeling is often accompanied by perivascular inflammation. The inflammation is characterized by the accumulation of activated macrophages and lymphocytes within the adventitial stroma, which is comprised primarily of fibroblasts. The well-known ability of fibroblasts to secrete interleukins and chemokines has previously been implicated as contributing to this tissue-specific inflammation in PH vessels. We were interested if pulmonary fibroblasts from PH arteries contribute to microenvironmental changes that could activate and polarize T-cells in PH.. We used single-cell RNA sequencing of intact bovine distal pulmonary arteries (dPAs) from PH and control animals and flow cytometry, mRNA expression analysis, and respirometry analysis of blood-derived bovine/human T-cells exposed to conditioned media obtained from pulmonary fibroblasts of PH/control animals and IPAH/control patients (CM-(h)PH Fibs vs CM-(h)CO Fibs).. Single-cell RNA sequencing of intact bovine dPAs from PH and control animals revealed a pro-inflammatory phenotype of CD4+ T-cells and simultaneous absence of regulatory T-cells (FoxP3+ Tregs). By exposing T-cells to CM-(h)PH Fibs we stimulated their proinflammatory differentiation documented by increased IFNγ and decreased IL4, IL10, and TGFβ mRNA and protein expression. Interestingly, we demonstrated a reduction in the number of suppressive T-cell subsets, i.e., human/bovine Tregs and bovine γδ T-cells treated with CM-(h)PH-Fibs. We also noted inhibition of anti-inflammatory cytokine expression (IL10, TGFβ, IL4). Pro-inflammatory polarization of bovine T-cells exposed to CM-PH Fibs correlated with metabolic shift to glycolysis and lactate production with increased prooxidant intracellular status as well as increased proliferation of T-cells. To determine whether metabolic reprogramming of PH-Fibs was directly contributing to the effects of PH-Fibs conditioned media on T-cell polarization, we treated PH-Fibs with the HDAC inhibitor SAHA, which was previously shown to normalize metabolic status and examined the effects of the conditioned media. We observed significant suppression of inflammatory polarization associated with decreased T-cell proliferation and recovery of mitochondrial energy metabolism.. This study demonstrates how the pulmonary fibroblast-derived microenvironment can activate and differentiate T-cells to trigger local inflammation, which is part of the vascular wall remodeling process in PH.

Topics: Animals; Cattle; Culture Media, Conditioned; Humans; Hypertension, Pulmonary; Inflammation; Interleukin-10; Interleukin-4; T-Lymphocyte Subsets; Transforming Growth Factor beta

Changes in metabolism of macrophages are required to sustain macrophage activation in response to different stimuli. We showed that the cytokine TGF-β (transforming growth factor-β) regulates glycolysis in macrophages independently of inflammatory cytokine production and affects survival in mouse models of sepsis. During macrophage activation, TGF-β increased the expression and activity of the glycolytic enzyme PFKL (phosphofructokinase-1 liver type) and promoted glycolysis but suppressed the production of proinflammatory cytokines. The increase in glycolysis was mediated by an mTOR-c-MYC-dependent pathway, whereas the inhibition of cytokine production was due to activation of the transcriptional coactivator SMAD3 and suppression of the activity of the proinflammatory transcription factors AP-1, NF-κB, and STAT1. In mice with LPS-induced endotoxemia and experimentally induced sepsis, the TGF-β-induced enhancement in macrophage glycolysis led to decreased survival, which was associated with increased blood coagulation. Analysis of septic patient cohorts revealed that the expression of

Topics: Animals; COVID-19; Cytokines; Glycolysis; Inflammation; Lipopolysaccharides; Macrophages; Mice; Sepsis; Transforming Growth Factor beta

Chronic wounds affect more than 2% of the population worldwide, with a significant burden on affected individuals, healthcare systems, and societies. A key regulator of the entire wound healing cascade is transforming growth factor beta (TGF-β), which regulates not only inflammation and extracellular matrix formation but also revascularization. This present work aimed at characterizing wound tissues obtained from acute and chronic wounds regarding angiogenesis, inflammation, as well as ECM formation and degradation, to identify common disturbances in the healing process. Serum and wound tissues from 38 patients (N = 20 acute and N = 18 chronic wounds) were analyzed. The patients' sera suggested a shift from VEGF/VEGFR to ANGPT/TIE2 signaling in the chronic wounds. However, this shift was not confirmed in the wound tissues. Instead, the chronic wound tissues showed increased levels of MMP9, a known activator of TGF-β. However, regulation of TGF-β target genes, such as

Topics: Biological Assay; Blotting, Western; Humans; Inflammation; Membrane Proteins; Transforming Growth Factor beta; Transforming Growth Factor beta3

Cardiac fibrosis is a common pathological process in heart disease, representing a therapeutic target. Transforming growth factor β (TGFβ) is the canonical driver of cardiac fibrosis and was recently shown to be dependent on interleukin 11 (IL11) for its profibrotic effects in fibroblasts. In the opposite direction, recombinant human IL11 has been reported as anti-fibrotic and anti-inflammatory in the mouse heart. In this study, we determined the effects of IL11 expression in cardiomyocytes on cardiac pathobiology and function. We used the Cre-loxP system to generate a tamoxifen-inducible mouse with cardiomyocyte-restricted murine

Topics: Animals; Cytokines; Humans; Inflammation; Interleukin-11; Mice; Myocytes, Cardiac; Transforming Growth Factor beta

Non-small cell lung cancer (NSCLC) imposes a significant economic burden on patients and society due to its low overall cure and survival rates. Tumour-associated macrophages (TAM) affect tumour development and may be a novel therapeutic target for cancer. We collected NSCLC and tumour-adjacent tissue samples. Compared with the tumour-adjacent tissues, the Activation Transcription Factor 3 (ATF3) and Colony Stimulating Factor 1 (CSF-1) were increased in NSCLC tissues. Levels of ATF3 and CSF-1 were identified in different cell lines (HBE, A549, SPC-A-1, NCI-H1299 and NCI-H1795). Overexpression of ATF3 in A549 cells increased the expression of CD68, CD206 and CSF-1. Moreover, levels of CD206, CD163, IL-10 and TGF-β increased when A549 cells were co-cultured with M0 macrophages under the stimulation of CSF-1. Using the starbase online software prediction and dual-luciferase assays, we identified the targeting between miR-27a-3p and ATF3. Levels of ATF3, CSF-1, CD206, CD163, IL-10 and TGF-β decreased in the miR-27a mimics, and the tumour growth was slowed in the miR-27a mimics compared with the mimics NC group. Overall, the study suggested that miR-27a-3p might inhibit the ATF3/CFS1 axis, regulate the M2 polarization of macrophages and ultimately hinder the progress of NSCLC. This research might provide a new therapeutic strategy for NSCLC.

Topics: Activating Transcription Factor 3; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Humans; Inflammation; Interleukin-10; Lung Neoplasms; Macrophage Colony-Stimulating Factor; Macrophages; MicroRNAs; Transcription Factor 3; Transforming Growth Factor beta

Transforming growth factor-β1 (TGFβ1) is the key profibrotic cytokine in idiopathic pulmonary fibrosis (IPF), but the primary source of this cytokine in this disease is unknown. Platelets have abundant stores of TGFβ1, although the role of these cells in IPF is ill-defined. In this study, we investigated whether platelets, and specifically platelet-derived TGFβ1, mediate IPF disease progression. Patients with IPF and non-IPF patients were recruited to determine platelet reactivity, and separate cohorts of patients with IPF were followed for mortality. To study whether platelet-derived TGFβ1 modulates pulmonary fibrosis (PF), mice with a targeted deletion of TGFβ1 in megakaryocytes and platelets (TGFβ1

Topics: Animals; Bleomycin; Fibrosis; Humans; Idiopathic Pulmonary Fibrosis; Inflammation; Lung; Mice; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factors

The fibrogenic process plays a significant pathophysiological role in the progression of chronic kidney disease. Inhibition of the renin-angiotensin system (RAS) is one strategy to delay disease progression but does not reverse established fibrosis. In this context, induced pluripotent stem cells (iPSCs) have been considered an alternative due to their regenerative potential. iPSCs exert their effects through paracrine signaling, which releases specific biomolecules into the extracellular environment, either directly or within extracellular vesicle (EVs), that can reach target cells. This study aims to evaluate the potential beneficial effects of iPSC-derived EVs (EV-iPSCs) in an in vitro model of fibrosis using mouse mesangial cells (MMCs) stimulated with TGF-β. EV-iPSCs were obtained by differentially ultracentrifuging iPSCs culture medium. MMCs were stimulated with 5 ng/mL of TGF-β and simultaneously treated with or without EV-iPSCs for 24 h. Markers of inflammation, fibrosis, and RAS components were assessed using RT-PCR, western blotting, and immunofluorescence. Under TGF-β stimulus, MMCs exhibited increased expression of inflammation markers, RAS components, and fibrosis. However, these changes were mitigated in the presence of EV-iPSCs. EV-iPSCs effectively reduced inflammation, RAS activation, and fibrogenesis in this fibrosis model involving mesangial cells, suggesting their potential as a strategy to reduce glomerular sclerosis.

Topics: Animals; Extracellular Vesicles; Induced Pluripotent Stem Cells; Inflammation; Mesangial Cells; Mice; Transforming Growth Factor beta

Renovascular hypertension (RHV) is the cause of high blood pressure due to left renal ischemia, and obesity and hypertension cause an inflammatory response. This work analyzed the inflammatory and tissue repair profile in renal, hepatic, and cardiac tissues in an animal model of RVH associated with a high-fat diet and caloric restriction. The expressions of RORγ-t, IL-17, T-bet, and TNF-α decreased and IFN-γ increased in the right kidney. In relation to the left kidney, caloric restriction decreased the expression of IFN-γ. In the liver, caloric restriction decreased RORγ-t, IL-17, and T-bet. Hypertension associated with obesity decreased the expression of IFN-γ, while caloric restriction increased. In the right kidney, hypertension and obesity, associated or not with caloric restriction, increased the area of collagen fibers. In the heart and liver, caloric restriction reduced the area of collagen fibers. Caloric restriction increased vascular endothelial growth factor, reduced levels of growth transformation factor-β1 (TGF-β), and increased collagen I in the left kidney. Hypertension/obesity, submitted or not having caloric restriction, increased TGF-β in liver. The results suggest that caloric restriction has beneficial effects in lowering blood pressure and regulating tissue proinflammatory cytokines. However, there was no change in the structure and composition of tissue repair markers.

Topics: Animals; Caloric Restriction; Collagen; Hypertension, Renovascular; Inflammation; Interleukin-17; Obesity; Rats; Rats, Wistar; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

To evaluate the influence of RORγT inhibition by digoxin on inflammatory changes related to interleukin-17 (IL-17) in the pulp of rats treated with zoledronate (ZOL).. Forty male Wistar rats were divided into a negative control group (NCG) treated with saline solution, a positive control group (PCG) treated with ZOL (0.20 mg/kg), and three groups treated with ZOL and co-treated with digoxin 1, 2, or 4 mg/kg (DG1, 2, and 4). After four intravenous administrations of ZOL or saline solution in a 70-day protocol, the right molars were evaluated by histomorphometry (number of blood vessels, blood vessels/µm2, cells/µm2, total blood vessel area, and average blood vessel area) and immunohistochemistry (IL-17, TNF-α, IL-6, and TGF-β). The Kruskal-Wallis/Dunn test was used for statistical analysis.. PCG showed an increase in total blood vessel area (p=0.008) and average blood vessel area (p=0.014), and digoxin treatment reversed these changes. DG4 showed a reduction in blood vessels/µm2 (p<0.001). In PCG odontoblasts, there was an increase in IL-17 (p=0.002) and TNF-α (p=0.002) immunostaining, and in DG4, these changes were reversed. Odontoblasts in the digoxin-treated groups also showed an increase in IL-6 immunostaining (p<0.001) and a reduction in TGF-β immunostaining (p=0.002), and all ZOL-treated groups showed an increase in IL-17 (p=0.011) and TNF-α (p=0.017) in non-odontoblasts cells.. ZOL induces TNF-α- and IL-17-dependent vasodilation and ectasia, and the classical Th17 response activation pathway does not seem to participate in this process.

Topics: Animals; Dental Pulp; Digoxin; Immunity; Inflammation; Interleukin-17; Interleukin-6; Male; Rats; Rats, Wistar; Saline Solution; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Zoledronic Acid

Dilated cardiomyopathy (DCM) is a severe, non-ischemic heart disease which ultimately results in heart failure (HF). Decades of research on DCM have revealed diverse aetiologies. Among them, familial DCM is the major form of DCM, with pathogenic variants in LMNA being the second most common form of autosomal dominant DCM. LMNA DCM is a multifactorial and complex disease with no specific treatment thus far. Many studies have demonstrated that perturbing candidates related to various dysregulated pathways ameliorate LMNA DCM. However, it is unknown whether these candidates could serve as potential therapeutic targets especially in long term efficacy.. We evaluated 14 potential candidates including Lmna gene products (Lamin A and Lamin C), key signaling pathways (Tgfβ/Smad, mTor and Fgf/Mapk), calcium handling, proliferation regulators and modifiers of LINC complex function in a cardiac specific Lmna DCM model. Positive candidates for improved cardiac function were further assessed by survival analysis. Suppressive roles and mechanisms of these candidates in ameliorating Lmna DCM were dissected by comparing marker gene expression, Tgfβ signaling pathway activation, fibrosis, inflammation, proliferation and DNA damage. Furthermore, transcriptome profiling compared the differences between Lamin A and Lamin C treatment.. Cardiac function was restored by several positive candidates (Smad3, Yy1, Bmp7, Ctgf, aYAP1, Sun1, Lamin A, and Lamin C), which significantly correlated with suppression of HF/fibrosis marker expression and cardiac fibrosis in Lmna DCM. Lamin C or Sun1 shRNA administration achieved consistent, prolonged survival which highly correlated with reduced heart inflammation and DNA damage. Importantly, Lamin A treatment improved but could not reproduce long term survival, and Lamin A administration to healthy hearts itself induced DCM. Mechanistically, we identified this lapse as caused by a dose-dependent toxicity of Lamin A, which was independent from its maturation.. In vivo candidate evaluation revealed that supplementation of Lamin C or knockdown of Sun1 significantly suppressed Lmna DCM and achieve prolonged survival. Conversely, Lamin A supplementation did not rescue long term survival and may impart detrimental cardiotoxicity risk. This study highlights a potential of advancing Lamin C and Sun1 as therapeutic targets for the treatment of LMNA DCM.

Topics: Cardiomyopathies; Cardiomyopathy, Dilated; Fibrosis; Humans; Inflammation; Lamin Type A; Mutation; Transforming Growth Factor beta

Dual-specificity phosphatase 8 (DUSP8) is a MAPK phosphatase that dephosphorylates and inactivates the kinase JNK. DUSP8 is highly expressed in T cells; however, the in vivo role of DUSP8 in T cells remains unclear. Using T cell-specific Dusp8 conditional KO (T-Dusp8 cKO) mice, mass spectrometry analysis, ChIP-Seq, and immune analysis, we found that DUSP8 interacted with Pur-α, stimulated interleukin-9 (IL-9) gene expression, and promoted Th9 differentiation. Mechanistically, DUSP8 dephosphorylated the transcriptional repressor Pur-α upon TGF-β signaling, leading to the nuclear export of Pur-α and subsequent IL-9 transcriptional activation. Furthermore, Il-9 mRNA levels were induced in Pur-α-deficient T cells. In addition, T-Dusp8-cKO mice displayed reduction of IL-9 and Th9-mediated immune responses in the allergic asthma model. Reduction of Il-9 mRNA levels in T cells and allergic responses of T-Dusp8-cKO mice was reversed by Pur-α knockout. Remarkably, DUSP8 protein levels and the DUSP8-Pur-α interaction were indeed increased in the cytoplasm of T cells from people with asthma and patients with atopic dermatitis. Collectively, DUSP8 induces TGF-β-stimulated IL-9 transcription and Th9-induced allergic responses by inhibiting the nuclear translocation of the transcriptional repressor Pur-α. DUSP8 may be a T-cell biomarker and therapeutic target for asthma and atopic dermatitis.

Topics: Active Transport, Cell Nucleus; Animals; Asthma; Dermatitis, Atopic; Dual-Specificity Phosphatases; Humans; Hypersensitivity; Inflammation; Interleukin-9; Mice; RNA, Messenger; Transcription Factors; Transforming Growth Factor beta

Depressive disorder is a common comorbidity of chronic obstructive pulmonary disease (COPD); according to some studies, it occurs in approximately 80% of patients. The presence of depressive symptoms influences the quality of life and affects the course and treatment of this disease. The cause of depressive symptoms in COPD and the linking mechanism between COPD and depressive disorder have not been clearly elucidated, and more studies are warranted. Inflammation and inflammation-related processes and biomarkers are involved in the etiology of COPD and depressive disorder and may be an explanation for the potential occurrence of depressive disorder in patients diagnosed with COPD. The scope of this study was to measure and compare the profiles of IL-18, TGF-β, RANTES, ICAM-1, and uPAR among stable COPD patients, recurrent depressive disorder (rDD) patients, and healthy controls.. Inflammation and inflammation-related factors were evaluated in COPD patients, patients diagnosed with depressive disorder, and control individuals using enzyme-linked immunosorbent assays.. Interleukin (IL)-18, transforming growth factor (TGF)-β, chemokine RANTES, and urokinase plasminogen activator receptor (uPAR) concentrations were higher in patients suffering from COPD and depression than in control patients. Intercellular adhesive molecule (ICAM)-1 levels were significantly higher in COPD patients and lower in depressive disorder patients than in controls.. Higher levels of IL-18, TGF-β, RANTES, and uPAR in patients with COPD might indicate the presence of depressive disorder and suggest the need for further evaluation of the mental state of these patients.

Topics: Biomarkers; Depressive Disorder; Humans; Inflammation; Interleukin-18; Pulmonary Disease, Chronic Obstructive; Quality of Life; Transforming Growth Factor beta

To explore the underlying mechanisms of the effects of Yangqing Chenfei formula (, YCF) on inflammation and fibrosis in silicosis. YCF treatment effectively inhibited lung pathological changes, including inflammatory cell infiltration and tissue damage, and increased the forced expiratory volume in the first 0.3 s, functional residual capacity, and maximal mid-expiratory flow in weeks 2 and 8. Furthermore, the treatment improved lung functions by upregulating tidal volume, pause increase, and expiratory flow at 50% tidal volume from weeks 5 to 8. Moreover, YCF could significantly suppressed the progression of inflammation and fibrosis, by reducing the levels of inflammatory cytokines, as well as collagen- I and III. YCF treatment also decreased the numbers of macrophages and M1/M2 macrophages and the level of transforming growth factor-β (TGF-β). Additionally, YCF5, the effective substance in YCF, decreased lipopolysaccharide and interferon-γ-induced M1 macrophage polarization in a concentration-dependent manner. The mechanism of anti-M1 polarization might be related to a decrease in extracellular signal-regulated kinase, c-JUN N-terminal kinase, P38, and P65 phosphorylation. Furthermore, YCF5 inhibited interleukin-4-induced M2 macrophages by decreasing the protein and mRNA expressions of arginase-1 and CD206 as well as the levels of profibrotic factors, such as TGF-β and connective tissue growth factor. The mechanisms underlying the anti-M2 polarization of YCF5 were primarily associated with the inhibition of the nuclear translocation of phosphorylated signal transducer and activator of transcription 6 (p-STAT6).

Topics: Animals; Fibrosis; Inflammation; Macrophages; Mice; Pneumonia; Rats; Silicon Dioxide; Transforming Growth Factor beta

Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (COVID-19) pandemic. It is the final outcome of the acute respiratory distress syndrome (ARDS), characterized by an initial exacerbated inflammatory response, metabolic derangement and ultimate tissue scarring. A positive balance of cellular energy may result crucial for the recovery of clinical COVID-19. Hence, we asked if two key pathways involved in cellular energy generation, AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) signaling and fatty acid oxidation (FAO) could be beneficial. We tested the drugs metformin (AMPK activator) and baicalin (CPT1A activator) in different experimental models mimicking COVID-19 associated inflammation in lung and kidney. We also studied two different cohorts of COVID-19 patients that had been previously treated with metformin. These drugs ameliorated lung damage in an ARDS animal model, while activation of AMPK/ACC signaling increased mitochondrial function and decreased TGF-β-induced fibrosis, apoptosis and inflammation markers in lung epithelial cells. Similar results were observed with two indole derivatives, IND6 and IND8 with AMPK activating capacity. Consistently, a reduced time of hospitalization and need of intensive care was observed in COVID-19 patients previously exposed to metformin. Baicalin also mitigated the activation of pro-inflammatory bone marrow-derived macrophages (BMDMs) and reduced kidney fibrosis in two animal models of kidney injury, another key target of COVID-19. In human epithelial lung and kidney cells, both drugs improved mitochondrial function and prevented TGF-β-induced renal epithelial cell dedifferentiation. Our results support that favoring cellular energy production through enhanced FAO may prove useful in the prevention of COVID-19-induced lung and renal damage.

Topics: AMP-Activated Protein Kinases; Animals; COVID-19; Fatty Acids; Fibrosis; Humans; Inflammation; Kidney; Lung; Metformin; Respiratory Distress Syndrome; Transforming Growth Factor beta

Previous studies showed that Trichinella spiralis galectin (Tsgal) facilitates larval invasion of intestinal epithelium cells (IECs). However, IEC proteins binding with Tsgal were not identified, and the mechanism by which Tsgal promotes larval invasion is not clear. Toll-like receptors (TLRs) are protein receptors responsible for recognition of pathogens. The aim of this study was to investigate whether recombinant Tsgal (rTsgal) binds to TLR-4, activates inflammatory pathway in gut epithelium and mediates T. spiralis invasion. Indirect immunofluorescence (IIF), GST pull-down and co-immunoprecipitation (Co-IP) assays confirmed specific binding between rTsgal and TLR-4 in Caco-2 cells. qPCR and Western blotting showed that binding of rTsgal with TLR-4 up-regulated the TLR-4 transcription and expression in Caco-2 cells, and activated p-NF-κB p65 and p-ERK1/2. Activation of inflammatory pathway TLR-4/MAPK-NF-κB by rTsgal up-regulated pro-inflammatory cytokines (IL-1β and IL-6) and down-regulated anti-inflammatory cytokine TGF-β in Caco-2 cells, and induced intestinal inflammation. TAK-242 (TLR-4 inhibitor) and PDTC (NF-κB inhibitor) significantly inhibited the activation of TLR-4 and MAPK-NF-κB pathway. Moreover, the two inhibitors also inhibited IL-1β and IL-6 expression, and increased TGF-β expression in Caco-2 cells. In T. spiralis infected mice, the two inhibitors also inhibited the activation of TLR-4/MAPK-NF-κB pathway, ameliorated intestinal inflammation, impeded larval invasion of gut mucosa and reduced intestinal adult burdens. The results showed that rTsgal binding to TLR-4 in gut epithelium activated MAPK-NF-κB signaling pathway, induced the expression of TLR-4 and pro-inflammatory cytokines, and mediated larval invasion. Tsgal might be regarded as a candidate molecular target of vaccine against T. spiralis enteral invasive stage.

Topics: Animals; Caco-2 Cells; Cytokines; Galectins; Humans; Inflammation; Interleukin-6; Intestinal Mucosa; Larva; Mice; NF-kappa B; Rodent Diseases; Toll-Like Receptor 4; Transforming Growth Factor beta; Trichinella spiralis

Glycation, oxidative stress, and inflammation due to the elevation of transforming growth factor-β1 (TGF-β1) participate in diabetic nephropathy (DN). Thus, we investigated for the first time the effect of crocetin (Crt) on the renal histopathological parameters, TGF-β1 and glycation, oxidative stress, as well as inflammatory markers in the DN rat model.. Forty male Wistar rats were randomly divided into 4 equal groups: normal (N), N + Crt, DN, and DN + Crt. DN was induced in rats with a combination of nephrectomy and streptozotocin. Treated groups received 100 mg/kg of Crt via intraperitoneal injection monthly for 3 months. Different glycation (glycated albumin, glycated LDL, Methylglyoxal, and pentosidine), oxidative stress (advanced oxidation protein products, malondialdehyde, glutathione, and paraoxonase-I (PON-1)), and inflammatory markers (tumor necrosis factor-α, myeloperoxidase, and TGF-β1), blood glucose, insulin, lipid profile, creatinine in the serum, and proteinuria, as well as the glyoxalase-1 (GLO-1) activity, was determined.. Crt decreased renal biochemical (Cre and PU) and histopathological (glomerulosclerosis) renal dysfunction parameters, diverse glycation, oxidative stress, and inflammatory markers in the DN rats. Furthermore, the treatment corrected glycemia, insulin resistance, and dyslipidemia as well as induced the activities of GLO-1 and PON-1. Over and above, the treatment decreased TGF-β1 in their serum (p > 0.001).. Crocetin improved DN owing to an advantageous effect on metabolic profile. Further, the treatment with a reducing effect on TGF-β1, oxidative stress, glycation, and inflammation markers along with an increase in Glo-1 activity showed multiple protective effects on kidney tissue.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Inflammation; Male; Rats; Rats, Wistar; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factors

Diabetes mellitus, as an important metabolic disorder, affects the health of millions of people worldwide. A diabetic wound is one of the complications of diabetes. The stem cell secretome can particularly affect the wound healing process in diabetic wounds. The present study aimed to investigate the effects of Adipose-derived stem cells (ASCs) secretome on the skin wound healing process, angiogenesis, and inflammation in diabetic rats. For this purpose, ASCs were extracted from Adipose tissue and confirmed by flow cytometry and cell differentiation. Secretome was prepared. 27 rats were divided into three groups, non-diabetic, diabetic (treated with phosphate-buffered saline), and diabetics treated with secretome. The levels of vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-β) were examined by the enzyme-linked immunosorbent assay (ELISA) was performed in the skin tissues of all groups. Hematoxylin and eosin (H&E) staining was performed. The level of VEGF was higher in the diabetic group treated with secretome as compared to the other two groups, while the level of TGF-β was lower in this group, compared to the diabetic group. Based on the results of H&E staining, the epidermal thickness and angiogenesis were higher in the diabetic group treated with secretome, whereas edema, number of inflammatory cells, and epidermal damage were lower in this group, compared to the diabetic group. Subcutaneous injection of secretome can lead to diabetic wound healing by increasing growth factors associated with angiogenesis such as VEGF, increasing angiogenesis, regulating TGF-β levels, reducing inflammatory cells.

Topics: Animals; Diabetes Mellitus, Experimental; Humans; Inflammation; Neovascularization, Physiologic; Rats; Secretome; Stem Cells; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Cervical-cancer is among the most commonly diagnosed cancers in women, and infection with human papillomavirus (HPV) is associated with an increased risk of cervical cancer and altered serum concentrations of inflammatory cytokines. We have explored the association between a genetic variation in the Interleukin-10 (IL-10) gene (rs1800896) and cervical cancer risk and its relationship with tissue Interferon gamma (IFN-γ), Transforming growth factor beta (TGF-β), Tumor necrosis factor alpha (TNF-α) concentrations in women with cervical cancer.. A total of 315 women with, or without cervical cancer, were recruited into the study. DNA was extracted from cervical cells, and genotyping was undertaken using Taq-man real-time PCR. The genotype frequency and allele distribution were analyzed together with their association with pathological data. The association of the rs1800896 gene variation with tissue levels of the inflammatory cytokines was also investigated.. Our data showed a significant association between the A allele of the rs1800896 gene variant and the presence of cervical cancer. In particular, patients with AG/AA genotypes had an increased risk of cervical cancer with an odds ratio of 1.929 (95% confidence interval [CI]: 0.879-4.23, P < 0.001) in a recessive model, compared with the GG genotype. Also, the tissue concentrations of IFN-γ, TGF-β, and TNF-α in cervical tissues were significantly higher in women with cervical cancer (P < 0.001) and were associated with the AA genotype.. We have found an association between the polymorphism rs1800896 in the IL-10 gene and an increased risk of cervical cancer as well as a higher level of tissue inflammatory cytokines. Further investigations are necessary on the value of emerging biomarkers for the risk stratification for the management of cervical cancer patients.

Topics: Adult; Alleles; Alphapapillomavirus; Cytokines; Female; Gene Frequency; Genotype; Humans; Inflammation; Interferon-gamma; Interleukin-10; Middle Aged; Odds Ratio; Papillomaviridae; Polymorphism, Single Nucleotide; Real-Time Polymerase Chain Reaction; Risk Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Uterine Cervical Neoplasms

Laminectomy can effectively decompress the spinal cord and expand the vertebral canal. However, the fibrosis that appears may cause adherence and recompression of the spinal cord or/and nerve root, which may cause failed back syndrome (FBS) and make the reexposure process more difficult. Reconstruction of the epidural fat may be an ideal method to achieve satisfactory results. Thirty-six New Zealand rabbits were randomly divided into three groups: control, extracellular matrix (ECM), and ECM+aMSCs groups. Saline, ECM gel, and ECM+aMSC complex were placed, respectively, at the fifth lumbar vertebrate of the rabbits. Epidural fat and fibrosis formation were detected by magnetic resonance imaging (MRI) and histologically at the 4th, 8th, and 12th weeks. Quantitative RT-PCR was used to detect the expression of interleukin 6 (IL-6) and transforming growth factor β (TGF-β). MRI and Oil Red O staining revealed epidural fat formation at the 12th week in the ECM+aMSCs group. Hematoxylin and eosin staining showed that the numbers of fibroblasts in the ECM gel and ECM+aMSCs groups were less than the control group at the 4th and 8th weeks (

Topics: Animals; Fibrosis; Inflammation; Interleukin-6; Laminectomy; Rabbits; Transforming Growth Factor beta

This study aimed to examine the levels of transforming growth factor-beta (TGF-β) and inhibitory-Smads (I-Smads) in saliva and gingival crevicular fluid (GCF) in patients with Stage 3 Grade B periodontitis before and after non-surgical periodontal treatment.. Recently, it has been stated that Smads play an active role in all conditions where TGF-β is involved, including periodontal inflammation.. Twenty healthy participants (control) and 20 patients with Stage 3, Grade B periodontitis were recruited. GCF and saliva samples and clinical periodontal recordings were investigated at the baseline and 1 month after treatment. TGF-β and I-Smads (Smads 6 and 7) were determined by ELISA.. Salivary Smad6 and Smad7 levels were significantly lower in the periodontitis group than healthy controls (p < .05), while there was no difference in salivary TGF-β levels between groups at baseline (p > .05). The total amounts and concentrations of GCF TGF-β, Smad6, and Smad7 were significantly lower in the periodontitis group than healthy controls at baseline (p < .05), and then decreased in concentration levels with treatment (p < .001). Positive correlations were found between total amounts and concentrations of GCF TGF-β, Smad6, and Smad7 (p < .05).. Our findings revealed that Smad6 and Smad7 in GCF and saliva decreased in periodontitis and then increased after periodontal treatment. Our study suggests that I-Smads act in parallel with TGF-β in periodontal inflammation and may have a role in the development of periodontitis.

Topics: Gingival Crevicular Fluid; Humans; Inflammation; Periodontitis; Saliva; Transforming Growth Factor beta

Bone marrow failure syndromes are characterized by ineffective hematopoiesis due to impaired fitness of hematopoietic stem cells. They can be acquired during bone marrow stress or innate and are associated with driver genetic mutations. Patients with a bone marrow failure syndrome are at higher risk of developing secondary neoplasms, including myelodysplastic syndromes and leukemia. Despite the identification of genetic driver mutations, the hematopoietic presentation of the disease is quite heterogeneous, raising the possibility that non-genetic factors contribute to the pathogenesis of the disease. The role of inflammation has emerged as an important contributing factor, but remains to be understood in detail. In this study, we examined the effect of increased transforming growth factor-b (TGFb) signaling, in combination or not with an acute innate immune challenge using polyinosinc:polycytidilic acid (pIC), on the hematopoietic system without genetic mutations. We show that acute rounds of pIC alone drive a benign age-related myeloid cell expansion and increased TGFb signaling alone causes a modest anemia in old mice. In sharp contrast, increased TGFb signaling plus acute pIC challenge result in chronic pancytopenia, expanded hematopoietic stem and progenitor cell pools, and increased bone marrow dysplasia 3-4 months after stress, which are phenotypes similar to human bone marrow failure syndromes. Mechanistically, this disease phenotype is uniquely associated with increased mitochondrial content, increased reactive oxygen species and enhanced caspase-1 activity. Our results suggest that chronic increased TGFb signaling modifies the memory of an acute immune response to drive bone marrow failure without the need for a preexisting genetic insult. Hence, non-genetic factors in combination are sufficient to drive bone marrow failure.

Topics: Animals; Bone Marrow Failure Disorders; Hematopoiesis; Hematopoietic Stem Cells; Humans; Inflammation; Mice; Myelodysplastic Syndromes; Pancytopenia; Transforming Growth Factor beta; Transforming Growth Factors

Obesity-induced inflamed visceral adipose tissue (VAT) secretes pro-inflammatory cytokines thereby promoting systemic inflammation and insulin resistance which further exacerbate obesity-associated nonalcoholic fatty liver disease (NAFLD). Transforming growth factor (TGF)-β /Smad3 signaling plays a crucial role in the inflammatory events within the VAT. Here, we investigate whether SP-1154, a novel synthetic verbenone derivative, can inhibit TGF-β/Smad3 signaling thereby exhibiting a therapeutic effect against obesity-induced inflamed VAT and subsequent NAFLD in high-fat diet-induced mice.. NAFLD was induced by a high-fat diet (60% fat) for 20 weeks using the male C57BL/6 mice. SP-1154 (50 mg/kg) was orally given daily for 20 weeks. In vivo VAT- and systemic inflammation were measured by using. SP-1154 inhibited TGF-β/Smad3 signaling pathway and remarkably suppressed high-fat diet-induced VAT inflammation and its related systemic inflammation. Furthermore, SP-1154 significantly improved insulin sensitivity with glucose homeostasis and reduced hepatic steatosis. SP-1154 significantly improves VAT inflammation and obesity-related NAFLD.. Our novel findings support the potential use of SP-1154 as a therapeutic drug for obesity and its related NAFLD by targeting the inflamed VAT.

Topics: Animals; Diet, High-Fat; Glucose Tolerance Test; Inflammation; Insulin Resistance; Intra-Abdominal Fat; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Positron-Emission Tomography; Smad3 Protein; Transforming Growth Factor beta

Although the mechanism of onset and progression of radiation-induced fibrosis (RIF) has been studied, most studies to date have focused on pulmonary fibrosis. There are few studies on murine RIF in the skeletal muscle, and the pathogenic mechanism remains unclear. This pilot study aimed to evaluate the feasibility to create a murine model of RIF in the skeletal muscle and analyze strain differences in fibrosis sensitivity.. Two mouse strains, C57BL/6 and C3H/He, were used. Their right hind limbs were irradiated at a dose of 25 Gy once a week for three fractions. Gastrocnemius muscles were collected at day 4, and weeks 2, 4, 8, 12, and 24 after the third irradiation and subjected to histopathological examination and immunoblotting.. In C57BL/6 mice, chronic inflammation and an increased expression of transforming growth factor-β (TGF-β) and fibronectin were observed 2 weeks after irradiation. A significant increase in fibrosis was detected after 8 weeks. However, in C3H/He mice, the expression of TGF-β and fibronectin increased 8 weeks after irradiation, and fibrosis significantly increased after 12 weeks. Moreover, the degrees of inflammation and fibrosis were more remarkable in C57BL/6 mice than in C3H/He mice.. The onset and degree of fibrosis may be associated with the expression of TGF-β and fibronectin, and inflammation, in a strain-specific manner. Therefore, a murine model of RIF in the skeletal muscle could be created using the indicated method, suggesting that the C57BL/6 strain is more sensitive to fibrosis in the skeletal muscle, as well as the lung, than the C3H/He strain. Radiation-induced fibrosis in the skeletal muscle could be detected in C57BL/6 and C3H/He mice, with C57BL/6 mice being more sensitive to fibrosis in the skeletal muscle than C3H/He mice.

Topics: Animals; Disease Models, Animal; Feasibility Studies; Fibronectins; Fibrosis; Humans; Inflammation; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Muscle, Skeletal; Pilot Projects; Transforming Growth Factor beta

Renal inflammation and fibrosis are observed in underlying diseases associated with the pathological progression of chronic kidney disease (CKD). The inhibition of renal inflammation and fibrosis is one method to suppress the progression of CKD. Juzentaihoto (TJ-48), a Kampo medicine, effectively relieves chronic wasting diseases and fatigue and has been reported to decrease inflammation. In this study, we investigated whether TJ-48 has a renal protective effect and its underlying mechanism in mice with adenine-induced CKD. BALB/c mice were divided into four groups for examination: (1) control, (2) dietary restriction, (3) adenine, and (4) adenine + TJ-48. Biochemical and histological analyses, gene expression analysis, and complete blood counts were performed. TJ-48 treatment decreased tubular damage and fibrosis. TJ-48 also decreased creatinine levels exacerbated by adenine, suppressed the mRNA expression of tumor necrosis factor-α, chemokine ligand 2, transforming growth factor-β, and kidney injury molecule-1, and decreased the neutrophil/lymphocyte ratio increased by adenine. TJ-48 exerts a renoprotective effect possibly via the suppression of fibrosis and inflammation.

Topics: Adenine; Administration, Oral; Animals; Disease Models, Animal; Disease Progression; Drugs, Chinese Herbal; Fibrosis; Hepatitis A Virus Cellular Receptor 1; Inflammation; Kidney Failure, Chronic; Kidney Tubules; Mice, Inbred BALB C; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Loss of Klotho, an anti-aging protein, plays a critical role in the pathogenesis of chronic kidney diseases. As Klotho is a large transmembrane protein, it is challenging to harness it as a therapeutic remedy. Here we report the discovery of a Klotho-derived peptide 1 (KP1) protecting kidneys by targeting TGF-β signaling. By screening a series of peptides derived from human Klotho protein, we identified KP1 that repressed fibroblast activation by binding to TGF-β receptor 2 (TβR2) and disrupting the TGF-β/TβR2 engagement. As such, KP1 blocked TGF-β-induced activation of Smad2/3 and mitogen-activated protein kinases. In mouse models of renal fibrosis, intravenous injection of KP1 resulted in its preferential accumulation in injured kidneys. KP1 preserved kidney function, repressed TGF-β signaling, ameliorated renal fibrosis and restored endogenous Klotho expression. Together, our findings suggest that KP1 recapitulates the anti-fibrotic action of Klotho and offers a potential remedy in the fight against fibrotic kidney diseases.

Topics: Amino Acid Sequence; Animals; Cell Line; Disease Models, Animal; Fibrosis; Humans; Inflammation; Kidney; Kidney Diseases; Klotho Proteins; Male; Mice, Inbred BALB C; Peptides; Phosphorylation; Protective Agents; Protein Binding; Rats; Receptors, Transforming Growth Factor beta; Reperfusion Injury; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Ureteral Obstruction

Topics: Aeromonas; Animal Feed; Animals; Bacillus subtilis; Carps; Dietary Supplements; Ecosystem; Gastrointestinal Microbiome; Immunity, Innate; Immunoglobulin M; Inflammation; Interleukin-10; Interleukin-8; Mercury; NF-kappa B; Probiotics; RNA, Messenger; Selenium; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Anti-CD20 therapy delays type 1 diabetes mellitus (T1DM) progression in both nonobese diabetic (NOD) mice and new-onset patients. The mechanism is not completely defined. This study aimed to investigate the effects of anti-CD20 therapy on T helper 17 (Th17) cells and regulatory T cells (Tregs) in NOD mice. The role of B cell depletion in T1DM development was also examined.. NOD mice were randomly divided into two groups. The mice in the experimental group were treated with an anti-CD20 antibody, while the control mice were treated with an isotype-matched control antibody. After treatment, islet morphology and inflammation, Th17 and Treg cell frequencies in the pancreas and spleen, serum cytokine and anti-glutamic acid decarboxylase (GAD) antibody levels, interleukin (IL)-17A levels in the pancreas and spleen, insulin expression in islet cells and islet β cell function were measured.. Decreased blood glucose and increased insulin secretion were found in the exprimental group compared with the CON group. A lower islet inflammation score was also found in the experimental group. Decreased Th17 cell and IL-17A levels and augmented Treg cell levels were found in the spleen and pancreas after anti-CD20 treatment. The serum levels of B cell activating factor (BAFF), IL-17A, IL-17F, IL-23 and anti-GAD autoantibodies were decreased in the experimental group, while higher serum levels of IL-10 and transforming growth factor (TGF)-β were found.. Anti-CD20 therapy might have some beneficial effects that improve β cell function by relieving islet inflammation through regulation of Th17/Treg cells and the proinflammatory/anti-inflammatory balance.

Topics: Animals; Diabetes Mellitus, Type 1; Humans; Inflammation; Interleukin-17; Mice; Mice, Inbred NOD; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

Topics: Eosinophilia; Humans; Hypersensitivity; Inflammation; Transforming Growth Factor beta

Topics: Brain; DNA Methylation; Humans; Inflammation; Microglia; Multiple Sclerosis; Neurodegenerative Diseases; Transforming Growth Factor beta; White Matter

Marfan syndrome (MFS) is associated with TGF (transforming growth factor) β-stimulated ERK (extracellular signal-regulated kinase) activity in vascular smooth muscle cells (VSMCs), which adopt a mixed synthetic/contractile phenotype. In VSMCs, TGFβ induces IL (interleukin) 11) that stimulates ERK-dependent secretion of collagens and MMPs (matrix metalloproteinases). Here, we examined the role of IL11 in the MFS aorta.. We used echocardiography, histology, immunostaining, and biochemical methods to study aortic anatomy, physiology, and molecular endophenotypes in. In MFS, IL11 is upregulated in aortic VSMCs to cause ERK-related thoracic aortic dilatation, inflammation, and fibrosis. Therapeutic inhibition of IL11, imminent in clinical trials, might be considered as a new approach in MFS.

Topics: Animals; Antibodies, Neutralizing; Aorta; Aortic Diseases; Disease Models, Animal; Elastin; Fibrosis; Immunoglobulin G; Inflammation; Interleukin-11; Interleukin-11 Receptor alpha Subunit; Marfan Syndrome; Matrix Metalloproteinase 2; Mice; Muscle, Smooth, Vascular; Receptors, Interleukin-11; Transforming Growth Factor beta

Inflammation contributes to the pathogenesis of liver disease, and inflammasome activation has been identified as a major contributor to the amplification of liver inflammation. Transforming growth factor-beta (TGF-β) is a key regulator of liver physiology, contributing to all stages of liver disease. We investigated whether TGF-β is involved in inflammasome-mediated fibrosis in hepatic stellate cells. Treatment with TGF-β increased priming of NLRP3 inflammasome signaling by increasing NLRP3 levels and activating TAK1-NF-kB signaling. Moreover, TGF-β increased the expression of p-Smad2/3-NOX4 in LX-2 cells and consequently increased ROS content, which is a trigger for NLRP3 inflammasome activation. Elevated expression of NEK7 and active caspase-1 was also shown in TGF-β-induced LX-2 cells, and this level was reduced by (5Z)-oxozeaenol, a TAK inhibitor. Finally, TGF-β-treated cells significantly increased TGF-β secretion levels, and their production was inhibited by IL-1β receptor antagonist treatment. In conclusion, TGF-β may represent an endogenous danger signal to the active NLRP3 inflammasome, by which IL-1β mediates TGF-β expression in an autocrine manner. Therefore, targeting the NLRP3 inflammasome may be a promising approach for the development of therapies for TGF-β-induced liver fibrosis.

Topics: Hepatic Stellate Cells; Humans; Inflammasomes; Inflammation; Interleukin-1beta; NLR Family, Pyrin Domain-Containing 3 Protein; Transforming Growth Factor beta

The optimal fat processing technique of fat grafting has not been determined. We have proved the importance of washing lipoaspirate to remove blood, but the necessity of washing when there is no obvious bleeding during liposuction is not clear.. The purpose of this study is to further investigate the effect of washing on fat graft survival and the underlying mechanisms, from the perspective of inflammation, oxidative stress and apoptosis.. To exclude the influence of blood, de-erythrocyte infranatant (dEI) isolated from lipoaspirate was obtained. Purified fat processed by cotton pad filtration mixed with dEIs after sedimentation (sedimentation group), washing (washing group) or phosphate buffer solution (control group) was transplanted to nude mice subcutaneously. Samples were harvested at 1 day and 1, 3, 8 weeks after transplantation. Volume and weight retention, histologic examination, immunostaining of perilipin-1, CD31, CD45 and Ly6g, mRNA expression of PPAR-γ, C/EBPα, VEGF, bFGF, IL-6, IL10, TNF-α, TGF-β, Bax and Bcl-2, and protein contents of 8-iso-PGF2α, IL-6, IL10, TNF-α and TGF-β were all compared among groups.. After transplantation, volume and weight retention, histologic scores, viable adipocytes and vascularization were all improved in the washing group, with increased expression of adipogenic and angiogenic genes. Compared with the sedimentation group, the washing group had milder inflammation, lower levels of oxidative stress and apoptosis.. Washing lipoaspirate to eliminate mixed components can improve fat graft survival and promote adipogenesis and angiogenesis, possibly by relieving inflammation, reducing oxidative stress injury and inhibiting apoptosis.. This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of 47 these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266 .

Topics: Adipose Tissue; Animals; Graft Survival; Inflammation; Interleukin-10; Interleukin-6; Mice; Mice, Nude; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Much efforts have been made to probe the mechanism underlying ischemic stroke (IS). This study was proposed to uncover the role of long non-coding RNA rhabdomyosarcoma 2 related transcript (RMST) in IS through microRNA-221-3p (miR-221-3p)/phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1)/transforming growth factor-β (TGF-β) axis. Neurological behavioral function, pathological changes in brain tissue, oxidative stress, and inflammation responses in middle cerebral artery occlusion (MCAO) mice were tested. RMST, miR-221-3p, PIK3R1, and TGF-β signaling-related protein expression in brain tissues of MCAO mice were detected. RMST and PIK3R1 were elevated, miR-221-3p was downregulated, and TGF-β pathway was activated in mice after MCAO. Restored miR-221-3p or depleted RMST improved neurological behavioral functions, relieved pathological injury in brain tissue, and repressed oxidative stress and inflammation in mice after MCAO. Depleted PIK3R1 or restored miR-221-3p offsets the negative effects of overexpressed RMST on mice with MCAO. The present work highlights that RMST augments IS through reducing miR-221-3p-mediated regulation of PIK3R1 and activating TGF-β pathway.

Topics: Animals; Apoptosis; Class Ia Phosphatidylinositol 3-Kinase; Infarction, Middle Cerebral Artery; Inflammation; Ischemic Stroke; Mice; MicroRNAs; RNA, Long Noncoding; Signal Transduction; Stroke; Transforming Growth Factor beta

The pathogenesis of chronic rhinosinusitis (CRS) is still unclear, and little is known about angiogenesis in this disease. We utilized a fully convolutional network (FCN), which has been extensively used in image processing to study angiogenesis in CRS.. To explore the tissue quantification of microvessels and their potential association with inflammation in CRS by using FCN to reflect the angiogenesis condition in CRS.. For endotyping of CRS, tissue homogenates of 79 patients with CRS who had undergone functional endoscopic sinus surgery and 17 control subjects were analyzed for interferon gamma, transforming growth factor beta, interleukin (IL)-1β, IL-5, IL-6, IL-8, IL-10, IL-17, tumor necrosis factor alpha, eosinophilic cationic protein, immunoglobulin E, and Staphylococcus aureus-immunoglobulin E(SE-IgE). A total of 552 hematoxylin and eosin-stained images of 27 CRS tissue samples were used to develop an FCN, going through training, validation, and evaluation processes. An optimized FCN was applied to quantify the microvessels of tissue samples of all subjects. Correlation analysis between microvessel quantification with phenotype, endotype, clinical characteristics, and cytokine expression of CRS was carried out.. Quantification of microvessels in type 2 and non-type 2 CRS demonstrated considerable differences, with a higher expression in type 2 CRS. There was a strong negative correlation between the area ratio of microvessels with tissue tumor necrosis factor alpha and transforming growth factor beta levels and a mildly positive correlation with tissue IL-5 and eosinophilic cationic protein concentration.. FCN proved to facilitate the analysis of microvessels in airway tissue samples. This study elucidated the close association of angiogenesis with endotyping, suggesting that treatment aiming at antagonizing angiogenesis may assist to the therapy for the recrudescent and refractory CRS.

Topics: Chronic Disease; Eosinophil Cationic Protein; Humans; Immunoglobulin E; Inflammation; Interleukin-5; Microvessels; Nasal Polyps; Neural Networks, Computer; Rhinitis; Sinusitis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Obesity is a common comorbid condition in adult asthmatics and known as a feature of asthma severity. However, the molecular mechanism under obesity-induced inflammation has not yet been fully understood.. Considering the essential role of hydrophobic surfactant protein B (SP-B) in lung function, SP-B was targeted to examine its involvement in the development of obesity-induced airway inflammation in asthmatics.. The aim was to examine an alteration in circulating SP-B according to obesity in adult asthmatics, 129 asthmatics were enrolled and classified into 3 groups (obese, overweight and normal-weight groups) according to body mass index (BMI). Circulating SP-B levels were determined by enzyme-linked immunosorbent assay. Four single nucleotide polymorphisms of SFTPB gene were genotyped. Serum ceramide levels were measured by liquid chromatography-tandem mass spectrometry.. Significantly lower serum SP-B levels were noted in the obese group than in the overweight or normal-weight group (p = .002). The serum SP-B level was significantly correlated with serum levels of C18:0 ceramide and transforming growth factor beta 1 as well as BMI (r = -0.200; r = -0.215; r = -0.332, p < .050 for all). An inverse correlation was noted between serum SP-B and fractional exhaled nitric oxide levels in female asthmatics (r = -0.287, p = .009). Genetic predisposition of the SFTPB gene at 9306 A>G to the obese and overweight groups was noted.. Obesity altered ceramide metabolism leading to pulmonary surfactant dysfunction and impaired resolution of airway inflammation, finally contributing to the phenotypes of obese asthmatics.

Topics: Asthma; Ceramides; Female; Humans; Inflammation; Obesity; Overweight; Surface-Active Agents; Transforming Growth Factor beta

Airway inflammation and airway hyperresponsiveness (AHR) are pivotal characteristics of equine asthma. Lipopolysaccharide (LPS) may have a central role in modulating airway inflammation and dysfunction. Therefore, the aim of this study was to match the inflammatory and contractile profile in LPS-challenged equine isolated bronchi to identify molecular targets potentially suitable to counteract AHR in asthmatic horses.. Equine isolated bronchi were incubated overnight with LPS (0.1-100 ng/ml). The contractile response to electrical field stimulation (EFS) and the levels of cytokines, chemokines, and neurokinin A (NKA) were quantified. The role of capsaicin sensitive-sensory nerves, neurokinin-2 (NK. LPS 1 ng/ml elicited AHR to EFS (+238.17 ± 25.20% P < 0.001 vs. control). LPS significantly (P < 0.05 vs. control) increased the levels of IL-4 (+36.08 ± 1.62%), IL-5 (+38.60 ± 3.58%), IL-6 (+33.79 ± 2.59%), IL-13 (+40.91 ± 1.93%), IL-1β (+1650.16 ± 71.16%), IL-33 (+88.14 ± 8.93%), TGF-β (22.29 ± 1.03%), TNF-α (+56.13 ± 4.61%), CXCL-8 (+98.49 ± 17.70%), EOTAXIN (+32.26 ± 2.27%), MCP-1 (+49.63 ± 4.59%), RANTES (+36.38 ± 2.24%), and NKA (+112.81 ± 6.42%). Capsaicin sensitive-sensory nerves, NK. Targeting IL-6 with specific antibody may represent an effective strategy to treat equine asthma, especially in those animals suffering from severe forms of this disease.

Topics: Animals; Asthma; Bronchi; Capsaicin; Horses; Inflammation; Interleukin-33; Interleukin-6; Lipopolysaccharides; Neurokinin A; Transforming Growth Factor beta

Macrophages, mainly divided into M1 pro-inflammatory and M2 anti-inflammatory types, play a key role in the transition from inflammation to repair after trauma. In chronic inflammation, such as diabetes and complex bone injury, or the process of certain inflammatory specific emergencies, the ratio of M1/M2 cell populations is imbalanced so that M1-macrophages cannot be converted into M2 macrophages in time, resulting in delayed trauma repair. Early and timely transformation of macrophages from the pro-inflammatory M1-type into the pro-reparative M2-type is an effective strategy to guide trauma repair and establish the original homeostasis. We prepared purified nano-platelet vesicles (NPVs) and assessed their effects on macrophage phenotype switching through transcriptome analysis. The results elucidate that NPVs promote pathways related to angiogenesis, collagen synthesis, cell adhesion, and migration in macrophages, and we speculate that these advantages may promote healing in traumatic diseases.

Topics: Blood Platelets; Humans; Inflammation; Macrophages; Signal Transduction; Transforming Growth Factor beta

Nonalcoholic steatohepatitis (NASH) is a disease with a high incidence worldwide, but its diagnosis and treatment are poorly managed. In this study, NASH pathophysiology and DNA damage biomarkers were investigated in mice with NASH treated and untreated with melatonin (MLT). C57BL/6 mice were fed a methionine- and choline-deficient (MCD) diet for 4 weeks to develop NASH. Melatonin was administered at 20 mg/kg during the last 2 weeks. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured, and hepatic tissue was dissected for histological analysis, evaluation of lipoperoxidation, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as nuclear factor-erythroid 2 (Nrf2), tumor necrosis factor alpha (TNF-α), inducible nitric oxide synthase (iNOS), and transforming growth factor beta (TGF-β) expression by immunohistochemistry. DNA damage was evaluated using Comet assay, while a micronucleus test in bone marrow was performed to assess the genomic instability associated with the disease. Melatonin decreased AST and ALT, liver inflammatory processes, balloonization, and fibrosis in mice with NASH, decreasing TNF-α, iNOS, and TGF-β, as well as oxidative stress, shown by reducing lipoperoxidation and intensifying Nrf2 expression. The SOD and GPx activities were increased, while CAT was decreased by treatment with MLT. Although the micronucleus frequency was not increased in mice with NASH, a protective effect on DNA was observed with MLT treatment in blood and liver tissues using Comet assay. As conclusions, MLT slows down the progression of NASH, reducing hepatic oxidative stress and inflammatory processes, inhibiting DNA damage via anti-inflammatory and antioxidant actions.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Antioxidants; Aspartate Aminotransferases; Biomarkers; Catalase; Choline; Choline Deficiency; Diet; DNA Damage; Glutathione Peroxidase; Inflammation; Liver; Melatonin; Methionine; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Nitric Oxide Synthase Type II; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Superoxide Dismutase; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

SMAD4, a mediator of TGF-β signaling, plays an important role in T cells to prevent inflammatory bowel disease (IBD). However, the precise mechanisms underlying this control remain elusive. Using both genetic and epigenetic approaches, we revealed an unexpected mechanism by which SMAD4 prevents naive CD8+ T cells from becoming pathogenic for the gut. Prior to the engagement of the TGF-β receptor, SMAD4 restrains the epigenetic, transcriptional, and functional landscape of the TGF-β signature in naive CD8+ T cells. Mechanistically, prior to TGF-β signaling, SMAD4 binds to promoters and enhancers of several TGF-β target genes, and by regulating histone deacetylation, suppresses their expression. Consequently, regardless of a TGF-β signal, SMAD4 limits the expression of TGF-β negative feedback loop genes, such as Smad7 and Ski, and likely conditions CD8+ T cells for the immunoregulatory effects of TGF-β. In addition, SMAD4 ablation conferred naive CD8+ T cells with both a superior survival capacity, by enhancing their response to IL-7, as well as an enhanced capacity to be retained within the intestinal epithelium, by promoting the expression of Itgae, which encodes the integrin CD103. Accumulation, epithelial retention, and escape from TGF-β control elicited chronic microbiota-driven CD8+ T cell activation in the gut. Hence, in a TGF-β-independent manner, SMAD4 imprints a program that preconditions naive CD8+ T cell fate, preventing IBD.

Topics: CD8-Positive T-Lymphocytes; Graft vs Host Disease; Humans; Inflammation; Inflammatory Bowel Diseases; Receptors, Transforming Growth Factor beta; Smad4 Protein; Transforming Growth Factor beta

Endothelial-to-mesenchymal transition (EndMT) has been identified as a critical driver of vascular inflammation and atherosclerosis, and TGF-β (transforming growth factor β) is a key mediator of EndMT. Both EndMT and atherosclerosis are promoted by disturbed flow, whereas unidirectional laminar flow limits EndMT and is atheroprotective. How EndMT and endothelial TGF-β signaling are regulated by different flow patterns is, however, still poorly understood.. Flow chamber experiments in vitro and endothelium-specific knockout mice were used to study the role of tenascin-X in the regulation of EndMT and atherosclerosis as well as the underlying mechanisms.. In human endothelial cells as well as in human and mouse aortae, unidirectional laminar flow but not disturbed flow strongly increased endothelial expression of the extracellular matrix protein TN-X (tenascin-X) in a KLF4 (Krüppel-like factor 4) dependent manner. Mice with endothelium-specific loss of TN-X (EC-Tnxb-KO) showed increased endothelial TGF-β signaling as well as increased endothelial expression of EndMT and inflammatory marker genes. When EC-Tnxb-KO mice were subjected to partial carotid artery ligation, we observed increased vascular remodeling. EC-Tnxb-KO mice crossed to low-density lipoprotein receptor-deficient mice showed advanced atherosclerotic lesions after being fed a high-fat diet. Treatment of EC-Tnxb-KO mice with an anti-TGF-beta antibody or additional endothelial loss of TGF-beta receptors 1 and 2 normalized endothelial TGF-beta signaling and prevented EndMT. In in vitro studies, we found that TN-X through its fibrinogen-like domain directly interacts with TGF-β and thereby interferes with its binding to the TGF-β receptor.. In summary, we show that TN-X is a central mediator of flow-induced inhibition of EndMT, endothelial inflammation and atherogenesis, which functions by binding to and by blocking the activity of TGF-β. Our data identify a novel mechanism of flow-dependent regulation of vascular TGF-β, which holds promise for generating new strategies to prevent vascular inflammation and atherosclerosis.

Topics: Animals; Atherosclerosis; Cells, Cultured; Endothelial Cells; Endothelium; Epithelial-Mesenchymal Transition; Inflammation; Mice; Signal Transduction; Tenascin; Transforming Growth Factor beta

Sarcoidosis is a multisystemic granulomatous inflammation associated with Th17/regulatory T cell (Treg) polarization. As a marker of inflammation, serum amyloid A (SAA) could upregulate the expression of chemokine ligand 20 (CCL20), which induces the migration of Treg cells and Th17 cells by binding and activating thechemokine C-C receptor (CCR) 6. Our goal was to determine whether SAA/anti-CCL20 induces Th17/Treg rebalance in pulmonary sarcoidosis. The deposition of SAA- and Th17/Treg-related proteins in SodA-induced granulomas was tested using immunohistochemistry. Mice with SodA-induced sarcoidosis were treated with SAA or SAA + anti-CCL20, and then Th1/Th2 and Th17/Treg cells were detected by fluorescence-activated cell sorting (FACS) analysis. The expression of SAA/CCL20 and IL-23/IL-17A was detected by enzyme-linked immunosorbent assay (ELISA) and multiplex. Key proteins in the TGF-β/Smad signaling pathway were tested by western blot. SAA mainly plays a pro-inflammatory role by promoting the expression of CCL20 and IL-17A in bronchoalveolar lavage fluid (BALF) and serum, exacerbating this elevation of CD4+/CD8+ T cells in both mediastinal lymph nodes (LNs) and BALF, as well as proliferating Th1 in LNs in SodA-induced pulmonary sarcoidosis. In addition, SAA could also promote the proliferation of Tregs in LNs. Intriguingly, blocking of CCL20 could partially reverse the expression of Th17-related cytokine, ameliorate Th1/Th2 and Treg/Th17 bias in mice with SodA-induced pulmonary sarcoidosis, and rescue the overactivation of the TGF-β/Smad2/Smad3 signaling pathway. Anti-CCL20 may have the potential for therapeutic translation, targeting on the immunopathogenesis of pulmonary sarcoidosis.

Topics: Animals; Chemokines; Inflammation; Interleukin-17; Ligands; Mice; Sarcoidosis; Sarcoidosis, Pulmonary; Serum Amyloid A Protein; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

Topics: Animals; Fibrosis; Hyperuricemia; Inflammation; Iridoids; Kidney Diseases; Mice; Molecular Docking Simulation; Transforming Growth Factor beta; Uric Acid; Xanthine Oxidase

Transforming growth factor-β (TGF-β) is considered to be an important immune regulatory cytokine. However, it remains unknown whether and how the muscle fiber specific-TGF-β signaling is directly involved in intramuscular inflammatory regulation by affecting T cells. Here, we addressed these in a mouse tibialis anterior muscle Cardiotoxin injection-induced injury repair model in muscle creatine kinase (MCK)-Cre control or transgenic mice with TGF-β receptor II (TGF-βr2) being specifically deleted in muscle cells (

Topics: Animals; Cell Differentiation; Inflammation; Interleukin-6; Mice; Muscles; Regeneration; Signal Transduction; Transforming Growth Factor beta

To investigate the therapeutic effect and mechanism of Qingfei oral liquid in idiopathic pulmonary fibrosis. Seventy-two male SD rats were divided into control group, model group, pirofenidone group and Qingfei group with 18 animals in each group. The idiopathic pulmonary fibrosis was induced in last three groups by intratracheal injection of bleomycin; pirofenidone group was given oral administration of pirofenidone b.i.d for 21 d, and Qingfei group was given Qingfei oral liquid 3.6 mL/kg q.d for Lung tissues were obtained for HE staining, Masson staining and transforming growth factor (TGF)-β immunohistochemical staining. Superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione (GSH) were detected in tissue homogenates. The BATMAN-TCM database was used to retrieve the chemical components and their corresponding targets of Qingfei oral solution by network pharmacology method, and then the component-target-disease network diagram was constructed. Finally, the pathway enrichment analysis was carried out to explore the molecular mechanism of Qingfei oral liquid against idiopathic fibrosis. Histopathology results showed that Qingfei oral liquid had a similar relieving effect on pulmonary fibrosis as the positive drug pirfenidone; TGF-β secretion had a significant reduction in lung tissues of Qingfei group; and Qingfei oral liquid had better regulatory effect on SOD, MDA and GSH than pirfenidone. The results of component-target-disease network and pathway enrichment analysis showed that the related molecular pathways were concentrated in inflammation, extracellular matrix and cytokines. Qingfei oral liquid has a good therapeutic effect on idiopathic pulmonary fibrosis in rats via regulation of inflammation, extracellular matrix and cytokines.

Topics: Animals; Bleomycin; Cytokines; Drugs, Chinese Herbal; Glutathione; Idiopathic Pulmonary Fibrosis; Inflammation; Lung; Male; Network Pharmacology; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Transforming Growth Factor beta

The objective of the present research was to assess the influence of inositol supplementation on growth performance, histological morphology of liver, immunity and expression of immune-related genes in juvenile hybrid grouper (♀ Epinephelus fuscoguttatus × ♂ E. lanceolatu). Hybrid grouper (initial weight 6.76 ± 0.34 g) were fed isonitrogenous and isolipidic diets (16%) with various inositol levels of 0.17 g/kg (J1, the control group), 0.62 g/kg (J2), 1.03 g/kg (J3), 1.78 g/kg (J4), 3.43 g/kg (J5), 6.59 g/kg (J6), respectively. The growth experiment lasted for 8 weeks. The results indicated that dietary inositol had a significant promoting effect on final mean body weight of the J5 and J6 groups and specific growth rate (SGR) of the J3, J4, J5 and J6 groups (P < 0.05). In the serum, superoxide dismutase (SOD) of the J4 group became significantly active compared with that of the control group (P < 0.05), while aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (AKP) activities in the inositol-treated groups showed distinctly decreased compared with those of the control group (P < 0.05). In the liver, dietary inositol could significantly increase the activities of SOD, catalase (CAT), lysozyme (LYZ) and the contents of total antioxidative capacity (T-AOC) and immunoglobulin M (IgM) (P < 0.05), and distinctly reduce the content of malondialdehyde (MDA) as well as reactive oxygen species (ROS) (P < 0.05). Compared with the control group, the damaged histological morphology of the liver was relieved and even returned to normal after an inositol increase (0.4-3.2 g/kg). In the liver, the remarkable up-regulation of SOD, CAT, glutathione peroxidase (GPX), heat shock protein70 (HSP70) and heat shock protein90 (HSP90) expression levels were stimulated by supply of inositol, while interleukin 6 (IL6), interleukin 8 (IL8) and transforming growth factor β (TGF-β) expression levels were down-regulated by supply of inositol. In head kidney, the mRNA of toll-like receptor 22 (TLR22), myeloid differentiation factor 88 (MyD88) and interleukin 1β (IL1β) expression levels were significantly down-regulated (P < 0.05), which could further lead to remarkable down-regulation of IL6 and tumor necrosis factor α (TNF-α) expression (P < 0.05). These results indicated that high-lipid diets with supply of inositol promoted growth, increased the antioxidant capacity, and suppressed the inflammation of the liver and head kidney by inhibiting the expression

Topics: Animal Feed; Animals; Antioxidants; Bass; Diet; Dietary Supplements; Immunity, Innate; Inflammation; Inositol; Interleukin-6; Interleukin-8; Lipids; Superoxide Dismutase; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Allergic rhinitis (AR) is regarded as a prevalent and non-infectious inflammation in nasal mucosa, and astragalus polysaccharide (APS) could mitigate inflammation.. Herein, this study probed the specific mechanism of APS in inflammatory responses in AR.. APS reduced Treg/Th17 imbalance via suppressing NF-kB expression, thereby ameliorating inflammatory responses in AR.

Topics: Animals; Disease Models, Animal; Forkhead Transcription Factors; Guinea Pigs; Immunoglobulin E; Inflammation; Interleukin-6; Mice; Mice, Inbred BALB C; Nasal Mucosa; NF-kappa B; Ovalbumin; Polysaccharides; Rhinitis, Allergic; Sneezing; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

CD4

Topics: Animals; Forkhead Transcription Factors; Inflammation; Mice; Neuropilin-1; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Macrophages play a role in preventing inflammation in the respiratory tract. To investigate the mechanisms that lead to tolerance in macrophages, we examined the crosstalk between airway epithelial cells (AECs) and macrophages using a 2D coculture model. Culture of macrophages with AECs led to a significant inhibition of LPS induced pro-inflammatory responses. More importantly, AECs induced the secretion of TGF-β and IL-10 from macrophages even in the absence of LPS stimulation. In addition, the expression of inhibitory molecule, CD200R was also upregulated on AEC exposed macrophages. Furthermore, the AECs exposed macrophages induced significantly increased level of T regulatory cells. Investigation into the possible mechanisms indicated that a combination of growth factor, G-CSF, and metabolites, Kynurenine and lactic acid produced by AECs is responsible for inducing tolerance in macrophages. Interestingly, all these molecules had differential effect on macrophages with G-CSF inducing TGF-β, Kynurenine elevating IL-10, and lactic acid upregulating CD200R. Furthermore, a cocktail of these factors/metabolites induced similar changes in macrophages as AEC exposure. Altogether, these data identify factors secreted by AECs that enhance tolerance in the respiratory tract. These mediators thus have the potential to be used for therapeutic purposes to modulate respiratory inflammation following local viral infections and lung diseases.

Topics: Epithelial Cells; Granulocyte Colony-Stimulating Factor; Humans; Inflammation; Interleukin-10; Kynurenine; Lactic Acid; Lipopolysaccharides; Macrophages; Respiratory Mucosa; Transforming Growth Factor beta

We investigated a role of bone morphogenic protein 7 (BMP7), a member of the TGF-β superfamily on pathogenic mechanism of Graves' orbitopathy (GO). The therapeutic effects of BMP7 on inflammation and fibrosis were evaluated in cultured Graves' orbital fibroblasts.. Expression of BMP7 was compared in cultured orbital tissue explants from GO (n = 12) and normal control (n = 12) subjects using real-time PCR. Orbital fibroblasts were cultured from orbital connective tissues obtained from GO (n = 3) and normal control patients (n = 3). Cells were pretreated with recombinant human BMP7 (rhBMP7) before stimulation with TGF-β, IL-1β, and TNF-α. Fibrosis-related proteins and inflammatory cytokines were analyzed by Western blotting. The activation of signaling molecules in inflammation and fibrosis was also analyzed.. The expressions of BMP7 mRNA were lower in GO orbital tissues than control. Fibrosis-related proteins, fibronectin, collagen 1α, and α-SMA induced by TGF-β were suppressed by treating rhBMP7, and rhBMP7 upregulated TGF-β induced SMAD1/5/8 protein expression, whereas downregulated SMAD2/3. Increased pro-inflammatory molecules, IL-6, IL-8, and intercellular adhesion molecule-1 (ICAM-1) by IL-1β or TNF-α were blocked by rhBMP7 treatment, and the expression of phosphorylated NFκB and Akt was suppressed by rhBMP7 treatment.. BMP7 transcript levels were downregulated in Graves' orbital tissues. Exogenous BMP7 treatment showed inhibitory effects on the production of profibrotic proteins and proinflammatory cytokines in orbital fibroblasts. Our results provide a molecular basis of BMP7 as a new potential therapeutic agent through the opposing mechanism of profibrotic TGF-β/SMAD signaling and proinflammatory cytokine production.

Topics: Bone Morphogenetic Protein 7; Cells, Cultured; Cytokines; Fibroblasts; Fibrosis; Graves Ophthalmopathy; Humans; Inflammation; Orbit; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The preparation of platelet-rich fibrin (PRF) requires blood centrifugation to separate the yellow plasma from the red erythrocyte fraction. PRF membranes prepared from coagulated yellow plasma are then transferred to the defect sites to support tissue regeneration. During natural wound healing, however, it is the unfractionated blood clot (UBC) that fills the defect site. It is unclear whether centrifugation is necessary to prepare a blood-derived matrix that supports tissue regeneration. The aim of the present study was to compare lysates prepared from PRF and UBC based on bioassays and degradation of the respective membranes. We report here that lysates prepared from PRF and UBC membranes similarly activate TGF-β signaling, as indicated by the expression of interleukin 11 (IL-11), NADPH oxidase 4 (NOX-4) and proteoglycan 4 (PRG4) in gingival fibroblasts. Consistently, PRF and UBC lysates stimulated the phosphorylation and nuclear translocation of Smad3 in gingival fibroblasts. We further observed that PRF and UBC lysates have comparable anti-inflammatory activity, as shown by the reduction in lipopolysaccharide (LPS)-induced IL-6, inducible nitric oxidase synthase (iNOS) and cyclooxygenase 2 (COX-2) expression in RAW264.7 cells. Moreover, inflammation induced by Poly (1:C) HMW and FSL-1, which are agonists of Toll-like receptor (TLR) 3 and 2/6, respectively, was reduced by both PRF and UBC. PRF and UBC lysates reduced the nuclear translocation of p65 in LPS-induced RAW264.7 cells. In contrast to the similar activity observed in the bioassays, UBC membranes lack the structural integrity of PRF membranes, as indicated by the rapid and spontaneous disintegration of UBC membranes. We show here that the lysates prepared from PRF and UBC possess robust TGF-β and anti-inflammatory activity. However, visual inspection of the PRF and UBC membranes confirmed the negative impact of erythrocytes on the structural integrity of membranes prepared from whole blood. The data from the present study suggest that although both UBC and PRF have potent TGF-β and anti-inflammatory activity, UBC does not have the strength properties required to be used clinically to prepare applicable membranes. Thus, centrifugation is necessary to generate durable and clinically applicable blood-derived membranes.

Topics: Anti-Inflammatory Agents; Blood Platelets; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Lipopolysaccharides; Platelet-Rich Fibrin; Thrombosis; Transforming Growth Factor beta

The present study aimed to explore the pathogenesis of autoimmune myocarditis induced by PD-1 inhibitors and their potential therapeutic targets. Mouse models of autoimmune myocarditis induced by PD-1 inhibitor in mouse models of polymyositis were established. The expression level of PD-1 and regulatory T cells (Tregs), CD4, CD8 + T cells, inflammation, apoptosis and autophagy-related factors, including IL-6, TGF-β, AMA-M2, Fas/FasL, LC3 and p62 were detected in peripheral blood, muscle or myocardium of mice in each group, using ELISA, RT-PCR, Western Blot and immunofluorescence. In addition, HE and TUNEL staining and ultrastructural scanning were performed on the myocardium of mice in each group. Results showed that the expression level of PD-1 in the two myositis groups was significantly lower than that in the control group, and the level of PD-1 was lower in the myocarditis group than that in the polymyositis group. In the myocardium, TGF-β, p62, and Tregs proportion showed the same expression level trend as PD-1, while CD8, IL-6, IL-10 and LC3 showed the opposite trend. Levels of Fas/FasL were significantly higher in both myositis groups, but were slightly lower in the myocarditis group, as was AMA-M2. Inflammation, apoptosis, and autophagy were observed in both myositis groups, but were more severe in the myocarditis group. In summary, the decreased expression level of PD-1 leads to decreased Tregs level in the myocardium, aggravated inflammatory response, apoptosis and autophagy, which may be the pathological mechanism of myocarditis induced by PD-1 inhibitors.

Topics: Animals; Apoptosis; Autophagy; Immune Checkpoint Inhibitors; Inflammation; Interleukin-6; Mice; Myocarditis; Myocardium; Myositis; Polymyositis; Programmed Cell Death 1 Receptor; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Smad7 restrains TGF-β responses, and has been suggested to exert both pro- and anti-inflammatory actions that may involve effects on macrophages. Myocardial infarction triggers a macrophage-driven inflammatory response that not only plays a central role in cardiac repair, but also contributes to adverse remodeling and fibrosis. We hypothesized that macrophage Smad7 expression may regulate inflammation and fibrosis in the infarcted heart through suppression of TGF-β responses, or via TGF-independent actions. In a mouse model of myocardial infarction, infiltration with Smad7+ macrophages peaked 7 days after coronary occlusion. Myeloid cell-specific Smad7 loss in mice had no effects on homeostatic functions and did not affect baseline macrophage gene expression. RNA-seq predicted that Smad7 may promote TREM1-mediated inflammation in infarct macrophages. However, these alterations in the transcriptional profile of macrophages were associated with a modest and transient reduction in infarct myofibroblast infiltration, and did not affect dysfunction, chamber dilation, scar remodeling, collagen deposition, and macrophage recruitment. In vitro, RNA-seq and PCR arrays showed that TGF-β has profound effects on macrophage profile, attenuating pro-inflammatory cytokine/chemokine expression, modulating synthesis of matrix remodeling genes, inducing genes associated with sphingosine-1 phosphate activation and integrin signaling, and inhibiting cholesterol biosynthesis genes. However, Smad7 loss did not significantly affect TGF-β-mediated macrophage responses, modulating synthesis of only a small fraction of TGF-β-induced genes, including Itga5, Olfml3, and Fabp7. Our findings suggest a limited role for macrophage Smad7 in regulation of post-infarction inflammation and repair, and demonstrate that the anti-inflammatory effects of TGF-β in macrophages are not restrained by endogenous Smad7 induction.

Topics: Animals; Fibrosis; Inflammation; Macrophages; Mice; Myocardial Infarction; Phenotype; Smad7 Protein; Transforming Growth Factor beta

Systemic lupus erythematosus (SLE) is propelled by pathogenic autoantibody (AutoAb) and immune pathway dysregulation. Identifying populations at risk of reaching classified SLE is essential to curtail inflammatory damage. Lupus blood relatives (Rel) have an increased risk of developing SLE. We tested factors to identify Rel at risk of developing incomplete lupus (ILE) or classified SLE vs. clinically unaffected Rel and healthy controls (HC), drawing from two unique, well characterized lupus cohorts, the lupus autoimmunity in relatives (LAUREL) follow-up cohort, consisting of Rel meeting <4 ACR criteria at baseline, and the Lupus Family Registry and Repository (LFRR), made up of SLE patients, lupus Rel, and HC. Medical record review determined ACR SLE classification criteria; study participants completed the SLE portion of the connective tissue disease questionnaire (SLE-CSQ), type 2 symptom questions, and provided samples for assessment of serum SLE-associated AutoAb specificities and 52 plasma immune mediators. Elevated SLE-CSQ scores were associated with type 2 symptoms, ACR scores, and serology in both cohorts. Fatigue at BL was associated with transition to classified SLE in the LAUREL cohort (

Topics: Autoantibodies; Autoimmunity; Humans; Inflammation; Interleukin-10; Lupus Erythematosus, Systemic; Self Report; Surveys and Questionnaires; Transforming Growth Factor beta

Asthma is characterized by persistent inflammation, airway hypersensitivity and remodelling. Bone Morphogenetic Proteins belong to the Transforming Growth Factor Superfamily and have a similar signalling transduction pathway and common co-mediating protein. However, the BMPs role in the remodelling remains unclear; they appear to be involved in the airway inflammation and fibrogenesis process.. 60 patients with asthma and 48 healthy volunteers were recruited for the study. Blood samples were collected before, 1 hour, 24 and 48 hours after the allergen or the methacholine challenge test. Evaluation of BMP-4 and BMP-7 serum concentration and expression was performed using ELISA and real time PCR methods, respectively.. Statistically significant differences in BMP-7 concentration between healthy controls and asthmatics before the chal-lenge were noted. We found two statistically significant correlations: between the basal BMP-4 concentration and the FEV1(L) raw value and FEV1/FVC(%) index. We did not observe significant changes in the gene expression of BMP-4 and BMP-7 in different time points.. Observed differences in BMP-7 concentration between asthmatic and healthy groups and correlations between BMP-4 concentration and some lung function test values may indicate the role of the BMPs in the etiopathogenesis of asthma. The unique characteristic of our study is the evaluation of BMPs serum levels, not in the bronchial epithelium.

Topics: Asthma; Bone Morphogenetic Protein 4; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Humans; Inflammation; Smad Proteins; Transforming Growth Factor beta

This study aimed to investigate whether Forkhead box O3a (FOXO3a) modulates inflammation and oxidative stress in ankylosing spondylitis (AS). We applied bioinformatics analysis, quantitative real-time polymerase chain reaction, immunoblotting, enzyme linked immunosorbent assay, chromatin immunoprecipitation, and dual-luciferase reporter assay. Gene overexpression and knockdown of FOXO3a were conducted

Topics: Antioxidants; Forkhead Box Protein O3; Heme Oxygenase-1; Humans; Inflammation; Oxidative Stress; Spondylitis, Ankylosing; Transforming Growth Factor beta

To study the effects and mechanism of Shenqihuatan formula (, SQHT) of the transforming growth factor-beta (TGF-β)-stimulated cell processes in airway remodeling.. The current study examined cell viability using a Cell Counting Kit-8 assay. Furthermore, a Transwell assay was conducted to detect the ability of cell migration, and apoptosis was detected via flowcytometry. Western Blot and quantitative real-time polymerase chain reaction (qRT-PCR) were used to determine the expression levels of apoptosis or inflammation-related factors, such as TGF-β, Interleukin-1β (IL-1β), B cell lymphoma 2 (Bcl-2), Bcl-2-Associated X (Bax), Ras homolog gene family, member A (RhoA), recombinant rho associated coiled coil containing protein kinase 1/2 (ROCK1/2), extracellular regulated protein kinases 1/2 (ERK1/2), Snail, and Slug. Finally, the expression levels of matrix metalloproteinase-9 (MMP-9) and Tissue inhibitor of metalloproteinase (TIMP-1) were admeasured by enzyme-linked immuno sorbent assay.. The results demonstrated that SQHT inhibited the viability and migration, as well as the the F-actin formation and cytoskeletal reorganization of airway smooth muscle cells (ASMCs) stimulated by TGF-β. By monitoring the changes of critical regulators in the presence of the formula, it was observed that the expression levels of TGF-β, IL-1β, Bcl-2, RhoA, ROCK1/2, ERK1/2, Snail, and Slug were markedly suppressed, whereas Bax expression exhibited the opposite effect. Compared with a well-characterized RhoA pathway inhibitor, Fasudil, SQHT generated equivalent or even higher inhibitory effects on these processes in ASMCs.. Collectively, these suggested that SQHT can reduce airway inflammation by inhibiting TGF-β-stimulated signaling pathways in ASMCs. These findings may provide a novel remedy for treating ASMC inflammation, which causes thickening and obstruction of the airway in chronic obstructive pulmonary disease.

Topics: bcl-2-Associated X Protein; Humans; Inflammation; Myocytes, Smooth Muscle; rho-Associated Kinases; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factors

This study aimed to evaluate the effect of direct pulp capping on the expression of erythropoietin (Epo) and Epo-receptor (Epor) genes in relation to the expression of inflammatory and osteogenic genes in rat pulp. Dental pulps of the first maxillary molars of Wistar Albino rats were exposed and capped with either calcium hydroxide or mineral trioxide aggregate, or were left untreated. After 4 wk, animals were euthanized, and maxillae were prepared for histological and real-time polymerase chain reaction analysis. Histological scores of pulp inflammation and mineralization, and relative expressions of Epo, Epor, inflammatory cytokines, and pulp osteogenic genes were evaluated. The capped pulps showed higher expressions of Epo, while the untreated pulps had the highest expression of Epor. Both calcium hydroxide and mineral trioxide aggregate downregulated the expression of tumor necrosis factor alpha compared to untreated controls, and upregulated transforming growth factor beta compared to healthy controls. Alkaline phosphatase expression was significantly higher in experimental groups. Relative expression of Epo negatively correlated with pulp inflammation, and positively correlated with pulp mineralization. Pulp exposure promoted expression of Epor and pro-inflammatory cytokines, while pulp capping promoted expression of Epo, alkaline phosphatase, and downregulated Epor and pro-inflammatory cytokines.

Topics: Alkaline Phosphatase; Aluminum Compounds; Animals; Calcium Hydroxide; Dental Pulp; Dental Pulp Capping; Drug Combinations; Erythropoietin; Inflammation; Oxides; Rats; Rats, Wistar; Receptors, Erythropoietin; Silicates; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Excessive dietary carbohydrate commonly impairs the functions of liver and intestine in carnivorous fish. In the present study, a 10-week feeding trial was carried out to explore the regulation of biotin on the hepatic and intestinal inflammation and apoptosis in turbot (Scophthalmus maximus L.) fed with high carbohydrate diets. Three isonitrogenous and isolipidic experimental diets were designed as follows: the CC diet with 18.6% of carbohydrate and 0.04 mg/kg of biotin, the HC diet with 26.9% of carbohydrate and 0.05 mg/kg of biotin, and the HCB diet with 26.9% of carbohydrate and 1.62 mg/kg of biotin. Results showed that high dietary carbohydrate (HC diet) impaired the morphology of liver and intestine, however, inclusion of dietary biotin (HCB diet) normalized their morphology. Inflammation-related gene expression of nuclear factor κB p65 (nf-κb p65), tumor necrosis factor α (tnf-α), interleukin-1β (il-1β), il-6 and il-8, and the protein expression of NF-κB p65 in the liver and intestine were significantly up-regulated in the HC group compared to those in the CC group (P < 0.05), the HCB diet decreased their expression compared to the HC group (P < 0.05). The gene expression of il-10 and transforming growth factor-β (tgf-β) in the liver and intestine were significantly decreased in the HC group compared to the CC group (P < 0.05), and inclusion of dietary biotin increased the il-10 and tgf-β expression in the liver and intestine (P < 0.05). Moreover, compared to the CC group, the HC group had a stronger degree of DNA fragmentation and more TUNEL-positive cells in the liver and intestine, and the HCB group had a slighter degree of DNA fragmentation and fewer TUNEL-positive cells compared to the HC group. Meanwhile, the gene expression of B-cell lymphoma protein-2-associated X protein (bax) and executor apoptosis-related cysteine peptidase 3 (caspase-3) were significantly up-regulated and the gene expression of B-cell lymphoma-2 (bcl-2) was significantly down-regulated both in the liver and intestine in the HC group compared with those in the CC group (P < 0.05). Inclusion of dietary biotin significantly decreased the bax and caspase-3 mRNA levels and increased bcl-2 mRNA level in the liver and intestine (P < 0.05). In conclusion, high dietary carbohydrate (26.9% vs 18.6%) induced inflammation and apoptosis in liver and intestine. Supplementation of biotin (1.62 mg/kg vs 0.05 mg/kg) in diet can alleviate the high-dietary-carbohydrate-induced hepatic and

Topics: Animal Feed; Animals; Apoptosis; bcl-2-Associated X Protein; Biotin; Caspase 3; Cysteine; Diet; Dietary Carbohydrates; Dietary Supplements; Flatfishes; Inflammation; Interleukin-10; Interleukin-1beta; Interleukin-6; Interleukin-8; Liver; NF-kappa B; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factors; Tumor Necrosis Factor-alpha

Endogenously produced peptide growth factors such as keratinocyte growth factor-2 (KGF-2) and nerve growth factor (NGF) play a key role in the natural corneal wound healing process. However, this self-healing ability of the corneal tissue is often impaired in cases of severe corneal damage, as in corneal alkali injuries. In the present study, we investigated the clinical and histopathological effects of topical recombinant human keratinocyte growth factor-2 and nerve growth factor treatments in a rabbit model of corneal alkali burn. After induction of an alkali burn, 24 rabbits were divided equally into three groups: control group, KGF-2 group, and NGF group. Clinical parameters including epithelial healing, opacification, neovascularization and central corneal thickness were evaluated on the first (D1), seventh (D7) and fourteenth (D14) days after injury. Corneal histology was performed using hematoxylin/eosin (H&E) and Masson's Trichrome stains. Immunohistochemical staining for matrix metalloproteinase-2 (MMP-2), MMP-9 and transforming growth factor-β (TGF-β) was performed. On D14, the percentage of epithelial defect and opacity were significantly less in the KGF-2 and NGF groups compared to the control group (p < 0.05). There was no significant difference between the groups in central corneal thickness. In the evaluation of neovascularization on D14, the NGF group was significantly less vascularized than the control group (p = 0.011). Histological examination showed a significant increase in stromal edema and inflammation in the control group compared to both treatment groups (p < 0.05). There was also a significant difference between the NGF and control groups in histological evaluation of epithelial repair and vascularization (p < 0.05). When immunoreactivity of MMP-2, MMP-9 and TGF-β was examined, there was a significant increase in the control group compared to the NGF group (p < 0.05). Taken together, both NGF and KGF-2 treatments were effective for early re-epithelialization and decrease in inflammation, opacity and neovascularization after corneal alkali burn. The inhibitory effect of NGF treatment on chemical-induced neovascularization was found to be superior to KGF-2 treatment.

Topics: Alkalies; Animals; Burns, Chemical; Corneal Injuries; Disease Models, Animal; Eosine Yellowish-(YS); Eye Burns; Fibroblast Growth Factor 10; Hematoxylin; Humans; Inflammation; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Nerve Growth Factor; Rabbits; Transforming Growth Factor beta; Transforming Growth Factors; Wound Healing

Toll-like receptor 4 (TLR4) signaling plays a detrimental role in traumatic brain injury (TBI) pathology. Pharmacologic or genetic inactivating TLR4 diminish TBI inflammation and neurological complications. Nonetheless, TLR4 priming alleviates TBI inflammation and seizure susceptibility. We investigated impact of postconditioning with TLR4 agonist monophosphoryl lipid A (MPL) on TBI neuroinflammation and epileptogenesis in rats. TBI was induced in temporo-parietal cortex of rats by Controlled Cortical Impact device. Then rats received a single dose (0.1 μg/rat) of MPL by intracerebroventricular injection. After 24 h, CCI-injured rats received intraperitoneal injection of pentylenetetrazole 35 mg/kg once every other day until acquisition of generalized seizures. The injury size, number of survived neurons, and brain protein level of TNF-α, TGF-β, IL-10, and arginase1 (Arg1) were determined. Astrocytes and macrophage/microglia activation/polarization was assessed by double immunostaining with anti GFAP/Arg1 or anti Iba1/Arg1 antibodies. The CCI-injured rats developed generalized seizures after 5.9 ± 1.3 pentylenetetrazole injections (p < 0.001, compared to 12.3 ± 1.4 injections for sham-operated rats). MPL treatment returned the accelerated rate of epileptogenesis in TBI state to the sham-operated level. MPL did not change damage volume but attenuated number of dead neurons (p < 0.01). MPL decreased TNF-α overexpression (6 h post-TBI p < 0.0001), upregulated expression of TGF-β (48 h post-TBI, p < 0.0001), and IL-10 (48 h post-TBI, p < 0.0001) but did not change Arg1 expression. GFAP/Arg1 and Iba1/Arg1 positive cells were detected in TBI area with no significant change following MPL administration. MPL administration after TBI reduces vulnerability to seizure acquisition through down regulating neural death and inflammation, and up-regulating anti-inflammatory cytokines. This capacity along with the clinical safety, makes MPL a potential candidate for development of drugs against neurological deficits of TBI.

Topics: Animals; Brain Injuries, Traumatic; Disease Models, Animal; Inflammation; Interleukin-10; Neuroinflammatory Diseases; Pentylenetetrazole; Rats; Seizures; Toll-Like Receptor 4; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease, with few therapeutic options available to slow its progression. Aerobic exercise training is an effective strategy for diabetes mellitus and its complications' prevention and treatment. The purpose of this study was to determine the effects of aerobic exercise training on diabetic kidney injury in db/db mice and to characterize the mechanism underlying the renal protective effects. The db/db mice were exercised 5 days a week for 60 min each day for 8 weeks at a speed of 5.6 m/min, after which renal function, morphology, oxidative stress, inflammation, fibrosis, and the expression of the Nox4/ROS/NF-κB/NLRP3 signaling pathway-related protein were assessed. Our results showed that aerobic exercise training significantly reduced body weight and microalbuminuria, improved renal function, and attenuated renal pathological changes in db/db mice independent of hyperglycemic state. Aerobic exercise training was also found to significantly improve oxidative stress and inflammation in the kidneys of db/db mice by decreasing the activity of complex I, the levels of MDA, 8-OHdG, Nox4, ROS, TNF-α, MCP-1, IL-6, and IL-18, increasing the activities of SOD and GSH-Px, the expression of klotho and NPHS2, and decreasing the phosphorylation of NF-κB p65 and IκBα, as well as the expression of NLRP3, ASC, caspase-1 p20, and IL-1β. Additionally, aerobic exercise training decreased TGF-β, collagen I, collagen IV, and α-SMA expression, thereby slowing the progression of kidney fibrosis in db/db mice. In conclusion, aerobic exercise training effectively reduces oxidative stress, inflammation, and renal fibrosis by modulating the Nox4/ROS/NF-κB/NLRP3 signaling pathway, implying that aerobic exercise training has significant potential to protect diabetic kidney injury and should be given more emphasis in DKD treatment.

Topics: Animals; Caspases; Collagen; Diabetic Nephropathies; Exercise; Fibrosis; Inflammasomes; Inflammation; Interleukin-18; Interleukin-6; Kidney; Mice; NADPH Oxidase 4; NF-kappa B; NF-KappaB Inhibitor alpha; NLR Family, Pyrin Domain-Containing 3 Protein; Reactive Oxygen Species; Superoxide Dismutase; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

In this study, we have investigated the effect of Astragaloside IV on keratinocytes' proliferation, migration, oxidative stress, apoptosis, inflammation, and relevant signaling pathway, using human keratinocytes exposed to high glucose.. Astragaloside IV is one of the main active ingredients of Astragalus membranaceus (Fisch.) Bunge. Previous studies have found that Astragaloside IV exerts positive effects in various disease models and promotes wound healing.. Cell proliferation and migration of keratinocytes, oxidative stress indicators, cell apoptosis rate, inflammatory factors, and key proteins in the TGF-β/Smad signaling pathway were evaluated by molecular biology/biochemical techniques, fluorescence microscope, and flow cytometry.. High glucose inhibited the cell proliferation and migration of keratinocytes, upregulated the levels of MDA, ROS, IL-6, IL-8, and Smad7, and decreased the levels of SOD, IL-10, TGF-β1, p-Smad2, and p-Smad3. Astragaloside IV attenuated the dysfunction of keratinocytes, oxidative stress, cell apoptosis, and inflammation, but activated TGF-β/Smad signaling pathway. Meanwhile, the addition of SB431542 (the inhibitor of TGF-β/Smad signaling pathway) eliminated the impact of Astragaloside IV on high glucose-induced keratinocytes.. These results strongly suggest that Astragaloside IV may be a potential drug candidate for accelerating diabetic wound healing, by protecting keratinocytes against damages induced by high glucose and TGF-β/Smad pathway is involved in this process at the cellular level.

Topics: Glucose; Humans; Inflammation; Keratinocytes; Signal Transduction; Transforming Growth Factor beta

In general, starch, as a complex carbohydrate, is the most economical energy source in aquaculture for its relatively low cost. However, excessive dietary levels of carbohydrate result in pathological conditions. An 8-week feeding trial with CT (control diet, containing 21% carbohydrate), HC (a high-carbohydrate diet, containing 50% carbohydrate) and HCR (a HC diet supplemented with 0.015% Rhizoma curcumae Longae) was performed to investigate the protective effect of curcumin on high-carbohydrate-induced hepatic oxidative stress and intestine lesion in juvenile Trachinotus ovatus. In the current study, HC group significantly decreased WGR, SGR, plasma CAT activity, intestinal C4 levels, hepatic Nrf2, Keap1, Bach1, HO1, CAT, and GPX mRNA expression as well as ZO-1, Occludin, and Claudin-3, TGF-β mRNA transcription levels, while the opposite was true for plasma AST activity, hepatic MDA contents, intestinal Claudin-15, NF-κB, IL-1β, IL-6, and TNF-α mRNA expression. In contrast with the HC group, the HCR group significantly increased the activities of hepatic CAT, SOD, intestinal C3, C4, IgG and LZM levels, hepatic Nrf2, Bach1, CAT, and GPX mRNA expression as well as intestinal ZO-1, Occludin, Claudin-3, TGF-β and IL-10 mRNA expression levels, but the opposite trend was found in plasma triglyceride content, hepatic lipid deposition, hepatic Keap1 mRNA level as well as intestinal NF-κB, IL-6. In conclusion, high-carbohydrate diet can cause detrimental effect on physiological health status in Trachinotus ovatus, while adding Rhizoma curcumae Longae can improve hepatic and intestinal health status via attenuating the oxidative stress, inflammation, and reducing lipid deposition.

Topics: Animal Feed; Animals; Claudin-3; Curcumin; Diet; Dietary Carbohydrates; Dietary Supplements; Immunoglobulin G; Inflammation; Interleukin-10; Interleukin-6; Kelch-Like ECH-Associated Protein 1; Lipids; NF-E2-Related Factor 2; NF-kappa B; Occludin; Oxidative Stress; Perciformes; RNA, Messenger; Starch; Superoxide Dismutase; Transforming Growth Factor beta; Triglycerides; Tumor Necrosis Factor-alpha

The Preeclampsia (PE) molecular mechanisms are not fully revealed and different biological processes are involved in the pathogenesis of PE. We aimed to evaluate adenosine and hypoxia-related signaling molecules in PE patients in the current study.. Decidua tissue and peripheral blood samples were taken from 25 healthy pregnant and 25 PE women at delivery time. CD39, CD73, and Hypoxia-inducible factor-alpha (HIF-α) were evaluated in mRNA and protein level using real-time PCR and western blotting techniques, respectively. Also, miR-30a, miR-206, and miR-18a expression were evaluated by real-time PCR. At last, secretion levels of IGF and TGF-β in the taken serum of blood samples were measured by ELISA.. Our results revealed that Expression of CD39 is decreased in PE cases versus healthy controls at mRNA and protein levels (p = 0.0003 for both). CD73 and HIF-α showed an increased level of expression in PE patients at RNA and protein status (p = 0.0157 and p < 0.0001 for protein evaluation of CD73 and HIF-α, respectively). The miRNA-30a (p = 0.0037) and miR-206 (p = 0.0113) showed elevated expression in the decidua of the PE group. The concentration of secreted IGF-1 (p = 0.0002) and TGF-β (p = 0.0101) in serum samples of PE cases compared to the healthy group were decreased.. In conclusion, our results showed that aberrant expression of molecules that are involved in ATP catabolism and the hypoxic conditions is observed in PE cases and involved in their hypertension and inflammation could be served as PE prognosis by more confirming in comprehensive future studies. miR-206 and miR-30a play a role by regulating CD39 and CD73 as molecules that are involved in ATP catabolism as well as regulating the production of IGF-1 in the process of hypertension, which is the main feature in patients with preeclampsia. On the other hand, decreased level of miR-18a lead to upregulation of HIF-1a, and the consequence condition of hypoxia increases hypertension and inflammation in these patients.

Topics: Adenosine Triphosphate; Decidua; Female; Humans; Hypertension; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Insulin-Like Growth Factor I; MicroRNAs; Pre-Eclampsia; Pregnancy; Pregnant Women; RNA, Messenger; Transforming Growth Factor beta

Activation of melanocortin 1 receptor (MC1R) is known to exert broad anti-inflammatory and anti-fibrotic effects. The purpose of this study is to investigate the potential of dersimelagon, a novel oral MC1R agonist, as a therapeutic agent for systemic sclerosis (SSc).. The effects of dersimelagon phosphoric acid (MT-7117) on skin fibrosis and lung inflammation were evaluated in bleomycin (BLM)-induced SSc murine models that were optimized for prophylactic and therapeutic evaluation. Microarray-based gene expression analysis and serum protein profiling were performed in the BLM-induced SSc models. The effect of MT-7117 on transforming growth factor-β (TGF-β)-induced activation of human dermal fibroblasts was evaluated in vitro. Immunohistochemical analyses of MC1R expression in the skin of SSc patients were performed.. Prophylactic treatment with MT-7117 (≥ 0.3 mg/kg/day p.o.) significantly inhibited skin fibrosis and lung inflammation, and therapeutic treatment with MT-7117 (≥ 3 mg/kg/day p.o.) significantly suppressed the development of skin fibrosis in the BLM-induced SSc models. Gene array analysis demonstrated that MT-7117 exerts an anti-inflammatory effect via suppression of the activation of inflammatory cells and inflammation-related signals; additionally, vascular dysfunction was extracted as the pathology targeted by MT-7117. Serum protein profiling revealed that multiple SSc-related biomarkers including P-selectin, osteoprotegerin, cystatin C, growth and differentiation factor-15, and S100A9 were suppressed by MT-7117. MT-7117 inhibited the activation of human dermal fibroblasts by suppressing TGF-β-induced ACTA2 (encoding α-smooth muscle actin) mRNA elevation. MC1R was expressed by monocytes/macrophages, neutrophils, blood vessels (endothelial cells), fibroblasts, and epidermis (keratinocytes) in the skin of SSc patients, suggesting that these MC1R-positive cells could be targets for MT-7117.. MT-7117 demonstrates disease-modifying effects in preclinical models of SSc. Investigations of its mechanism of action and target expression analyses indicate that MT-7117 exerts its positive effect by affecting inflammation, vascular dysfunction, and fibrosis, which are all key pathologies of SSc. The results of the present study suggest that MT-7117 is a potential therapeutic agent for SSc. A phase 2 clinical trial investigating the efficacy and tolerability of MT-7117 in patients with early, progressive diffuse cutaneous SSc is currently in progress.

Topics: Animals; Bleomycin; Blood Proteins; Disease Models, Animal; Endothelial Cells; Fibroblasts; Fibrosis; Humans; Inflammation; Mice; Pneumonia; Receptor, Melanocortin, Type 1; Scleroderma, Systemic; Signal Transduction; Skin; Transforming Growth Factor beta

Wound healing is a highly conserved process that restores the integrity and functionality of injured tissues. Transforming growth factor (TGF)-β is a master regulator of wound healing, whose signaling is attenuated by the E3 ubiquitin ligase Smurf2. Herein, the roles of Smurf2 in cutaneous wound healing were examined using a murine incisional cutaneous model. Loss of Smurf2 increased early inflammation in the wounds and led to narrower wounds with greater breaking strength. Loss of Smurf2 also led to more linearized collagen bundles in normal and wounded skin. Gene expression analyses by real-time quantitative PCR indicated that Smurf2-deficient fibroblasts had increased levels of TGF-β/Smad3 signaling and changes in expression profile of genes related to matrix turnover. The effect of Smurf2 loss on wound healing and collagen bundling was attenuated by the heterozygous loss of Smad3. Together, these results show that Smurf2 affects inflammation and collagen processing in cutaneous wounds by down-regulating TGF-β/Smad3 signaling.

Topics: Animals; Collagen; Inflammation; Mice; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factors; Wound Healing

Berberine (BBR), an alkaloid produced by a traditional Chinese plant, was recently attributed multiple effects on lipometabolism, inflammation, and fibrosis. Thyroid-associated ophthalmopathy (TAO) is highly associated with these pathologic changes. Thus, we aimed to examine the potential therapeutic effect of BBR in an in vitro model of TAO.. Orbital fibroblasts (OFs) obtained from control donors (n = 6) or patients with TAO (n = 6) were cultured. The CCK-8 assay was conducted for assessing the optimal concentration range. Oil Red O staining, Western blotting, and quantitative RT-PCR (qRT-PCR) were conducted to assess adipogenesis in OFs. RNA sequencing (RNA-seq) was used to screen the key pathways of the antiadipogenic effect mediated by BBR. Along with incremental concentrations of BBR, IL-1β-induced expression of proinflammatory molecules was determined by ELISA and qRT-PCR. In addition, TGF-β-induced hyaluronan (HA) production and fibrosis were evaluated by ELISA, qRT-PCR, and Western blotting.. TAO-OFs, but not control fibroblasts (CON-OFs), were readily differentiated into adipocytes with the commercial medium. Intracellular lipid accumulation was dose-dependently decreased by BBR, and adipogenic markers were also downregulated. Moreover, the PPARγ and AMPK pathways were screened out by RNA-seq and their downstream effectors were suppressed by BBR. Besides, BBR attenuated IL-1β-induced expression of proinflammatory molecules in both TAO-OFs and CON-OFs by blocking nuclear factor-κB signaling. BBR's inhibitory effect on TGF-β-mediated tissue remodeling was also confirmed in OFs.. These findings demonstrate BBR has outstanding capabilities of controlling adipogenesis, inflammation, HA production, and fibrosis in OFs, highlighting its potential therapeutic role in TAO management.

Topics: Berberine; Fibroblasts; Fibrosis; Graves Ophthalmopathy; Humans; Hyaluronic Acid; Inflammation; Orbit; Transforming Growth Factor beta

Zinc oxide nanoparticles (ZnO-NPs) are currently employed in various products such as rubber, paint, and cosmetics. Our group reported recently that Nrf2 protein provides protection against pulmonary inflammation induced by ZnO-NPs in male mice. The current study investigated the effect of Nrf2 deletion on the lung inflammatory response in female mice exposed to ZnO-NPs.. We conclude that Nrf2 provides protection in female mice against increase in BALF eosinophils, probably through down-regulation of proinflammatory cytokines/chemokines and upregulation of oxidative stress-related genes. The study also suggests lower susceptibility to lung tissue inflammation in female mice relative to their male counterparts and the synergistic effects of Nrf2 and exposure to ZnO-NPs on mRNA expression of GcLc, GR, HO-1, TGF-β or TNF-α in female mice.

Topics: Animals; Antioxidants; Cytokines; Female; Glutathione Disulfide; Inflammation; Interleukin-6; Lung; Male; Mice; Nanoparticles; NF-E2-Related Factor 2; Oxidative Stress; Pneumonia; RNA, Messenger; Rubber; Sex Characteristics; Superoxide Dismutase-1; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Zinc Oxide

Cigarette smoke (CS) is one of the major risk factors for chronic obstructive pulmonary disease (COPD) and increases the risk of lung cancer (LC). Anemoside B4 (B4) is the main bioactive ingredient in Pulsatilla chinensis (P. chinensis), a traditional medicinal herb for various diseases. It has a wide range of anti-inflammatory, anti-oxidation and anti-cancer activities. However, in recent years, there is no relevant literature report on the therapeutic effect of B4 on COPD, and the anti-inflammatory and inhibitory effects of anemoside B4 on basal cell hyperplasia in CS-induced COPD have not been clearly established.. In the present study, we investigated whether anemoside B4 could alleviate CS or cigarette smoke extract (CSE) induced inflammation of COPD and further prevent basal cell hyperplasia, hoping to find its possible mechanism.. In this study, a COPD mouse model was established in C57BL mice by CS exposure 3 months. Bronchial pathology and basal cell hyperplasia were observed by HE staining and immunostaining. The contents of glutathione peroxidase catalase (GSH-PX), malondialdehyde (MDA) and superoxide dismutase (MPO) were determined by GSH-PX, MDA and SOD assay kits, respectively. 16HBE cells were cultured with 5% CSE with or without treatment with B4 (1, 10, 100 μM) or DEX (20 μM) in vitro. Cell viability was assessed by a cell counting kit 8 (CCK-8). Reactive oxygen species (ROS) generation was tested by DCFH-DA. Moreover, anti-inflammatory mechanism of anemoside B4 was further determined by pro-inflammatory cytokines production using RT-PCR. Protein expression levels of MAPK/AP-1/TGF-β signaling pathway were measured by western blot.. Anemoside B4 improved the lung function of mice, relieved lung inflammation and reduced the MDA, MPO and GSH-Px in the plasma. At the same time, B4 repressed the oxidative stress response and played a role in balancing the levels of protease and anti-protease. During the process of bronchial basal cell hyperplasia, B4 alleviated the degree of cell hyperplasia, and prevented further deterioration of hyperplasia through increased P53 and inhibited FHIT protein. In addition, B4 reduced ROS levels in human bronchial epithelial cells stimulated by CSE in vitro study. Meanwhile, B4 treatment also significantly attenuated increased IL-1β, TGF-β, IL-8 and TNF-α from CSE treated human bronchial epithelial cells. The expression of p-P38, AP-1(c-fos, and c-Jun), TGF-β proteins in MAPK/AP-1/TGF-β signaling pathway were decreased and the signal cascade reaction was blocked.. Anemoside B4 protects against CS-induced COPD. These findings indicated that B4 may have therapeutic potential for the prevention and treatment of COPD.

Topics: Animals; Anti-Inflammatory Agents; Catalase; Cigarette Smoking; Glutathione Peroxidase; Humans; Hyperplasia; Inflammation; Interleukin-8; Malondialdehyde; Mice; Mice, Inbred C57BL; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Saponins; Superoxide Dismutase; Transcription Factor AP-1; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by progressive heterotopic ossification (HO) in soft tissues due to a heterozygous mutation of the ACVR1A gene (FOP-ACVR1A), which erroneously transduces the BMP signal by Activin-A. Although inflammation is known to trigger HO in FOP, the role of FOP-ACVR1A on inflammatory cells remains to be elucidated.. We generated immortalized monocytic cell lines from FOP-iPSCs (FOP-ML) and mutation rescued iPSCs (resFOP-ML). Cell morphology was evaluated during the monocyte induction and after immortalization. Fluorescence-activated cell sorting (FACS) was performed to evaluate the cell surface markers CD14 and CD16 on MLs. MLs were stimulated with lipopolysaccharide or Activin-A and the gene expression was evaluated by quantitative PCR and microarray analysis. Histological analysis was performed for HO tissue obtained from wild type mice and FOP-ACVR1A mice which conditionally express human mutant ACVR1A gene by doxycycline administration. Without any stimulation, FOP-ML showed the pro-inflammatory signature of CD16+ monocytes with an upregulation of INHBA gene, and treatment of resFOP-ML with Activin-A induced an expression profile mimicking that of FOP-ML at baseline. Treatment of FOP-ML with Activin-A further induced the inflammatory profile with an up-regulation of inflammation-associated genes, of which some, but not all, of which were suppressed by corticosteroid. Experiments using an inhibitor for TGFβ or BMP signal demonstrated that Activin-A-induced genes such as CD16 and CCL7, were regulated by both signals, indicating Activin-A transduced dual signals in FOP-ML. A comparison with resFOP-ML identified several down-regulated genes in FOP-ML including LYVE-1, which is known to suppress matrix-formation in vivo. The down-regulation of LYVE-1 in HO tissues was confirmed in FOP model mice, verifying the significance of the in vitro experiments.. These results indicate that FOP-ML faithfully recapitulated the phenotype of primary monocytes of FOP and the combination with resFOP-ML is a useful tool to investigate molecular events at the initial inflammation stage of HO in FOP.

Topics: Activin Receptors, Type I; Activins; Animals; Doxycycline; Humans; Inflammation; Lipopolysaccharides; Mice; Monocytes; Mutation; Myositis Ossificans; Ossification, Heterotopic; Signal Transduction; Transforming Growth Factor beta

The dramatic upsurge of Clostridioides difficile infection (CDI) by hypervirulent isolates along with the paucity of effective conventional treatment call for the development of new alternative medicines against CDI. The inhibitory effects of curcumin (CCM) and capsaicin (CAP) were investigated on the activity of toxigenic cell-free supernatants (Tox-S) of C. difficile RT 001, RT 126 and RT 084, and culture-filtrate of C. difficile ATCC 700057.. Cell viability of HT-29 cells exposed to varying concentrations of CCM, CAP, C. difficile Tox-S and culture-filtrate was assessed by MTT assay. Anti-inflammatory and anti-apoptotic effects of CCM and CAP were examined by treatment of HT-29 cells with C. difficile Tox-S and culture-filtrate. Expression of BCL-2, SMAD3, NF-κB, TGF-β and TNF-α genes in stimulated HT-29 cells was measured using RT-qPCR.. C. difficile Tox-S significantly (P < 0.05) reduced the cell viability of HT-29 cells in comparison with untreated cells. Both CAP and CCM significantly (P < 0.05) downregulated the gene expression level of BCL-2, SMAD3, NF-κB and TNF-α in Tox-S treated HT-29 cells. Moreover, the gene expression of TGF-β decreased in Tox-S stimulated HT-29 cells by both CAP and CCM, although these reductions were not significantly different (P > 0.05).. The results of the present study highlighted that CCM and CAP can modulate the inflammatory response and apoptotic effects induced by Tox-S from different clinical C. difficile strains in vitro. Further studies are required to accurately explore the anti-toxin activity of natural components, and their probable adverse risks in clinical practice.

Topics: Anti-Inflammatory Agents; Apoptosis; Bacterial Toxins; Capsaicin; Clostridioides; Clostridioides difficile; Clostridium Infections; Curcumin; Humans; Inflammation; NF-kappa B; Proto-Oncogene Proteins c-bcl-2; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by inflammation, microangiopathy, and progressive fibrosis in the skin and internal organs. To evaluate the pathophysiologic mechanisms and efficacies of potential therapeutics for SSc, a preclinical model recapitulating the disease phenotypes is needed. Here, we introduce a novel animal model for SSc using immunodeficient mice injected with peripheral blood mononuclear cells (PBMCs) from SSc patients. Human PBMCs acquired from SSc patients and healthy controls were transferred into NOD.Cg-Prkdc

Topics: Animals; Bleomycin; Disease Models, Animal; Fibrosis; Humans; Inflammation; Interleukin-17; Leukocytes, Mononuclear; Lung; Mice; Mice, Inbred NOD; Mice, SCID; Scleroderma, Systemic; Skin; Th17 Cells; Transforming Growth Factor beta

Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease (ESRD) worldwide. Currently, there is no effective treatment to completely prevent DKD progression to ESRD. Renal fibrosis and inflammation are the major pathological features of DKD, being pursued as potential therapeutic targets for DKD.. Inflammation and renal fibrosis are involved in the pathogenesis of DKD. Anti-inflammatory drugs have been developed to combat DKD but without efficacy demonstrated. Thus, we have focused on the mechanisms of TGF-β-induced renal fibrosis in DKD, as well as discussing the important molecules influencing the TGF-β signaling pathway and their potential development into new pharmacotherapies, rather than targeting the ligand TGF-β and/or its receptors, such options include Smads, microRNAs, histone deacetylases, connective tissue growth factor, bone morphogenetic protein 7, hepatocyte growth factor, and cell division autoantigen 1.. TGF-β is a critical driver of renal fibrosis in DKD. Molecules that modulate TGF-β signaling rather than TGF-β itself are potentially superior targets to safely combat DKD. A comprehensive elucidation of the pathogenesis of DKD is important, which requires a better model system and access to clinical samples via collaboration between basic and clinical researchers.

Topics: Autoantigens; Bone Morphogenetic Protein 7; Connective Tissue Growth Factor; Diabetes Mellitus; Diabetic Nephropathies; Fibrosis; Hepatocyte Growth Factor; Histone Deacetylases; Humans; Inflammation; Kidney; Kidney Failure, Chronic; Ligands; MicroRNAs; Transforming Growth Factor beta; Transforming Growth Factors

Transcatheter arterial embolization (TAE) is one of the first-line treatments for advanced hepatocellular cancer. The pain caused by TAE is a stark complication, which remains to be prevented by biomedical engineering methods.. In summary, CB/Lid-10 has relatively good biocompatibility and bioactivity, and it can serve as a promising candidate for painless transcatheter arterial embolization.

Topics: Carrageenan; Embolization, Therapeutic; Hemolysis; Humans; Inflammation; Interleukin-10; Interleukin-6; Lidocaine; Transforming Growth Factor beta

Airway epithelial damage is a common feature in respiratory diseases such as COPD and has been suggested to drive inflammation and progression of disease. These features manifest as remodeling and destruction of lung epithelial characteristics including loss of small airways which contributes to chronic airway inflammation. Histone deacetylase 6 (HDAC6) has been shown to play a role in epithelial function and dysregulation, such as in cilia disassembly, epithelial to mesenchymal transition (EMT) and oxidative stress responses, and has been implicated in several diseases. We thus used ACY-1083, an inhibitor with high selectivity for HDAC6, and characterized its effects on epithelial function including epithelial disruption, cytokine production, remodeling, mucociliary clearance and cell characteristics. Primary lung epithelial air-liquid interface cultures from COPD patients were used and the impacts of TNF, TGF-β, cigarette smoke and bacterial challenges on epithelial function in the presence and absence of ACY-1083 were tested. Each challenge increased the permeability of the epithelial barrier whilst ACY-1083 blocked this effect and even decreased permeability in the absence of challenge. TNF was also shown to increase production of cytokines and mucins, with ACY-1083 reducing the effect. We observed that COPD-relevant stimulations created damage to the epithelium as seen on immunohistochemistry sections and that treatment with ACY-1083 maintained an intact cell layer and preserved mucociliary function. Interestingly, there was no direct effect on ciliary beat frequency or tight junction proteins indicating other mechanisms for the protected epithelium. In summary, ACY-1083 shows protection of the respiratory epithelium during COPD-relevant challenges which indicates a future potential to restore epithelial structure and function to halt disease progression in clinical practice.

Topics: Cytokines; Epithelial Cells; Epithelial-Mesenchymal Transition; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Inflammation; Lung; Mucins; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Tight Junction Proteins; Transforming Growth Factor beta

Childhood obesity carries an increased risk of metabolic complications, sleep disturbances, and cancer. Visceral adiposity is independently associated with inflammation and insulin resistance in obese children. However, the underlying pathogenic mechanisms are still unclear. We aimed to detect the gene expression pattern and its regulatory network in the visceral adipose tissue of obese pediatric individuals. Using differentially-expressed genes (DEGs) identified from two publicly available datasets, GSE9624 and GSE88837, we performed functional enrichment, protein-protein interaction, and network analyses to identify pathways, targeting transcription factors (TFs), microRNA (miRNA), and regulatory networks. There were 184 overlapping DEGs with six significant clusters and 19 candidate hub genes. Furthermore, 24 TFs targeted these hub genes. The genes were regulated by miR-16-5p, miR-124-3p, miR-103a-3p, and miR-107, the top miRNA, according to a maximum number of miRNA-mRNA interaction pairs. The miRNA were significantly enriched in several pathways, including lipid metabolism, immune response, vascular inflammation, and brain development, and were associated with prediabetes, diabetic nephropathy, depression, solid tumors, and multiple sclerosis. The genes and miRNA detected in this study involve pathways and diseases related to obesity and obesity-associated complications. The results emphasize the importance of the TGF-β signaling pathway and its regulatory molecules, the immune system, and the adipocytic apoptotic pathway in pediatric obesity. The networks associated with this condition and the molecular mechanisms through which the potential regulators contribute to pathogenesis are open to investigation.

Topics: Child; Gene Regulatory Networks; Humans; Inflammation; Intra-Abdominal Fat; MicroRNAs; Pediatric Obesity; RNA, Messenger; Transcription Factors; Transforming Growth Factor beta

Topics: Amino Acids; Animals; Brain Neoplasms; Brain-Gut Axis; Carcinogenesis; Colitis; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Hippocampus; Inflammation; Inflammatory Bowel Diseases; Interleukin-6; Lipids; Mice; Mice, Inbred C57BL; Neurogenesis; Sulfates; Thiamine; Transforming Growth Factor beta

Chronic liver inflammation can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Kupffer cells (KC) secrete proinflammatory and fibrogenic cytokines in response to lipopolysaccharide (LPS), and so play an important role in liver inflammation, where they induce hepatocellular damage. LPS also activates hepatic stellate cells and induces extracellular matrix deposition. In this study, we used isolated primary KC, primary hepatocytes, and primary hepatic stellate cells (HSC) to investigate whether evogliptin directly inhibits inflammatory and fibrotic signaling. We found that evogliptin inhibited LPS-induced secretion of inducible nitric oxide synthase and transforming growth factor β (TGF-β) from KC. Moreover, evogliptin inhibited inflammatory mediator release from hepatocytes and hepatic stellate cell activation that were induced by KC-secreted cytokines. In hepatocytes, evogliptin also inhibited LPS-induced expression of proinflammatory cytokines and fibrotic TGF-β. In addition, evogliptin inhibited TGF-β-induced increases in connective tissue growth factor levels and HSC activation. These findings indicate that evogliptin inhibits inflammatory and fibrotic signaling in liver cells. We also showed that the inhibitory effect of evogliptin on inflammatory and fibrotic signaling is associated with the induction of autophagy.

Topics: Connective Tissue Growth Factor; Cytokines; Fibrosis; Hepatic Stellate Cells; Hepatocytes; Humans; Inflammation; Inflammation Mediators; Lipopolysaccharides; Liver; Liver Cirrhosis; Nitric Oxide Synthase Type II; Piperazines; Transforming Growth Factor beta

Topics: Adaptive Immunity; Animals; Arthrodermataceae; Cytokines; Inflammation; Interleukin-10; Interleukin-12; Interleukin-17; Interleukin-23; Interleukin-6; Microsporum; RNA, Messenger; Th17 Cells; Toll-Like Receptor 2; Toll-Like Receptor 4; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Ursidae

The mechanism of the recovery of immune inflammation in the intestine remains to be investigated. The calcitonin-related protein (CGRP; neuropeptide) has immune regulatory capacity. We observed that lower levels of CGRP were found in the colon biopsies of UC patients. CGRP were negatively correlated to TNF-α, IL-1β and IFN-γ in biopsy samples. The levels of TGF-β were lower in the UC group than that of the normal control (NC) group, which were positively correlated with the CGRP levels. Blocking CGRP significantly delayed recovery from colitis inflammation. CGRP induced the TGF-β-expressing CD4

Topics: Animals; Calcitonin Gene-Related Peptide; Colitis; Inflammation; Intestines; Macrophages; Mice; Transforming Growth Factor beta

Acute lung injury (ALI) is a systemic inflammatory process. A large number of studies have shown that astaxanthin (ASTA) has strong anti-inflammatory effects and almost non-toxic side effects. The purpose of this study was to explore the effect of ASTA on lipopolysaccharide (LPS)-induced ALI in mice and its underlying mechanism. The result showed that compared with the LPS group, the expression levels of the respiratory resistance (Re), inspiratory resistance (Ri), dynamic lung compliance (Cdyn), wet/dry weight (W/D) ratio, albumin (BA/SA) ratio and myeloperoxidase (MPO) activity in the ASTA pretreatment group were significantly reduced, and total cell, neutrophil and macrophage counts were significantly decreased. HE staining results showed that alveolar interstitial edema, bleeding and erythrocyte exudation were reduced. Compared with the LPS group, the percentage of Th17 cells and the content of interleukin (IL)-17 and tumor necrosis factor-α (TNF-α) in the ASTA pretreatment group were significantly decreased, while the content of the transforming growth factor (TGF)-β and the percentage of Treg cells were significantly increased. Western blot analysis showed that ASTA could up-regulate the expression level of the suppressor of cytokine signaling-3 (SOCS3) and down-regulate the expression levels of phosphorylated Janus kinase 2 (p-JAK2), phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in lung tissue. The results showed that ASTA had a protective effect on LPS-induced acute lung injury in mice, and its protective mechanism was through activating the SOCS3/JAK2/STAT3 signaling pathway, promoting Treg cell differentiation and reducing inflammatory reactions and Th17 cell differentiation, which provided a theoretical basis for the clinical treatment of ALI.

Topics: Acute Lung Injury; Animals; Inflammation; Janus Kinase 2; Lipopolysaccharides; Lung; Mice; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Transforming Growth Factor beta

Catechol-O-methyltransferase (COMT) has been shown to influence clinical pain, descending modulation, and exercise-induced symptom worsening. COMT regulates nociceptive processing and inflammation, key pathophysiological features of Chronic Fatigue Syndrome and Fibromyalgia (CFS/FM). We aimed to determine the interactions between genetic and epigenetic mechanisms regulating COMT and its influence on inflammatory markers and symptoms in patients with CFS/FM.. A case-control study with repeated-measures design was used to reduce the chance of false positive and increase the power of our findings. Fifty-four participants (28 patients with CFS/FM and 26 controls) were assessed twice within 4 days. The assessment included clinical questionnaires, neurophysiological assessment (pain thresholds, temporal summation, and conditioned pain modulation), and blood withdrawal in order to assess rs4818, rs4633, and rs4680 COMT polymorphisms and perform haplotype estimation, DNA methylation in the COMT gene (both MB-COMT and S-COMT promoters), and cytokine expression (TNF-α, IFN-γ, IL-6, and TGF-β).. COMT haplotypes were associated with DNA methylation in the S-COMT promoter, TGF-β expression, and symptoms. However, this was not specific for one condition. Significant between-group differences were found for increased DNA methylation in the MB-COMT promoter and decreased IFN-γ expression in patients.. Our results are consistent with basic and clinical research, providing interesting insights into genetic-epigenetic regulatory mechanisms. MB-COMT DNA methylation might be an independent factor contributing to the pathophysiology of CFS/FM. Further research on DNA methylation in complex conditions such as CFS/FM is warranted. We recommend future research to employ a repeated-measure design to control for biomarkers variability and within-subject changes.

Topics: Case-Control Studies; Catechol O-Methyltransferase; Epigenesis, Genetic; Fatigue Syndrome, Chronic; Fibromyalgia; Humans; Inflammation; Interleukin-6; Pain; Polymorphism, Single Nucleotide; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Sterile α motif domain-containing 9 (SAMD9) and SAMD9-like (SAMD9L) syndromes are inherited bone marrow failure syndromes known for their frequent development of myelodysplastic syndrome with monosomy 7. In this issue of the JCI, Abdelhamed, Thomas, et al. report a mouse model with a hematopoietic cell-specific heterozygous Samd9l mutation knockin. This mouse model resembles human disease in many ways, including bone marrow failure and the nonrandom loss of the mutant allele. Samd9l-mutant hematopoietic stem progenitor cells showed reduced fitness at baseline, which was further exacerbated by inflammation. TGF-β hyperactivation was found to underlie reduced fitness, which was partially rescued by a TGF-β inhibitor. These findings illustrate the potential role of TGF-β inhibitors in the treatment of SAMD9/SAMD9L syndromes.

Topics: Animals; Bone Marrow; Chromosome Deletion; Humans; Inflammation; Intracellular Signaling Peptides and Proteins; Mice; Mutation; Transforming Growth Factor beta; Tumor Suppressor Proteins

Adenosine receptors (ARs) are involved in the suppression and development of inflammatory and fibrotic conditions. Specifically, AR activation promotes differentiation of lung fibroblasts into myofibroblasts, typical of a fibrotic event. Pulmonary fibrosis is a severe disease characterized by inflammation and fibrosis of unknown etiology and lacking an effective treatment. The present investigation explored the action of MRS5980, a new, highly potent and selective A

Topics: Adenosine; Animals; Bleomycin; Fibroblasts; Fibrosis; Inflammation; Lung; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; Receptors, Purinergic P1; Transforming Growth Factor beta

Ginsenoside Rb1 (Rb1) is a biologically active component of ginseng [. This study determined the underlying mechanisms of Rb1 treatment that acted on diabetes-injured lungs in diabetic rats.. There was decreased activity of SOD (3.53-fold), CAT (2.55-fold) and GSH (1.63-fold) and increased levels of NO (4.47-fold) and MDA (3.86-fold) in the diabetic group from control. Rb1 treatment increased SOD (2.4-fold), CAT (1.9-fold) and GSH (1.29-fold) and decreased the levels of NO (1.76-fold) and MDA (1.51-fold) as compared with diabetic rats. The expression of IL-6 (5.13-fold), IL-1α (2.35-fold), TNF-α (2.35-fold) and TGF-β (2.39-fold) was increased in diabetic rats from control. IL-6 (2.43-fold), IL-1α (2.27-fold), TNF-α (1.68-fold) and TGF-β (2.3-fold) were decreased in the Rb1 treatment group. Diabetes increased the apoptosis rate (2.23-fold vs. control), and Rb1 treatment decreased the apoptosis rate (1.73-fold vs. the diabetic rats). Rb1 and insulin ameliorated lung tissue injury.. These findings indicate that Rb1 could be useful for mitigating oxidative damage and inflammatory infiltration in the diabetic lung.

Topics: Animals; Diabetes Mellitus, Experimental; Ginsenosides; Inflammation; Insulin; Interleukin-6; Lung; Male; Oxidative Stress; Panax; Rats; Rats, Sprague-Dawley; Streptozocin; Superoxide Dismutase; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

As a functional feed additive, yeast cultures are rich in nucleotides, and adding extra nuclease can significantly increase the content of nucleotides in yeast culture. In this experiment, the effects on growth, epidermal mucus, liver and intestinal health of zebrafish were evaluated by supplementing the yeast culture or nuclease-treated yeast culture with a high-fat diet (HFD). One-month-old zebrafish were fed four diets: normal diet (NORM), HFD, yeast culture diet (YC), and nuclease-treated yeast culture diet (YC (N)) for three weeks. Results showed that the complement 4 activity of the epidermal mucus in YC (N) group was significantly higher than those in HFD and YC groups (P < 0.05). The YC and YC (N) significantly reduced the content of hepatic triglyceride caused by HFD (P < 0.05). Moreover, compared with the YC group, the YC (N) significantly increased the expression of lipolysis genes, such as PPARα, PGC1α, ACOX3 (P < 0.05). Compared with the YC group, the YC (N) group significantly increased the expression of liver pro-inflammatory factors TNFα, IL-6, IL-1β and anti-inflammatory factors TGFβ, IL-10 (P < 0.05). The diet YC and YC (N) significantly improved the height of the intestinal villus (P < 0.05). Compared with the HFD group, the YC (N) group significantly increased the expression of intestinal pro-inflammatory factors TNFα, IL-6 and anti-inflammatory factors TGFβ, IL-10 (P < 0.05). The YC (N) group significantly decreased the abundance of intestinal Proteobacteria and Acinetobacter, and increased the abundance of intestinal Actinobacteria, Mycobacterium and Rhodobacter (P < 0.05). In conclusion, compared with the supplement of yeast culture, nuclease treated yeast culture can further alleviate the adverse effects of HFD on liver and intestinal health, and be used as feed additives for the nutritional and immune regulation of fish.

Topics: Animals; Diet, High-Fat; Gastrointestinal Microbiome; Inflammation; Interleukin-10; Interleukin-6; Lipid Metabolism; Liver; Mucus; Nucleotides; Saccharomyces cerevisiae; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Zebrafish

Previous studies have shown that a typical kind of oolong tea, Tieguanyin, has multiple health benefits, while there is no research investigating its effects on inflammatory bowel disease (IBD). In this study, we aimed to explore the alleviation effects of Tieguanyin water (TWE) and ethanol (TES) extracts on IBD. Physiological activity status, colitis severity (disease activity index (DAI), colon and spleen weight), inflammatory cytokines (interleukin (IL)-4, interferon-γ (IFN-γ), IL-17, transforming growth factor-β (TGF-β), and IL-10) and microbiota composition were measured in experimental colitis mice induced by dextran sulfate sodium (DSS). TWE and TES exerted remarkable protective effects against experimental colitis, showing decreased colitis severity and improved colon morphology. TES also suppressed colonic inflammation

Topics: Animals; Camellia sinensis; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Microbiome; Inflammation; Inflammatory Bowel Diseases; Interleukin-10; Interleukin-17; Mice; Mice, Inbred C57BL; Plant Extracts; Tea; Transforming Growth Factor beta

Hofbauer cells (HBCs) are resident macrophages of the human placenta, regulating immune tolerance and tissue homeostasis. HBCs of a normal placenta (CTR) exhibit mainly an anti-inflammatory M2 phenotype. Under exaggerated chronic inflammation during pregnancy, as in preeclampsia (PE), a phenotypic switch towards M1 polarization has been proposed. PE, defined as maternally derived syndrome can be distinguished into two different entities: early-onset (EO) preeclampsia and late-onset (LO) preeclampsia. Although the clinical presenting characteristics overlap, both can be identified by biochemical markers, heritability, and different maternal and fetal outcomes. To date, no study has specifically investigated polarization and phenotype of EO- and LO-PE HBCs and looked at possible changes in HBC functionality. Primary HBCs were isolated from CTR and PE placentae. First,

Topics: Female; Humans; Inflammation; Macrophages; Placenta; Pre-Eclampsia; Pregnancy; Transforming Growth Factor beta

Host immunity is crucial during periodontal inflammations. B cells are considered to have a function of immunoregulation, and TLRs are considered to be crucial in this process. The present study illustrates the potential roles and rules of CD25+ B cells during periodontitis, especially its effect on regulating host IL-35 level and Th1, Th17, and Treg differentiation.. The proportion of local and systemic CD25+ B cell subpopulations from periodontitis models were identified by flow cytometry. To illustrate further mechanism, B cells were cultured with a different type of TLR activators. Expression of IL-10, IL-35, and TGF-β was detected by ELISA and real-time PCR. We also set adoptive transfer models by using CD25+ B cells. Alveolar bone erosion, proportion of Th1, Th17, and Tregs, and levels of IFN-γ, TNF-α, IL-1β, and IL-17 were identified.. Periodontitis induces more CD25+ B cell subpopulations and promotes their IL-10, IL-35, and TGF-βproduction. TLR activators enhanced Breg proliferation and function. LPS+CpG obviously induced more CD25+ B cell differentiation and production of IL-10, IL-35, and TGF-β. Adoptive transfer of CD25+ B cells reduces alveolar bone destruction and local Tregs, proportion, especially the local level of IFN-γ and IL-17. In addition, adoptive transfer of CD25+ B cells remedies the pathological change in the proportion of IL-1β and Th1/Th17 in local lesions. We did not find any significant difference in peripheral blood, regardless of group and detected items.. Results of the present study clarify that CD25+ B cells enlarged and produced more IL-10, IL-35 and TGF-β during periodontitis, activation of TLR4 and TLR9 played crucial roles in this process. Also, CD25+ B cells alleviated periodontal inflammation and alveolar bone resorption. Our findings further expanded the potential of B cells during periodontitis.

Topics: Alveolar Bone Loss; Humans; Inflammation; Interleukin-10; Interleukin-17; Lipopolysaccharides; Periodontitis; T-Lymphocytes, Regulatory; Toll-Like Receptor 4; Toll-Like Receptor 9; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

TGF-β signaling is fundamental for both Th17 and regulatory T (Treg) cell differentiation. However, these cells differ in requirements for downstream signaling components, such as SMAD effectors. To further characterize mechanisms that distinguish TGF-β signaling requirements for Th17 and Treg cell differentiation, we investigated the role of Arkadia (RNF111), an E3 ubiquitin ligase that mediates TGF-β signaling during development. Inactivation of Arkadia in CD4+ T cells resulted in impaired Treg cell differentiation in vitro and loss of RORγt+FOXP3+ iTreg cells in the intestinal lamina propria, which increased susceptibility to microbiota-induced mucosal inflammation. In contrast, Arkadia was dispensable for Th17 cell responses. Furthermore, genetic ablation of two Arkadia substrates, the transcriptional corepressors SKI and SnoN, rescued Arkadia-deficient iTreg cell differentiation both in vitro and in vivo. These results reveal distinct TGF-β signaling modules governing Th17 and iTreg cell differentiation programs that could be targeted to selectively modulate T cell functions.

Topics: Animals; Cell Differentiation; Inflammation; Mice; Mice, Inbred C57BL; Proto-Oncogene Proteins; Signal Transduction; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta; Ubiquitin; Ubiquitin-Protein Ligases

The tumor necrosis factor-stimulated gene-6 (TSG-6) has been confirmed to inhibit inflammation. It is now generally accepted that local inflammatory stimulation around shoulder capsule causes proliferative fibrosis. This study aims to investigate the mechanism of recombinant TSG-6 protein inhibiting the growth of capsule fibroblasts in frozen shoulder via the TGF-β/Smad2 signal pathway.. Human frozen shoulder capsule tissue was taken for primary and passage culture, and the 3rd generation fibroblasts from pathological frozen shoulder capsule were treated with different concentrations of recombinant TSG-6 protein, or with TGF-β1 agonist SRI-011381. Immunoconfocal analysis was used to identify the isolated fibroblasts, and MTT assay, colony formation assay, and flow cytometry were used to detect the viability, proliferation, and apoptosis rate of fibroblast. The contents of fibrosis and inflammation indexes COL1A1, TNF-α, IL-6, and IL-1β in the cell supernatant were detected using ELISA and then further examined by qRT-PCR. The expression of Bax, Bcl-2, and proteins related to TGF-β/Smad2 pathway were detected by Western Blot.. Compared with the blank control group, fibroblasts intervened with TSG-6 (2 μg and 5 μg) showed significantly decreased viability and proliferation ability and enhanced cell apoptosis, concurrent with the reductions in Bcl-2 expression; COL1A1, TNF-α, IL-6, and IL-1β levels; and the expression of TGF-β1 and phosphorylated Smad22, and an increase in Bax expression, while SRI-011381 treatment would reverse the effect of recombinant TSG-6 protein.. Recombinant TSG-6 protein inhibited the growth of primary fibroblasts from human frozen shoulder capsule by suppressing the TGF-β/Smad2 signaling pathway.

Topics: bcl-2-Associated X Protein; Bursitis; Fibroblasts; Fibrosis; Humans; Inflammation; Interleukin-6; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Vestigial-like family member 3 (VGLL3), a member of the vestigial-like family, is a cofactor of the TEA-domain-containing transcription factor (TEAD). Although elevation in VGLL3 expression is associated with inflammatory diseases, such as inflammatory sarcomas and autoimmune diseases, the molecular mechanisms underlying VGLL3-mediated inflammation remain largely unknown. In this study, we analyzed the relationship between elevated VGLL3 expression and the levels of NF-κB, a transcription factor that plays a pivotal role in inflammation. NF-κB was found to be activated in a cell line stably expressing VGLL3. Mechanistically, VGLL3 was shown to promote the expression and secretion of the potent NF-κB-activating cytokine interleukin (IL)-1α, probably through its association with TEADs. As VGLL3 is a target of transforming growth factor β (TGF-β) signaling, we analyzed IL-1α induction upon TGF-β stimulation. TGF-β stimulation was observed to induce IL-1α secretion and NF-κB activation, and VGLL3 was associated with this phenomenon. The TGF-β transcription factors Smad3 and Smad4 were shown to be necessary for inducing VGLL3 and IL-1α expression. Lastly, we found that VGLL3-dependent IL-1α secretion is involved in constitutive NF-κB activation in highly malignant breast cancer cells. Collectively, the findings suggested that VGLL3 expression and TGF-β stimulation activate the inflammatory response by inducing IL-1α secretion.

Topics: A549 Cells; Fibroblasts; Humans; Inflammation; Interleukin-1alpha; MCF-7 Cells; NF-kappa B; Transcription Factors; Transforming Growth Factor beta

We previously reported that female mice exhibit protection against chemically induced pulmonary fibrosis and suggested a potential role of estrogen. Phytoestrogens act, at least in part, via stimulation of estrogen receptors; furthermore, compared to residents of Western countries, residents of East Asian countries consume higher amounts of phytoestrogens and exhibit lower rates of pulmonary fibrosis. Therefore, we tested the hypothesis that dietary phytoestrogens ameliorate the severity of experimentally induced pulmonary fibrosis. Male mice placed on either regular soybean diet or phytoestrogen-free diet were instilled with 0.1 N HCl to provoke pulmonary fibrosis. Thirty days later, lung mechanics were measured as indices of lung function and bronchoalveolar lavage fluid (BALF) and lung tissue were analyzed for biomarkers of fibrosis. Mice on phytoestrogen-free diet demonstrated increased mortality and stronger signs of chronic lung injury and pulmonary fibrosis, as reflected in the expression of collagen, extracellular matrix deposition, histology, and lung mechanics, compared to mice on regular diet. We conclude that dietary phytoestrogens play an important role in the pathogenesis of pulmonary fibrosis and suggest that phytoestrogens (e.g., genistein) may be useful as part of a therapeutic regimen against hydrochloric acid-induced lung fibrosis and chronic lung dysfunction.

Topics: Animals; Chronic Disease; Diet; Extracellular Matrix Proteins; Hydrochloric Acid; Inflammation; Leukocyte Count; Lung; Lung Injury; Male; Mice, Inbred C57BL; Models, Biological; Phytoestrogens; Pulmonary Fibrosis; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta

Rodent mast cells are classified into two major subsets, mucosal mast cells (MMCs) and connective tissue mast cells. MMCs arise from mast cell progenitors that are mobilized from the bone marrow to mucosal tissues in response to allergic inflammation or helminth infection. TGF-β is known as an inducer of MMC differentiation in mucosal tissues, but we have previously found that Notch receptor-mediated signaling also leads to the differentiation. Here, we examined the relationship between Notch and TGF-β signaling in MMC differentiation using mouse bone marrow-derived mast cells (BMMCs). We found that the coexistence of Notch and TGF-β signaling markedly upregulates the expression of MMC markers, mouse mast cell protease (mMCP)-1, mMCP-2, and αE integrin/CD103, more than Notch or TGF-β signaling alone, and that their signals act interdependently to induce these marker expressions. Notch and TGF-β-mediated transcription of MMC marker genes were both dependent on the TGF-β signaling transducer SMAD4. In addition, we also found that Notch signaling markedly upregulated mMCP-1 and mMCP-2 expression levels through epigenetic deregulation of the promoter regions of these genes, but did not affect the promoter of the CD103-encoding gene. Moreover, forced expression of the constitutively active Notch2 intracellular domain in BMMCs showed that Notch signaling promotes the nuclear localization of SMADs 3 and 4 and causes SMAD4-dependent gene transcription. These findings indicate that Notch and TGF-β signaling play interdependent roles in inducing the differentiation and maturation of MMCs. These roles may contribute to the rapid expansion of the number of MMCs during allergic mucosal inflammation.

Topics: Animals; Gene Expression; Inflammation; Mast Cells; Mice; Mucous Membrane; Transforming Growth Factor beta

Rheumatoid arthritis targets numerous organs in patients, including the skeletal muscle, resulting in rheumatoid cachexia. In the muscle niche, satellite cells, macrophages, and myofibroblasts may be affected and the factors they release altered. This study aimed to assess these cell types, cytokines, and growth factors and their relationships to muscle fiber size and number in a rodent collagen-induced arthritis (CIA) model, in order to identify new therapeutic targets. Fiber cross-sectional area (CSA) was 57% lower in CIA than controls (p < 0.0001), thus smaller but more fibers visible per field of view. Immunostaining indicated the increased presence of satellite cells, macrophages, myofibroblasts, and myonuclei per field of view in CIA (p < 0.01), but this finding was not maintained when taking fiber number into consideration. Western blots of gastrocnemius samples indicated that tumor necrosis factor-α was significantly elevated (p < 0.01) while interleukin-10 (IL-10) was decreased (p < 0.05) in CIA. This effect was maintained (and heightened for IL-10) when expressed per fiber number. Myogenic regulatory factors (MyoD and myogenin), transforming growth factor-β and inhibitor of differentiation were significantly elevated in CIA muscle and levels correlated significantly with CSA. Several of these factors remained elevated, but bone morphogenetic protein-7 decreased when considering fiber number per area. In conclusion, CIA-muscle demonstrated a good regenerative response. Myoblast numbers per fiber were not elevated, suggesting their activity results from the persistent inflammatory signaling which also significantly hampered maintenance of muscle fiber size. A clearer picture of signaling events at cellular level in arthritis muscle may be derived from expressing data per fiber.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Bone Morphogenetic Protein 7; Cachexia; Cytokines; Inflammation; Interleukin-10; Macrophages; Muscle, Skeletal; MyoD Protein; Myofibroblasts; Myogenin; Rats; Regeneration; Satellite Cells, Skeletal Muscle; Transforming Growth Factor beta

Interleukin (IL)-19, a member of the IL-10 family, is an anti-inflammatory cytokine produced primarily by macrophages. Nonalcoholic steatohepatitis (NASH) is a disease that has progressed from nonalcoholic fatty liver disease (NAFLD) and is characterized by inflammation and fibrosis. We evaluated the functions of IL-19 in a NAFLD/NASH mouse model using a 60% high fat diet with 0.1% methionine, without choline, and with 2% cholesterol (CDAHFD). Wild-type (WT) and IL-19 gene-deficient (KO) mice were fed a CDAHFD or standard diet for 9 weeks. Liver injury, inflammation, and fibrosis induced by CDAHFD were significantly worse in IL-19 KO mice than in WT mice. IL-6, TNF-α, and TGF-β were significantly higher in IL-19 KO mice than in WT mice. As a mechanism using an in vitro experiment, palmitate-induced triglyceride and cholesterol contents were decreased by the addition of IL-19 in HepG2 cells. Furthermore, addition of IL-19 decreased the expression of fatty acid synthesis-related enzymes and increased ATP content in HepG2 cells. The action of IL-19 in vitro suppressed lipid metabolism. In conclusion, IL-19 may play an important role in the development of steatosis and fibrosis by directly regulating liver metabolism and may be a potential target for the treatment of liver diseases.

Topics: Adenosine Triphosphate; Animals; Cholesterol; Diet, High-Fat; Disease Models, Animal; Fatty Acids; Hep G2 Cells; Humans; Inflammation; Interleukin-6; Interleukins; Lipid Metabolism; Liver; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Palmitates; Transforming Growth Factor beta; Triglycerides; Tumor Necrosis Factor-alpha

This study aims to explore the mechanism of fresh Phragmitis Rhizoma against chronic bronchitis airway inflammation. The SD rats of SPF grade were divided into control group, model group, Guilongkechuanning group(GLKCN, 1.125 g·kg~(-1)), high-dose fresh Phragmitis Rhizoma group(LG-HD, 15 g·kg~(-1)), and low-dose fresh Phragmitis Rhizoma group(LG-LD, 7.5 g·kg~(-1)). The chronic bronchitis models of rats in other groups except the control group were induced by the modified smoking method. From the 15 th day of modeling, the rats were given corresponding agents by gavage for 20 consecutive days. After the last administration, the rats were sacrificed for sample collection. Enzyme-linked immunosorbent assay(ELISA) was employed to detect serum transforming growth factor-β(TGF-β) and interleukin-6(IL-6) levels. The protein expression of TGF-β, IL-1β and IL-6 in lung tissue was detected by immunohistochemical method. Masson staining was performed to detect collagen fibers and muscle fibers in lung tissue, and HE staining to detect the pathological changes of lung tissue. Human bronchial epithelial(16 HBE) cells were cultured in vitro, and CCK-8(cell counting kit-8) method was used to detect the cytotoxicity of cigarette smoke extract(CSE) and fresh Phragmitis Rhizoma. After the exposure of 16 HBE cells to 3.5% CSE and appropriate concentration(800, 400 μg·mL~(-1)) of fresh Phragmitis Rhizoma for 24 h, quantitative real-time PCR was conducted to determine the mRNA levels of TGF-β and IL-1β, and Western blot was employed to determine the protein levels of TGF-β and IL-6 in the cells. The rat model of chronic bronchitis induced by smoking was successfully established. Fresh Phragmitis Rhizoma reduced serum TGF-β and IL-6 levels, down-regulated the protein levels of TGF-β, IL-1β, and IL-6 in lung tissue, and alleviated pathological changes and fibrotic lesions in lung tissue. Moreover, it down-regulated the CSE-induced protein expression of TGF-β and IL-6 as well as the mRNA level of TGF-β in 16 HBE cells. These results indicated that fresh Phragmitis Rhizoma could prevent airway inflammation from chronic bronchitis and promote cell repair by inhibiting the TGF-β signaling pathway.

Topics: Animals; Bronchitis, Chronic; Drugs, Chinese Herbal; Inflammation; Lung; Poaceae; Rats; Rats, Sprague-Dawley; Rhizome; Signal Transduction; Transforming Growth Factor beta

Topics: Animals; Antioxidants; Fibroblasts; Gout; Humans; Inflammation; Lactones; Male; MAP Kinase Kinase Kinases; Mice; Mice, Inbred C57BL; Proteasome Endopeptidase Complex; Resorcinols; Signal Transduction; Synovial Membrane; Transforming Growth Factor beta; Ubiquitin; Uric Acid

Cytokine dysregulation is the proposed mechanism for Coronavirus disease 2019 (COVID-19). The aim of this study was to evaluate the serum levels of interferon (IFN)-γ, interleukin (IL)-5, IL-8, Il-9, IL-17, TGF-β and IFN-γ in patients infected with SARS-CoV-2. The study was conducted between 63 adult patients with COVID-19 and compared with 33 age and gender-matched healthy subjects as controls. The age range in both groups was 50-70 years. The patients were classified into mild group (33 patients) and severe group (30 patients). Serum samples were collected from all participants and tested for the cytokine levels by ELISA (enzyme-linked immunosorbent assay) method. Statistical analysis was performed using the one-way ANOVA. The mean serum levels of IFN-γ, TGF-β, IL-17 and IL-8 in the COVID-19 patients were significantly higher than those observed in the control group. A comparison of between the mild and severe groups showed significant differences in TGF-β levels. The mean concentration of serum IL-5 and IL-9 in patients with COVID-19 did not differ from those in the control group. Systemic IL-17 levels correlated positively and significantly with TGF-β in patients with COVID-19. Th1 (IFN-γ), Treg (TGF-β), and Th17 (IL-17) cytokines concentration were increased in COVID-19 patients. Interferon-γ and IL-17 are involved in inducing and mediating proinflammatory responses. Our data suggest that TGF-β can be used as a predictive factor of disease severity in patients with COVID-19.

Topics: Aged; Biomarkers; COVID-19; Cytokines; Female; Humans; Inflammation; Interferon-gamma; Interleukin-17; Interleukin-5; Interleukin-8; Interleukin-9; Male; Middle Aged; Severity of Illness Index; Transforming Growth Factor beta

Probiotics are nonpathogenic bacterial strains that exert beneficial effects on the host. Previous studies have shown that topical use of some strains of probiotic bacteria have good effects on the healing of cutaneous wounds. In the current study, the wound healing potentials of bacterial probiotics on diabetic cutaneous wounds were evaluated. The effects of probiotics on migration, the viability of fibroblasts, and macrophage proliferation were measured through using wound healing assay, methylthiazol tetrazolium assay, and bromodeoxyuridine, respectively. In this regard, in vivo diabetic wound healing experiments in Wistar rats following treatment with nontoxic concentrations of Lactobacillus bulgaricus and Lactobacillus plantarum were conducted. The histopathological and gene expression analyses were performed following removal of wound sites 3, 7, and 14 days postwounding. Results showed that treatment with probiotics accelerated the healing process of diabetic wounds and modulated the inflammatory cells in wound sites during a 14-day period postwounding. The altered mRNA levels of inflammatory cytokines were observed in wound sites following treatment with probiotics. The findings of the current study reveal that L. bulgaricus and L. plantarum could improve the healing of diabetic wounds via regulation of inflammation.

Topics: Animals; Cell Survival; Cells, Cultured; Diabetes Mellitus; Humans; Inflammation; Interleukin-10; Interleukin-1beta; Lactobacillus delbrueckii; Lactobacillus plantarum; Mice; Probiotics; Rats; Rats, Wistar; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Wound Healing

Treatment of nonhuman primates and mice with a humanized antigen-binding fragment (Fab) antibody (UCBFab) inhibiting transforming growth factor β via daily inhalation for up to 13 weeks resulted in low systemic exposure but high local exposure in the lung. Target engagement was demonstrated by reduced levels of signal transducers, phosphoSMAD and plasminogen activator inhibitor-1 in the bronchoalveolar lavage fluid (BALF). Treatment was associated with a high frequency and titer of antidrug antibodies, indicating high local immunogenicity, and local pathology within the lung and draining lymph nodes. Microscopic changes were characterized by perivascular (PV) and peribronchiolar (PB) mononuclear inflammatory cell (MIC) infiltrates that were principally lymphocytic in nature and mixed inflammatory cell infiltrates and/or inflammation within the alveoli. Immunohistochemical investigation revealed a predominantly CD68-positive macrophage and CD3- and CD8>CD4-positive T-cell response in the alveoli, whereas within the airways, there was a variable mixture of CD3-positive T cells, CD20-positive B cells, and CD68-positive macrophages. Increased cellularity of the draining lymph nodes was also noted, indicating the presence of an immune response to the inhaled test article. Morphologic changes did not progress over time, and all changes partially recovered. Increased leukocytes (principally macrophages) in BALF cytology correlated with the changes seen by histopathology.

Topics: Animals; Antibodies; Bronchoalveolar Lavage Fluid; Inflammation; Lung; Mice; Primates; Transforming Growth Factor beta

Myocardial ischemia-reperfusion (MIR) represents critical challenge for the treatment of acute myocardial infarction diseases. Presently, identifying the molecular basis revealing MIR progression is scientifically essential and may provide effective therapeutic strategies. Phosphoglycerate mutase 1 (PGAM1) is a key aerobic glycolysis enzyme, and exhibits critical role in mediating several biological events, such as energy production and inflammation. However, whether PGAM1 can affect MIR is unknown. Here we showed that PGAM1 levels were increased in murine ischemic hearts. Mice with cardiac knockout of PGAM1 were resistant to MIR-induced heart injury, evidenced by the markedly reduced infarct volume, improved cardiac function and histological alterations in cardiac sections. In addition, inflammatory response, apoptosis and fibrosis in hearts of mice with MIR operation were significantly alleviated by the cardiac deletion of PGAM1. Mechanistically, the activation of nuclear transcription factor κB (NF-κB), p38, c-Jun NH2-terminal kinase (JNK) and transforming growth factor β (TGF-β) signaling pathways were effectively abrogated in MI-operated mice with specific knockout of PGAM1 in hearts. The potential of PGAM1 suppression to inhibit inflammatory response, apoptosis and fibrosis were verified in the isolated cardiomyocytes and fibroblasts treated with oxygen-glucose deprivation reperfusion (OGDR) and TGF-β, respectively. Importantly, PGAM1 directly interacted with TGF-β to subsequently mediate inflammation, apoptosis and collagen accumulation, thereby achieving its anti-MIR action. Collectively, these findings demonstrated that PGAM1 was a positive regulator of myocardial infarction remodeling due to its promotional modulation of TGF-β signaling, indicating that PGAM1 may be a promising therapeutic target for MIR treatment.

Topics: Animals; Apoptosis; Cells, Cultured; Fibrosis; Gene Deletion; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocardium; Phosphoglycerate Mutase; Rats, Sprague-Dawley; Transforming Growth Factor beta

Inflammation drives the growth of tumors and is an important predictor of cancer aggressiveness. CD68, a marker of tumor-associated macrophages (TAM), is routinely used to aid in prognosis and treatment choices for breast cancer patients. We report that thrombospondin-4 (TSP-4) mediates breast cancer inflammation and growth in mouse models in response to hyperglycemia and TGF-beta by increasing TAM infiltration and production of inflammatory signals in tumors. Analysis of breast cancers and noncancerous tissue specimens from hyperglycemic patients revealed that levels of TSP-4 and of macrophage marker CD68 are upregulated in diabetic tissues. TSP-4 was colocalized with macrophages in cancer tissues. Bone-marrow-derived macrophages (BMDM) responded to high glucose and TGF-beta by upregulating TSP-4 production and expression, as well as the expression of inflammatory markers. We report a novel function for TSP-4 in breast cancer: regulation of TAM infiltration and inflammation. The results of our study provide new insights into regulation of cancer growth by hyperglycemia and TGF-beta and suggest TSP-4 as a potential therapeutic target.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Cell Line, Tumor; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic; Humans; Hyperglycemia; Inflammation; Macrophages; Male; Mammary Neoplasms, Experimental; Mice, Inbred C57BL; Mice, Knockout; Thrombospondins; Transforming Growth Factor beta

Cross-talk among inflammation and colorectal cancer cells is chiefly reported through a complex of cytokines, chemokines, and growth factors. MicroRNA performs strategic roles in controlling a variety of signaling cascades. miR-34a is known as a master regulator of tumor suppression. Combined application of different miRNA-based agents and chemotherapeutic drugs has been used to augment drug sensitivity and may reinforce the antitumor effect. A lot of studies specify a substantial increase in the effectiveness of combination therapies. The anti-inflammatory activity of Zerumbone (ZER) was investigated in many cancers. In this study the level of the inflammatory cytokines including CXCL-12 (SDF-1), CCL-2 (MCP-1), TGF-β and IL-33 has been measured in pmiR-34a-5p transfected and pmiR-34a-5p +ZER treated CRC cell lines (HCT-116 and SW48) by QRT-PCR and ELISA methods, respectively. The results showed that miR-34a could significantly inhibit cytokine expression in both cell lines for 48 and 72 h except SDF-1 which no inhibition was observed in SW48 cells. ZER suppressed SDF-1 for all three time points in both cell lines, while in SW48 cells IL-33 and TGF-β were inhibited in 72 h and in HCT-116 cells MCP-1 diminished for only 24 h and TGF-β diminished for all three times. Combination of both miR-34a and ZER suppressed TGF-β, SDF-1 and MCP-1 in HCT-116 cells in all time points while in SW48 cells, suppression of most cytokines was observed in 48 and 72 h. Furthermore Colony formation assay and scratch test were employed to detect changes of proliferation and migration in CRC transfected and treated cells. Generally, we found that miR-34a could considerably decrease the expression of inflammatory cytokines and the combination of ZER+ miR-34 boosted this effect. Moreover the migration and proliferation decreased in treated and transfected cells and this reduction was more severe in miR-34a +ZER treatment. It is important to note that in the case of cell resistance to each of these therapeutic agents, inhibition of cytokines can be compensated by another one.

Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemokine CCL2; Chemokine CXCL12; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Inflammation; Interleukin-33; MicroRNAs; Sesquiterpenes; Transforming Growth Factor beta

Radiation enteropathy is one the most common clinical issue for patients receiving radiotherapy for abdominal/pelvic tumors which severely affect the quality of life of cancer patients due to dysplastic lesions (ischemia, ulcer, or fibrosis) that aggravate the radiation damage. Herein, this study demonstrated the prophylactic role of coenzyme Q10 (CoQ10), a powerful antioxidant, against radiotherapy-induced gastrointestinal injury. Male Sprague Dawley rats were divided into four groups: group 1 was defined as control, and group 2 was the irradiated group. Group 3 and 4 were CoQ10 control and radiation plus CoQ10 groups, respectively. CoQ10 (10 mg/kg) was orally administered for 10 days before 10 Gy whole-body radiation and was continued for 4 days post-irradiation. CoQ10 administration protected rats delivered a lethal dose of ϒ-radiation from changes in crypt-villus structures and promoted regeneration of the intestinal epithelium. CoQ10 attenuated radiation-induced oxidative stress by decreasing lipid peroxidation and increasing the antioxidant enzyme catalase activity and reduced glutathione level. CoQ10 also counteracts inflammatory response mediated after radiation exposure through downregulating intestinal NF-ĸB expression which subsequently decreased the level of inflammatory cytokine IL-6 and the expression of COX-2. Radiation-induced intestinal fibrosis confirmed via Masson's trichrome staining occurred through upregulating transforming growth factor (TGF)-β1 and matrix metalloproteinase (MMP)-9 expression, while CoQ10 administration significantly diminishes these effects which further confirmed the anti-fibrotic property of CoQ10. Therefore, CoQ10 is a promising radioprotector that could prevent intestinal complications and enhance the therapeutic ratio of radiotherapy in patients with pelvic tumors through suppressing the NF-kB/TGF-β1/MMP-9 signaling pathway.

Topics: Animals; Disease Models, Animal; Fibrosis; Gene Expression Regulation; Inflammation; Intestinal Diseases; Male; Matrix Metalloproteinase 9; NF-kappa B; Radiation Injuries; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta; Ubiquinone; Vitamins

Natural products are one of the best sources for the discovery of novel drugs and compounds for multiple diseases. Pulmonary fibrosis (PF) is a chronic, progressive, irreversible, and fatal fibrotic disorder of lungs with unknown etiology and finite therapeutic choices. The use of naturally occurring phytomedicines has emerged to counteract many fibrotic disorders involving oxidative stress and inflammation. In the present study, we evaluated the protective effects of ferulic acid (FA), in an animal model of silica-induced PF. Pulmonary function of mice was evaluated by performing radiological analysis, bronchoalveolar lavage fluid (BALF), inflammatory cytokines, histology and protein expression studies. Our findings revealed that mice challenged with silica displayed characteristic features of pulmonary injury and fibrosis. However, treatment with FA significantly restored the accumulation of inflammatory cells in BALF. FA led to a partial reversal of silica-induced fibrotic changes in the pulmonary tissue. Subsequently, FA halts the progression of PF in a dose-dependent manner by ameliorating the expression of fibrotic proteins including collagen-I, TGF-β, p-smad2/3 and prevented epithelial-mesenchymal transition (EMT). Collectively, the present study suggests that the inhibition of oxidative stress, inflammatory and TGF-β/smad signalling might be involved in the observed anti-fibrotic benefits of FA against silica-induced PF in mice.

Topics: Animals; Bronchoalveolar Lavage Fluid; Coumaric Acids; Gene Expression Regulation; Inflammation; Male; Mice; Oxidative Stress; Pulmonary Fibrosis; Random Allocation; Silicon Dioxide; Smad Proteins; Transforming Growth Factor beta

6-Gingerol, a pungent ingredient of ginger, has been reported to possess anti-inflammatory and antioxidant activities, but the effect of 6-gingerol on pressure overload-induced cardiac remodeling remains inconclusive. In this study, we investigated the effect of 6-gingerol on cardiac remodeling in in vivo and in vitro models, and to clarify the underlying mechanisms. C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with 6-gingerol (20 mg/kg, ig) three times a week (1 week in advance and continued until the end of the experiment). Four weeks after TAC surgery, the mice were subjected to echocardiography, and then sacrificed to harvest the hearts for analysis. For in vitro study, neonatal rat cardiomyocytes and cardiac fibroblasts were used to validate the protective effects of 6-gingerol in response to phenylephrine (PE) and transforming growth factor-β (TGF-β) challenge. We showed that 6-gingerol administration protected against pressure overload-induced cardiac hypertrophy, fibrosis, inflammation, and dysfunction in TAC mice. In the in vitro study, we showed that treatment with 6-gingerol (20 μM) blocked PE-induced-cardiomyocyte hypertrophy and TGF-β-induced cardiac fibroblast activation. Furthermore, 6-gingerol treatment significantly decreased mitogen-activated protein kinase p38 (p38) phosphorylation in response to pressure overload in vivo and extracellular stimuli in vitro, which was upregulated in the absence of 6-gingerol treatment. Moreover, transfection with mitogen-activated protein kinase kinase 6 expressing adenoviruses (Ad-MKK6), which specifically activated p38, abolished the protective effects of 6-gingerol in both in vitro and in vivo models. In conclusion, 6-gingerol improves cardiac function and alleviates cardiac remodeling induced by pressure overload in a p38-dependent manner. The present study demonstrates that 6-gingerol is a promising agent for the intervention of pathological cardiac remodeling.

Topics: Animals; Anti-Inflammatory Agents; Cardiomegaly; Cardiotonic Agents; Catechols; Fatty Alcohols; Fibroblasts; Fibrosis; Inflammation; Male; MAP Kinase Signaling System; Mice, Inbred C57BL; Myocardium; Myocytes, Cardiac; p38 Mitogen-Activated Protein Kinases; Phenylephrine; Rats, Sprague-Dawley; Transforming Growth Factor beta; Ventricular Remodeling

Ultrafine particles (UFPs) referred to particular matters with aerosol diameter less than 100 nm. Because of the lightweight and small size, UFPs have become an occupational inhalation risk. The UFPs will be accumulated in the deep lung through inhalation, and then reach into all the organs via circulation system; some UFPs even stay in the brain. As previous study reported, UFPs exposure is usually associated with cardiovascular disease, such as atherosclerosis (AS). In our study, we tried to understand how acute UFP exposure caused the biological dysregulation in atherosclerosis. Acute exposure of UFPs were applied to mice for 6 consecutive days, mice were sacrificed after 3, 5, 7, and 10 days post-exposure. Aorta and serum were collected for histological and biomarkers analysis. Mice aortic adventitial fibroblasts (MAFs) were isolated from mice and used to further study to understand the mechanism of UFPs induced atherosclerosis. Compared to the untreated control, the inflammation responses and nitrate stress were observed after acute exposure of UFPs, with increased IL-6, MCP-1, p47phox, and 3-NT levels in the mice serum. Besides, upregulation of microRNAs: miR-301b-3p and Let-7c-1-3p, and their downstream target: Smad2, Smad3, and TGFβ1 were also observed in mouse aorta after acute exposure of UFPs. Similar results were identified in vitro as well. Acute exposure of UFPs induced the systematic nitrate stress and inflammation responses, along with the changes of vascular permeability. Dysregulated miRNAs and TGFβ/Smads signaling pathway indicated the higher risk of atherosclerosis/vasculature remodeling when exposed to UFPs.

Topics: Animals; Aorta; Atherosclerosis; Cells, Cultured; Disease Models, Animal; Fibroblasts; Inflammation; Inflammation Mediators; Mice, Knockout, ApoE; Particle Size; Particulate Matter; Permeability; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Vascular Remodeling

Colonization by gut microbiota in early life confers beneficial effects on immunity throughout the host's lifespan. We sought to elucidate the mechanisms whereby neonatal supplementation with p40, a probiotic functional factor, reprograms intestinal epithelial cells for protection against adult-onset intestinal inflammation.. p40 was used to treat young adult mouse colonic (YAMC) epithelial cells with and without deletion of a methyltransferase, su(var)3-9, enhancer-of-zeste and trithorax domain-containing 1β (Setd1β), and mice in early life or in adulthood. Anti-transforming growth factor β (TGFβ)-neutralizing antibodies were administered to adult mice with and without colitis induced by 2,4,6-trinitrobenzenesulfonic acid or dextran sulfate sodium. We examined Setd1b and Tgfb gene expression, TGFβ production, monomethylation and trimethylation of histone H3 on the lysine 4 residue (H3K4me1/3), H3K4me3 enrichment in Tgfb promoter, differentiation of regulatory T cells (Tregs), and the inflammatory status.. p40 up-regulated expression of Setd1b in YAMC cells. Accordingly, p40 enhanced H3K4me1/3 in YAMC cells in a Setd1β-dependent manner. p40-regulated Setd1β mediated programming the TGFβ locus into a transcriptionally permissive chromatin state and promoting TGFβ production in YAMC. Furthermore, transient exposure to p40 during the neonatal period and in adulthood resulted in the immediate increase in Tgfb gene expression. However, only neonatal p40 supplementation induced the sustained H3K4me1/3 and Tgfb gene expression that persisted into adulthood. Interfering with TGFβ function by neutralizing antibodies diminished the long-lasting effects of neonatal p40 supplementation on differentiation of Tregs and protection against colitis in adult mice.. Exposure to p40 in early life enables an epigenetic imprint on TGFβ, leading to long-lasting production of TGFβ by intestinal epithelial cells to expand Tregs and protect the gut against inflammation.

Topics: Animals; Colitis; Epigenesis, Genetic; Epithelial Cells; Female; Inflammation; Intestinal Mucosa; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Pregnancy; Prenatal Exposure Delayed Effects; Probiotics; Transforming Growth Factor beta

There is growing inclination towards developing bioactive molecule-based strategies for the management of allergic airway inflammation associated respiratory diseases. Vitex negundo Linn., also known as Nirgundi, is one such medicinal plant enriched with phytochemicals and used for inflammatory and respiratory disorders including asthma in traditional system of medicine. Preliminary studies have claimed anti-tussive and bronchodilator potential of V. negundo Linn. However, its attributes as well as molecular mechanism (s) in modulation of asthma mediated by allergic inflammation are yet to be delineated scientifically.. Present study attempted to assess the effectiveness of Vitex negundo leaf extract (VNLE) in mitigation of allergen induced inflammation associated asthmatic lung damage with emphasis to delineate its molecular mechanism (s).. Allergic lung inflammation was established in Balb/c mice using Ovalbumin-lipopolysaccharide (OVA-LPS). Several allergic inflammatory parameters, histopathological changes, alveolar macrophage activation and signalling pathways were assessed to examine protective effects of VNLE. UHPLC-DAD-QTOF-ESI-IMS was used to characterize VLNE.. VNLE administration effectively attenuated LPS-induced oxi-inflammatory stress in macrophages suggesting its anti-inflammatory potential. Further, VNLE showed protective effect in mitigating asthmatic lung damage as evident by reversal of pathological changes including inflammatory cell influx, congestion, fibrosis, bronchial thickness and alveolar collapse observed in allergen group. VNLE suppressed expressions of inflammatory Th1/Th2 cytokines, chemokines, endopeptidases (MMPs), oxidative effector enzyme (iNOS), adhesion molecules, IL-4/IFN-γ release with simultaneous enhancement in levels of IL-10, IFN-γ, MUC3 and tight junction proteins. Subsequent mechanistic investigation revealed that OVA-LPS concomitantly enhanced phosphorylation of NF-κB, PI3K, Akt and p38MAPKs and downregulated AMPK which was categorically counteracted by VNLE treatment. VNLE also suppressed OVA-LPS induced fibrosis, apoptosis, autophagy and gap junction proteins which were affirmed by reduction in TGF-β, Smad2/3/4, Caspase9/3, Bax, LC3A/B, connexin 50, connexin 43 and enhancement in Bcl2 expression. Additionally, suppression of alveolar macrophage activation, inflammatory cells in blood and elevation of splenic CD8+T cells was demonstrated. UHPLC-DAD-QTOF-ESI-IMS revealed presence of iridoids glycoside and phenolics which might contribute these findings.. These findings confer protective effect of VNLE in attenuation of allergic lung inflammation and suggest that it could be considered as valuable medicinal source for developing safe natural therapeutics for mitigation of allergic inflammation during asthma.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Asthma; Caspases; Disease Models, Animal; Inflammation; Lipopolysaccharides; Lung Injury; Macrophage Activation; Mice, Inbred BALB C; Microtubule-Associated Proteins; NF-kappa B; Ovalbumin; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Plant Extracts; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Vitex

Globally, skin repair costs billion dollars per annum. Diversified matrices are fabricated to address this important area of healthcare. Most common limitations associated with them are the inflated production cost and insufficient functional repair. Our work explores the fabrication and potential utilization of Antheraea mylitta silk protein sericin (possessing inherent anti-bacterial and antioxidant properties) based hydrogels for skin tissue. The integrity of the hydrogels is achieved by combining sericin, chitosan (provide anti-bacterial and structural support), and glycosaminoglycans (component of biologically formed extracellular matrix). The hydrogels are functionalized by incorporation of vascular endothelial growth factor and transforming growth factor-β. They exhibit enhanced cellular functions in terms of their growth, production of matrix metalloproteinase, and collagen along with the recovery of impairment and the reconstruction of the lost dermal tissue. The in vivo biocompatibility analyses reveal that sericin-containing hydrogels promote the repair of skin tissue, angiogenesis, and illicit minimal immune response. These unique hydrogels mimicking the naturally occurring skin tissue and imparting additional beneficial features provide an appropriate physical environment and biological cues for the promotion of skin tissue repair.

Topics: Animals; Anti-Bacterial Agents; Antioxidants; Biocompatible Materials; Cell Line, Tumor; Chitosan; Collagen; Cytokines; Extracellular Matrix; Fibroblasts; Glycosaminoglycans; Humans; Hydrogels; In Vitro Techniques; Inflammation; Intercellular Signaling Peptides and Proteins; Keratinocytes; Male; Porosity; Rats; Rats, Wistar; Sericins; Silk; Skin; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

This study investigated the changes in the mRNA expression of transforming growth factor beta (TGF-β), plasminogen activators (PAs), and interleukin (IL) caused by sperm, as well as the regulatory mechanism of PA activity through TGF-β, in porcine uterine epithelial cells. The cells were isolated from the uterine horn of pig and co-incubated with Percoll-separated boar sperm (45% or 90%), or TGF-β for 24 h. The mRNA expression of TGF-β isoforms (TGF-β1, 2 and 3) and their receptors (TGF-β R1 and R2), PAs (urokinase-type, uPA; tissue-type, tPA; uPA receptor, uPAR; type 1 PA inhibitor, PAI-1), IL-6 and IL-8 was analyzed using real-time PCR. Supernatant was used to measure PA activity. Co-incubation with sperm from the 90% Percoll layer increased TGF-β1 mRNA, whereas TGF-β2 and TGF-β3 were decreased (P < 0.05). However, both TGF-βRs were not changed by the presence of the spermatozoa. Expression of tPA, PAI-1, IL-6, and IL-8 mRNA was down-regulated by 90% Percoll-separated sperm (P < 0.05), and sperm from 45% Percoll increased uPA expression (P < 0.05). TGF-β decreased tPA and IL-8 mRNA expression, and increased uPAR and PAI-1 mRNA (P < 0.05). The suppressive effect of TGF-β on PA activity was blocked by Smad2/3 and JNK1/2 signaling inhibitors (P < 0.05). In conclusion, sperm separated in 90% in porcine uterus could suppressed inflammation via modulation of TGF-β and down-regulation of PAs and ILs. Therefore, the regulatory mechanism of inflammation by sperm in the porcine uterus could be associated with interactions between numerous cytokines including TGF-β.

Topics: Animals; Antineoplastic Agents; Bortezomib; Enzyme Inhibitors; Epithelial Cells; Female; Gene Expression Regulation; Inflammation; Interleukins; Male; p38 Mitogen-Activated Protein Kinases; Plasminogen Activators; RNA, Messenger; Signal Transduction; Spermatozoa; Swine; Transforming Growth Factor beta; Uterus

Current asthma therapies remain unsatisfactory for controlling airway remodelling in asthma. MicroRNA-21 is a key player in asthma pathogenesis, but the molecular mechanisms underlying its effects on airway remodelling are not completely understood. We investigated the effects of inhibition of microRNA-21 on allergic airway inflammation and remodelling.. Female BALB/c mice were divided into four groups: control, ovalbumin-sensitized and -challenged for 3 months, microRNA-negative control-treated ovalbumin-treated, and microRNA-21 inhibitor-treated ovalbumin-treated groups. Parameters related to airway remodelling, cytokine production, airway inflammation, and airway hyperresponsiveness were compared between groups. Human bronchial smooth muscle cells were used in a mechanism study.. In this asthma model, ovalbumin-sensitized and -challenged mice exhibited allergic airway inf lammation and airway remodelling. MicroRNA-21 inhibitor-treated mice had fewer inflammatory cells, lower TH2 cytokine production, and suppressed parameters related to remodelling such as goblet cell hyperplasia, collagen deposition, hydroxyproline content, and expression of smooth muscle actin. Inhibition of microRNA-21 decreased transforming growth factor β1 expression and induced Smad7 expression in lung tissue. In human bronchial smooth muscle cells stimulated with transforming growth factor β1, microRNA-21 inhibition upregulated Smad7 expression and decreased markers of airway remodelling.. Inhibition of microRNA-21 had both anti-inflammatory and anti-remodelling effects in this model of ovalbumin-induced chronic asthma. Our data suggest that the microRNA-21-transforming growth factor β1-Smad7 axis modulates the pathogenesis of ovalbumin-induced chronic asthma and in human bronchial smooth muscle cells. MicroRNA-21 inhibitors may be a novel therapeutic target in patients with allergic asthma, especially those with airway remodelling.

Topics: Airway Remodeling; Animals; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Inflammation; Lung; Mice; Mice, Inbred BALB C; MicroRNAs; Ovalbumin; Smad7 Protein; Transforming Growth Factor beta

Interleukin (IL)-33 cytokine plays a critical role in allergic diseases and cancer. IL-33 also has a nuclear localization signal. However, the nuclear function of IL-33 and its impact on cancer is unknown. Here, we demonstrate that nuclear IL-33-mediated activation of SMAD signaling pathway in epithelial cells is essential for cancer development in chronic inflammation. Using RNA and ChIP sequencing, we found that nuclear IL-33 repressed the expression of an inhibitory SMAD, Smad6, by interacting with its transcription factor, RUNX2. IL-33 was highly expressed in the skin and pancreatic epithelial cells in chronic inflammation, leading to a markedly repressed Smad6 expression as well as dramatically upregulated p-SMAD2/3 and p-SMAD1/5 in the epithelial cells. Blocking TGF-β/SMAD signaling attenuated the IL-33-induced cell proliferation in vitro and inhibited IL-33-dependent epidermal hyperplasia and skin cancer development in vivo. IL-33 and SMAD signaling were upregulated in human skin cancer, pancreatitis, and pancreatitis-associated pancreatic cancer. Collectively, our findings reveal that nuclear IL-33/SMAD signaling is a cell-autonomous tumor-promoting axis in chronic inflammation, which can be targeted by small-molecule inhibitors for cancer treatment and prevention.

Topics: Animals; Carcinogenesis; Cell Line; Cell Line, Tumor; Cell Nucleus; Core Binding Factor Alpha 1 Subunit; Epithelial Cells; Female; Inflammation; Interleukin-33; Male; Mice; Mice, Inbred C57BL; Pancreatic Neoplasms; Signal Transduction; Skin Neoplasms; Smad6 Protein; Transforming Growth Factor beta

MicroRNAs are important regulators of immune responses. Here, we show miR-221 and miR-222 modulate the intestinal Th17 cell response. Expression of miR-221 and miR-222 was induced by proinflammatory cytokines and repressed by the cytokine TGF-β. Molecular targets of miR-221 and miR-222 included Maf and Il23r, and loss of miR-221 and miR-222 expression shifted the transcriptomic spectrum of intestinal Th17 cells to a proinflammatory signature. Although the loss of miR-221 and miR-222 was tolerated for maintaining intestinal Th17 cell homeostasis in healthy mice, Th17 cells lacking miR-221 and miR-222 expanded more efficiently in response to IL-23. Both global and T cell-specific deletion of miR-221 and miR-222 rendered mice prone to mucosal barrier damage. Collectively, these findings demonstrate that miR-221 and miR-222 are an integral part of intestinal Th17 cell response that are induced after IL-23 stimulation to constrain the magnitude of proinflammatory response.

Topics: Animals; Feedback, Physiological; Inflammation; Interleukin-23; Intestinal Mucosa; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Proto-Oncogene Proteins c-maf; Receptors, Interleukin; Signal Transduction; Th17 Cells; Transforming Growth Factor beta

CD4 T cell effector function is required for optimal containment of Mycobacterium tuberculosis (Mtb) infection. IFNɣ produced by CD4 T cells is a key cytokine that contributes to protection. However, lung-infiltrating CD4 T cells have a limited ability to produce IFNɣ, and IFNɣ plays a lesser protective role within the lung than at sites of Mtb dissemination. In a murine infection model, we observed that IFNɣ production by Mtb-specific CD4 T cells is rapidly extinguished within the granuloma but not within unaffected lung regions, suggesting localized immunosuppression. We identified a signature of TGFβ signaling within granuloma-infiltrating T cells in both mice and rhesus macaques. Selective blockade of TGFβ signaling in T cells resulted in an accumulation of terminally differentiated effector CD4 T cells, improved IFNɣ production within granulomas, and reduced bacterial burdens. These findings uncover a spatially localized immunosuppressive mechanism associated with Mtb infection and provide potential targets for host-directed therapy.

Topics: Adaptive Immunity; Animals; CD4-Positive T-Lymphocytes; Cell Death; Cytokines; Disease Models, Animal; Female; Granuloma; Inflammation; Interferon-gamma; Lung; Macaca mulatta; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mycobacterium tuberculosis; T-Lymphocytes; Th1 Cells; Transforming Growth Factor beta; Tuberculosis

Diabetic cardiomyopathy (DCM) is a common diabetic complication characterized by diastolic relaxation abnormalities, myocardial fibrosis and chronic heart failure. Although TGF-β/Smad3 signalling has been shown to play a critical role in chronic heart disease, the role and mechanisms of Smad3 in DCM remain unclear. We reported here the potential role of Smad3 in the development of DCM by genetically deleting the Smad3 gene from db/db mice. At the age of 32 weeks, Smad3WT-db/db mice developed moderate to severe DCM as demonstrated by a marked increase in the left ventricular (LV) mass, a significant fall in the LV ejection fraction (EF) and LV fractional shortening (FS), and progressive myocardial fibrosis and inflammation. In contrast, db/db mice lacking Smad3 (Smad3KO-db/db) were protected against the development of DCM with normal cardiac function and undetectable myocardial inflammation and fibrosis. Interestingly, db/db mice with deleting one copy of Smad3 (Smad3 ± db/db) did not show any cardioprotective effects. Mechanistically, we found that deletion of Smad3 from db/db mice largely protected cardiac Smad7 from Smurf2-mediated ubiquitin proteasome degradation, thereby inducing IBα to suppress NF-kB-driven cardiac inflammation. In addition, deletion of Smad3 also altered Smad3-dependent miRNAs by up-regulating cardiac miR-29b while suppressing miR-21 to exhibit the cardioprotective effect on Smad3KO-db/db mice. In conclusion, results from this study reveal that Smad3 is a key mediator in the pathogenesis of DCM. Targeting Smad3 may be a novel therapy for DCM.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Fibrosis; Inflammation; Mice; Mice, Inbred C57BL; Mice, Knockout; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

Microglia, brain-resident macrophages, require instruction from the CNS microenvironment to maintain their identity and morphology and regulate inflammatory responses, although what mediates this is unclear. Here, we show that neurons and astrocytes cooperate to promote microglial ramification, induce expression of microglial signature genes ordinarily lost in vitro and in age and disease in vivo, and repress infection- and injury-associated gene sets. The influence of neurons and astrocytes separately on microglia is weak, indicative of synergies between these cell types, which exert their effects via a mechanism involving transforming growth factor β2 (TGF-β2) signaling. Neurons and astrocytes also combine to provide immunomodulatory cues, repressing primed microglial responses to weak inflammatory stimuli (without affecting maximal responses) and consequently limiting the feedback effects of inflammation on the neurons and astrocytes themselves. These findings explain why microglia isolated ex vivo undergo de-differentiation and inflammatory deregulation and point to how disease- and age-associated changes may be counteracted.

Topics: Animals; Astrocytes; Gene Expression Profiling; Gene Expression Regulation; Homeostasis; Humans; Inflammation; Interferons; Lipopolysaccharides; Mice; Microglia; Multigene Family; Neurons; Phagocytosis; Rats; Signal Transduction; Transcriptome; Transforming Growth Factor beta

Contrast-enhanced magnetic resonance imaging (MRI) is a powerful diagnostic tool for many diseases. In many situations, the contrasts are repeatedly administrated in order to monitor and assess the disease progression.. To investigate and compare the biological effects of γ-Fe. Polydextrose sorbitol carboxymethyl ether coated γ-Fe. It showed that the proinflammatory responses elicited by the γ-Fe. The γ-Fe

Topics: Animals; Biomarkers; C-Reactive Protein; Cell Proliferation; Cell Survival; Contrast Media; Ferric Compounds; Ferritins; Gadolinium DTPA; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Kidney; Magnetic Resonance Imaging; Male; Mice; Nanoparticles; Spectrometry, X-Ray Emission; Transforming Growth Factor beta

Chronic pancreatitis (CP) is an inflammatory disease of the pancreas characterized by ductal obstructions, tissue fibrosis, atrophy and exocrine and endocrine pancreatic insufficiency. However, our understanding is very limited concerning the disease's progression from a single acute inflammation, via recurrent acute pancreatitis (AP) and early CP, to the late stage CP. Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor enzyme activated mostly by oxidative DNA damage. As a co-activator of inflammatory transcription factors, PARP1 is a central mediator of the inflammatory response and it has also been implicated in acute pancreatitis. Here, we set out to investigate whether PARP1 contributed to the pathogenesis of CP. We found that the clinically used PARP inhibitor olaparib (OLA) had protective effects in a murine model of CP induced by multiple cerulein injections. OLA reduced pancreas atrophy and expression of the inflammatory mediators TNFα and interleukin-6 (IL-6), both in the pancreas and in the lungs. Moreover, there was significantly less fibrosis (Masson's trichrome staining) in the pancreatic sections of OLA-treated mice compared to the cerulein-only group. mRNA expression of the fibrosis markers TGFβ, smooth muscle actin (SMA), and collagen-1 were markedly reduced by OLA. CP was also induced in PARP1 knockout (KO) mice and their wild-type (WT) counterparts. Inflammation and fibrosis markers showed lower expression in the KO compared to the WT mice. Moreover, reduced granulocyte infiltration (tissue myeloperoxidase activity) and a lower elevation of serum amylase and lipase activity could also be detected in the KO mice. Furthermore, primary acinar cells isolated from KO mice were also protected from cerulein-induced toxicity compared to WT cells. In summary, our data suggest that PARP inhibitors may be promising candidates for repurposing to treat not only acute but chronic pancreatitis as well.

Topics: Acinar Cells; Acute Disease; Animals; Ceruletide; Disease Models, Animal; Fibrosis; Inflammation; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Pancreas; Pancreatitis; Pancreatitis, Chronic; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Pulmonary sarcoidosis (PS) is a noncaseating granulomatous disease of unknown origin. Despite conflicting reports, it is considered that the regulatory T (Treg) cells are functionally impaired in PS, but the underlying mechanisms remain unclear. OX40, a pivotal costimulatory molecule, is essential for T-cell functions and memory development, but its impact on Treg cells is ambiguous.. Does the OX40 pathway influence the suppressive functions of Treg cells in PS?. Fifty treatment-naïve patients with PS and 30 healthy control participants were recruited for this study. Polychromatic flow cytometry-based immunologic assays were performed to enumerate effector T helper (Th) cells and Treg cells along with their functions. Using real-time polymerase chain reaction analysis, small interfering RNA, and pharmacologic inhibitors, the impact of OX40 on Treg cell function was investigated.. We observed enrichment of Th-9 cells perhaps for the first time along with Th-1, Th-17, and Treg cells in patients' BAL fluid (BALF) compared with peripheral blood. However, Treg cells were observed to be functionally defective at the pathological site. We observed higher expression of OX40 on both T effector (CD4. We propose that inhibiting the OX40 pathway may constitute a therapeutic strategy for controlling inflammatory T cells by restoring Treg cell functions in patients with PS.

Topics: Adult; Bronchoalveolar Lavage Fluid; Cross-Sectional Studies; Drug Discovery; Female; Humans; Immunologic Memory; Immunologic Tests; Inflammation; Interferon-gamma; Interleukin-10; Male; Receptors, OX40; Sarcoidosis, Pulmonary; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Concentration of hyaluronic acid (HA) in the lungs increases in idiopathic pulmonary fibrosis (IPF). HA is involved in the organization of fibrin, fibronectin, and collagen. HA has been proposed to be a biomarker of fibrosis and a potential target for antifibrotic therapy. Hyaluronidase (HD) breaks down HA into fragments, but is a subject of rapid hydrolysis. A conjugate of poloxamer hyaluronidase (pHD) was prepared using protein immobilization with ionizing radiation. In a model of bleomycin-induced pulmonary fibrosis, pHD decreased the level of tissue IL-1β and TGF-β, prevented the infiltration of the lung parenchyma by CD16

Topics: Animals; Cell Differentiation; Collagen Type I; Hyaluronic Acid; Hyaluronoglucosaminidase; Hydroxyproline; Idiopathic Pulmonary Fibrosis; Inflammation; Interleukin-1beta; Keratins; Lung; Male; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Platelet Endothelial Cell Adhesion Molecule-1; Poloxamer; Receptors, IgG; Spiperone; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFβ signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFβ-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1

Topics: Adaptor Proteins, Signal Transducing; Animals; Carcinogenesis; Cell Differentiation; Cell Survival; Colon; Colonic Neoplasms; Epithelial Cells; Fetus; Inflammation; Kaplan-Meier Estimate; MAP Kinase Signaling System; Mice, Inbred C57BL; Mutation; Prognosis; Proto-Oncogene Proteins B-raf; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Signal Transduction; Spheroids, Cellular; Transcription Factors; Transforming Growth Factor beta; Wnt Proteins; Wnt Signaling Pathway; YAP-Signaling Proteins

Hyperglycemia-induced SIRT1, DNMT1, SODs, as well as oxidative stress, play a pivotal role in the progression of diabetic nephropathy. Cissus quadrangularis, holds antioxidant and hypoglycemic activity; however, a direct link between its activity and prevention of diabetic nephropathy has not been ascertained yet. Accordingly, we aimed to delineate the protective effect of ethanolic extract of Cissus quadrangularis (EECQ) against high-fat diet/streptozotocin (HFD/STZ) induced diabetic nephropathy rats.. The control group was fed with a normal chow diet. Rats kept on an HFD for 12 weeks with a single low dose of STZ manifested the features of diabetic nephropathy. The treatment was done by the oral administration of EECQ (200 mg/kg) for six weeks (six rats in each group).. Treatment with EECQ demonstrated substantial attenuation of elevated insulin resistance, lipid profile and creatinine level. Additionally, EECQ restored albuminuria, glomerular filtration rate and creatinine clearance in diabetic nephropathy rats. Furthermore, HFD consumption in rats culminated in reduced SIRT1 and enhanced DNMT1 expression, nonetheless, rescued by EECQ. Moreover, EECQ augmented the SOD 1 and 3 levels, thereby safeguarded from oxidative damage and renal inflammation. Besides, treatment protected from renal fibrosis by downregulating TGFβ, Smad2/3 and col1/3 expression in diseased rats.. Thus, based on the above findings, we conclude that EECQ shows a protective effect against diabetic nephropathy.

Topics: Albuminuria; Animals; Antioxidants; Cissus; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Diet, High-Fat; Glomerular Filtration Rate; Hypoglycemic Agents; Inflammation; Insulin Resistance; Kidney; Lipids; Male; Oxidative Stress; Phytotherapy; Plant Extracts; Rats, Sprague-Dawley; Repressor Proteins; Sirtuin 1; Smad Proteins, Receptor-Regulated; Superoxide Dismutase; Transforming Growth Factor beta

Glutaric acidemia type 1 (GA1) is caused by glutaryl-CoA dehydrogenase deficiency that leads to a blockage in the metabolic route of the amino acids lysine and tryptophan and subsequent accumulation of glutaric acid (GA), 3-hydroxyglutaric acids and glutarylcarnitine (C5DC). Patients predominantly manifest neurological symptoms, associated with acute striatal degeneration, as well as progressive cortical and striatum injury whose pathogenesis is not yet fully established. Current treatment includes protein/lysine restriction and l-carnitine supplementation of (L-car). The aim of this work was to evaluate behavior parameters and pro-inflammatory factors (cytokines IL-1β, TNF-α and cathepsin-D levels), as well as the anti-inflammatory cytokine IL10 in striatum of knockout mice (Gcdh

Topics: Amino Acid Metabolism, Inborn Errors; Animals; Brain Diseases, Metabolic; Carnitine; Cathepsin D; Corpus Striatum; Glutaryl-CoA Dehydrogenase; Grooming; Inflammation; Interleukin-1beta; Locomotion; Lysine; Mice, Knockout; Neuroprotective Agents; Open Field Test; Transforming Growth Factor beta

Glucose-based solutions remain the most used osmotic agents in peritoneal dialysis (PD), but unavoidably they contribute to the loss of peritoneal filtration capacity. Here, we evaluated at a molecular level the effects of XyloCore, a new PD solution with a low glucose content, in mesothelial and endothelial cells. Cell viability, integrity of mesothelial and endothelial cell membrane, activation of mesothelial and endothelial to mesenchymal transition programs, inflammation, and angiogenesis were evaluated by several techniques. Results showed that XyloCore preserves mesothelial and endothelial cell viability and membrane integrity. Moreover XyloCore, unlike glucose-based solutions, does not exert pro-fibrotic, -inflammatory, and -angiogenic effects. Overall, the in vitro evidence suggests that XyloCore could represent a potential biocompatible solution promising better outcomes in clinical practice.

Topics: Biomarkers; Cell Line; Cell Shape; Cell Survival; Cell Transdifferentiation; Dialysis Solutions; Electric Impedance; Epithelial Cells; Epithelium; Glucose; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Mesoderm; Mitochondria; Neovascularization, Physiologic; Oxidative Stress; Peritoneal Dialysis; Permeability; Snail Family Transcription Factors; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses tumor progression, potentially displaying opposing effects on therapeutic outcomes. Chronic inflammation facilitates tumor progression and treatment resistance, whereas induction of acute inflammatory reactions often stimulates the maturation of dendritic cells (DCs) and antigen presentation, leading to anti-tumor immune responses. In addition, multiple signaling pathways, such as nuclear factor kappa B (NF-kB), Janus kinase/signal transducers and activators of transcription (JAK-STAT), toll-like receptor (TLR) pathways, cGAS/STING, and mitogen-activated protein kinase (MAPK); inflammatory factors, including cytokines (e.g., interleukin (IL), interferon (IFN), and tumor necrosis factor (TNF)-α), chemokines (e.g., C-C motif chemokine ligands (CCLs) and C-X-C motif chemokine ligands (CXCLs)), growth factors (e.g., vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β), and inflammasome; as well as inflammatory metabolites including prostaglandins, leukotrienes, thromboxane, and specialized proresolving mediators (SPM), have been identified as pivotal regulators of the initiation and resolution of inflammation. Nowadays, local irradiation, recombinant cytokines, neutralizing antibodies, small-molecule inhibitors, DC vaccines, oncolytic viruses, TLR agonists, and SPM have been developed to specifically modulate inflammation in cancer therapy, with some of these factors already undergoing clinical trials. Herein, we discuss the initiation and resolution of inflammation, the crosstalk between tumor development and inflammatory processes. We also highlight potential targets for harnessing inflammation in the treatment of cancer.

Topics: Antigen Presentation; Dendritic Cells; Humans; Immunity, Cellular; Inflammasomes; Inflammation; Interferons; Interleukins; Janus Kinases; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Neoplasms; NF-kappa B; Signal Transduction; STAT Transcription Factors; Toll-Like Receptors; Transforming Growth Factor beta

Growth differentiation factor 11 (GDF11) has been implicated in the regulation of embryonic development and age-related dysfunction, including the regulation of retinal progenitor cells. However, little is known about the functions of GDF11 in diabetic retinopathy. In this study, we demonstrated that GDF11 treatment improved diabetes-induced retinal cell death, capillary degeneration, pericyte loss, inflammation, and blood-retinal barrier breakdown in mice. Treatment of isolated mouse retinal microvascular endothelial cells with recombinant GDF11 in vitro attenuated glucotoxicity-induced retinal endothelial apoptosis and the inflammatory response. The protective mechanisms exerted are associated with TGF-β/Smad2, PI3k-Akt-FoxO1 activation，and NF-κB pathway inhibition. This study indicated that GDF11 is a novel therapeutic target for diabetic retinopathy.

Topics: Animals; Apoptosis; Blood-Retinal Barrier; Bone Morphogenetic Proteins; Cytokines; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Endothelial Cells; Forkhead Box Protein O1; Glucose; Growth Differentiation Factors; Inflammation; Male; Mice, Inbred C57BL; Microvessels; Neuroprotective Agents; NF-kappa B; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Retina; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

Regulatory T cells (T

Topics: Animals; Immunity, Innate; Inflammation; Mice; Mice, Congenic; Mice, Inbred C57BL; Mice, Transgenic; Skin; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Topics: Animals; Blotting, Western; Chronic Disease; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Epithelial-Mesenchymal Transition; Gene Expression Regulation; Inflammation; Mice; Mice, Inbred C57BL; Nasal Mucosa; Rhinitis; RNA; Signal Transduction; Sinusitis; Smad2 Protein; T-Box Domain Proteins; Transforming Growth Factor beta

Topics: Continuous Positive Airway Pressure; Gene Expression Profiling; Humans; Hypoxia; Inflammation; Interferon-alpha; Interferon-gamma; Leukocytes; NF-kappa B; Oxygen Inhalation Therapy; Sequence Analysis, RNA; Signal Transduction; Sleep Apnea, Obstructive; Transcriptome; Transforming Growth Factor beta; Up-Regulation

After a controlled human malaria infection (CHMI), presentation of clinical signs and symptoms and host responses is heterogeneous. Transforming growth factor-beta (TGF-β) is the first serum cytokine that changes in malaria-naïve volunteers after CHMI. We studied a possible relation between TGF-β changes, pro-inflammatory cytokines, activation of haemostasis and endothelial cells and clinical symptoms.. A panel of cytokines including TGF-β, and markers of activation of haemostasis and endothelial cells were measured in blood samples of 15 volunteers at baseline before CHMI and during CHMI at day of treatment. The change of the parameters on the day of treatment was examined for a significant alteration during infection.. Nine of 15 volunteers showed a significant decrease in TGF-β compared to baseline, with concomitant increased concentrations of D-dimer (p = 0.012), Von Willebrand factor (p = 0.017), IL-6 (p = 0.012) and IFN-γ (0.028) and a significantly decreased platelet count (p = 0.011). In contrast, 6 of 15 volunteers showed sustained or increased TGF-β concentrations without change in the aforementioned parameters. The sustained responders presented with less moderate and severe clinical symptoms than the negative responders (p = 0.036) and had a higher baseline lymphocyte count (p = 0.026). TGF-β concentrations did not correlate with the parasitaemia on day of treatment.. Early decreases of serum TGF-β might function a marker for a pro-inflammatory host response and downstream clinical symptoms and pathology during CHMI.

Topics: Adult; Blood Platelets; Correlation of Data; Down-Regulation; Endothelial Cells; Female; Fibrin Fibrinogen Degradation Products; Hemostasis; Humans; Inflammation; Interferon-gamma; Interferons; Interleukin-6; Lymphocytes; Malaria; Male; Parasitemia; Platelet Count; Transforming Growth Factor beta; Up-Regulation; von Willebrand Factor

Lipopolysaccharide (LPS) induces stress inflammation and apoptosis. Pulmonary epithelial cell apoptosis, which accelerates the progression of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), is the leading cause of mortality in patients with ALI/ARDS. The nephroblastoma overexpressed protein (CCN3), an inflammatory modulator, is reported to be a biomarker in ALI. Using the LPS-induced ALI model, this study investigated the expression of CCN3 and its possible molecular mechanism in lung alveolar epithelial cell inflammation and apoptosis. Our data revealed that LPS treatment greatly increased the level of CCN3 in A549 cells. The A549 cells were transfected with specific CCN3 small interfering RNA (siRNA) using transfection reagent. CCN3 siRNA not only largely attenuated the expressions of the inflammatory cytokines interleukin (IL)-1β and transforming growth factor (TGF)-β1, but also reduced the apoptotic rate of the AEC II cells and affected the expressions of the apoptosis-associated proteins (Bcl-2 and caspase-3). Furthermore, CCN3 knockdown greatly inhibited the activation of nuclear factor-κB p65 in A549 cells. In addition, TGF-β/p-Smad inhibitor (TP0427736) and NF-κB inhibitor (PDTC) significantly attenuated the expression level of CCN3 in A549 cells. In conclusion, our data indicated that CCN3 siRNA affected downstream signal through TGF-β/ p-Smad or NF-κB pathway, leading to the inhibition of cell inflammation and apoptosis in human alveolar epithelial cells.

Topics: A549 Cells; Acute Lung Injury; Alveolar Epithelial Cells; Apoptosis; Caspase 3; Gene Knockdown Techniques; Humans; Inflammation; Interleukin-1beta; Lipopolysaccharides; Lung; Nephroblastoma Overexpressed Protein; NF-kappa B; Proto-Oncogene Proteins c-bcl-2; RNA, Small Interfering; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

Inflammatory microenvironment is an important factor for promoting cancer invasion and metastasis, but the underlying molecular mechanisms remain unclear. Here, we mimicked an inflammatory microenvironment both in vitro and in vivo and investigated its effects on the invasion and metastasis of colon cancer. Moreover, colon cancer patient samples were also analyzed statistically. Conditioned medium from the differentiated macrophages induced invasion and migration of colon cancer cells in vitro, which could be reversed by the treatment of a neutralizing anti-growth differentiation factor 15 (GDF15) antibody, indicating GDF15 involvement in inflammation-induced invasiveness. Also, we observed similar effects of human recombinant GDF15 on colon cancer cells. Mechanistically, GDF15 activated c-Fos by separating it from Lamin A/C, increasing transcriptional activity of c-Fos and regulating EMT gene expressions. However, c-Fos knockdown using lentivirus shRNA plasmid inhibited GDF15-triggered invasion and migration in vitro. In vivo, inflammation caused by lipopolysaccharides obviously increased GDF15 secretion, and c-Fos knockdown reduced the lung metastasis of colon cancer cells in mice model. In addition, c-Fos expressions in patient samples were found to be associated with colon cancer metastasis and TNM stages. Taken together, GDF15 in inflammatory microenvironment induces colon cancer invasion and metastasis by regulating EMT genes by activating c-Fos, which might be a potential therapeutic target for metastatic colon cancer.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers, Tumor; Cell Line, Tumor; Colonic Neoplasms; Female; Gene Expression Regulation, Neoplastic; Growth Differentiation Factor 15; Humans; Inflammation; Lamin Type A; Macrophages; MAP Kinase Signaling System; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasms, Experimental; Proto-Oncogene Proteins c-fos; Transforming Growth Factor beta; Tumor Microenvironment

Persons with chronic kidney disease (CKD) are at high risk of infection. While low-grade inflammation could impair immune response, it is unknown whether inflammatory markers are associated with infection risk in this clinical population. Using 2003-2013 data from the Chronic Renal Insufficiency Cohort Study (3,597 participants with CKD), we assessed the association of baseline plasma levels of 4 inflammatory markers (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 receptor antagonist (IL-1RA), and transforming growth factor-β (TGF-β)) with incident hospitalization with major infection (pneumonia, urinary tract infection, cellulitis and osteomyelitis, and bacteremia and sepsis). During follow-up (median 7.5 years), 36% (n = 1,290) had incident hospitalization with major infection. In multivariable Cox analyses with each inflammatory marker modeled as a restricted cubic spline, higher levels of IL-6 and TNF-α were monotonically associated with increased risk of hospitalization with major infection (for 95th vs. 5th percentile, hazard ratio = 2.11 (95% confidence interval: 1.68, 2.66) for IL-6 and 1.88 (95% confidence interval: 1.51, 2.33) for TNF-α), while corresponding associations for IL-1RA or TGF-β were nonsignificant. Thus, higher plasma levels of IL-6 and TNF-α, but not IL-1RA or TGF-β, were significantly associated with increased risk of hospitalization with major infection. Future studies should investigate whether inflammatory pathways that involve IL-6 and TNF-α increase susceptibility to infection among individuals with CKD.

Topics: Adult; Aged; Biomarkers; Disease Susceptibility; Female; Hospitalization; Humans; Incidence; Infections; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-6; Male; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Topics: Animals; Dipeptidyl-Peptidase IV Inhibitors; Fibrosis; Inflammation; Kidney Diseases; Kidney Tubules, Proximal; Mice; Mice, Inbred C57BL; Piperazines; Protective Agents; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta; Ureteral Obstruction

Once thought to have revolutionized therapeutic intervention in surgery, Recombinant Human Bone Morphogenic Protein 2 (rhBMP2) is now in its second decade of sustained controversy over the side effects associated with its use. Side effects associated with clinical use of rhBMP2 (Infuse, Medtronic Inc) include a marked inflammatory response, pain, therapeutic failures, ectopic bone, tissue degradation, and death. What is missing, despite the depth of literature on the subject, is a direct interrogation of rhBMP2, specifically for inflammation. Here we set out to determine if rhBMP2 alters traditional macrophage markers associated with pro-inflammatory responses, and pro-reparative responses to injury. Based on our previous work, we hypothesized there would be no direct effect of the peptide on macrophage polarization. Here we utilized commercially available murine macrophages, RAW 264.7, and treated these cells with rhBMP2 in standard growth media or macrophage polarizing media (M1 and M2) at several doses of the peptide. Our readouts were cell viability, apoptosis, gene expression of M1 and M2 markers, and ELISA for M1 marker iNOS, and M2 marker Arg1. Our data give very little evidence to support an alteration in macrophage phenotype by rhBMP2 alone, or alteration of the phenotype when cultured in enriched M1 or M2 media. These results further suggest that other factors associated with the clinical use of Infuse, likely supraphysiological rhBMP2 doses and off label usage, are more likely the culprit for poor outcomes. This further reinforces the utility of rhBMP2 and other peptides in tissue engineering therapies when conditions are tightly controlled.

Topics: Animals; Apoptosis; Bone Morphogenetic Protein 2; Cell Differentiation; Cell Survival; Humans; Inflammation; Macrophage Activation; Macrophages; Mice; RAW 264.7 Cells; Recombinant Proteins; Transforming Growth Factor beta

Aim Liver fibrosis represents a massive global health burden with limited therapeutic options. Thus, the need for curative options is evident. Thus, this study aimed to assess the potential antifibrotic effect of honokiol in Concanavalin A (Con A) induced immunological model of liver fibrosis as well the possible underlying molecular mechanisms.. Male Sprague-Dawley rats were treated with either Con A (20 mg/kg, IV) and/or honokiol (10 mg/kg, orally) for 4 weeks. Hepatotoxicity indices were as well as histopathological evaluation was done. Hepatic fibrosis was assessed by measuring alpha smooth muscle actin (α-SMA) expression and collagen fibers deposition by Masson's trichrome stain and hydroxyproline content. To elucidate the underlying molecular mechanisms, the effect of honokiol on oxidative stress, inflammatory markers as well as transforming growth factor beta (TGF-β)/SMAD and mitogen-activated protein kinase (MAPK) pathways was assessed.. Honokiol effectively reversed the hepatotoxicity indices elevations and abnormal histopathological changes induced by Con A. Besides, honokiol attenuated Con A-induced liver fibrosis by down-regulation of hydroxyproline levels, α-SMA expression together with a marked decrease in collagen fibers deposition. Mechanistically Con A induced oxidative stress, provocation of inflammatory responses and activation of TGF-β/SMAD/MAPK pathways. Contrariwise, honokiol co-treatment significantly restored antioxidant defence mechanisms, down-regulated inflammatory cascades and inhibited TGF-β/SMAD/MAPK signaling pathways.. The results provide an evidence for the promising antifibrotic effect of honokiol that could be partially due to suppressing oxidative stress and inflammatory processes as well as inhibition of TGF-β/SMAD/MAPK signaling pathways.

Topics: Actins; Animals; Biphenyl Compounds; Concanavalin A; Hydroxyproline; Inflammation; Lignans; Liver Cirrhosis; Male; Mitogen-Activated Protein Kinases; Oxidative Stress; Rats; Rats, Sprague-Dawley; Signal Transduction; Smad Proteins; Survival Analysis; Transforming Growth Factor beta

Transforming growth factor β-induced protein (TGFBIp) is an extracellular matrix protein; its expression by several cell types is greatly increased by TGF-β. TGFBIp is released by primary human umbilical vein endothelial cells (HUVECs) and functions as a mediator of experimental sepsis. 2,2'-Bipyridine-containing natural products are generally accepted to have antimicrobial, cytotoxic and anti-inflammatory properties. We hypothesized that a 2,2'-bipyridine containing natural product, collismycin C, could reduce TGFBIp-mediated severe inflammatory responses in human endothelial cells and mice. Here we investigated the effects and underlying mechanisms of collismycin C against TGFBIp-mediated septic responses. Collismycin C effectively inhibited lipopolysaccharide-induced release of TGFBIp and suppressed TGFBIp-mediated septic responses. In addition, collismycin C suppressed TGFBIp-induced sepsis lethality and pulmonary injury. This suppression of TGFBIp-mediated and CLP-induced septic responses indicates that collismycin C is a potential therapeutic agent for various severe vascular inflammatory diseases, with inhibition of the TGFBIp signaling pathway as the mechanism of action.

Topics: 2,2'-Dipyridyl; Animals; Anti-Inflammatory Agents; Extracellular Matrix Proteins; Humans; Inflammation; Mice; Mice, Inbred C57BL; Sepsis; Transforming Growth Factor beta

Rheumatoid arthritis is a chronic and systemic autoimmune disease, which affects approximately 1% of the adult population worldwide. The present study investigated the therapeutic effect of theacrine (TC) on arthritis and its mechanisms in Freund's incomplete adjuvant (FIA)-induced SD rats. Rats were randomly divided into 5 groups: i) healthy control; ii) model; iii) positive control with methotrexate (MTX); iv) treatment with 12.5 mg/kg TC; and v) treatment with 25.0 mg/kg TC. The apparent scores, including changes in body weights, degree of paw swelling and arthritis indicators, were analyzed to evaluate the anti-chronic inflammatory effect of TC. The levels of interleukin (IL)-6 and transforming growth factor-β (TGF-β) in serum were measured by enzyme-linked immunosorbent assay. The protein and RNA expression levels of the critical factors in rats were measured to elucidate the mechanisms responsible for chronic inflammation and to verify molecular indexes of chronic inflammatory conditions. TC notably suppressed the severity of FIA-induced rat by attenuating the apparent scores, animal weight and inflammatory indexes in the 25 mg/kg TC group compared with the FIA rat model. Furthermore, TC significantly decreased the levels of IL-6 and increased the levels of TGF-β. Histopathological examinations indicated that TC rescued the synovial hyperplasia and inflammatory cell infiltration in joint tissues. In addition, TC enhanced TGF-β-mediated shifts in inflammatory marker expression in joint tissue. Overall, the present study demonstrated that TC exerted a superior anti-arthritic effect via the suppression of IL-6 and the activation of TGF-β by the TGF-β/SMAD pathway.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Chronic Disease; Freund's Adjuvant; Inflammation; Joints; Lipids; Rats; Rats, Sprague-Dawley; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Uric Acid

The secretome of mesenchymal stem cell (MSC) offers a series of immunoregulatory properties and is regarded as an effective method of mitigating secondary neuroinflammation induced by traumatic brain injury (TBI). The secretome of adipose-derived MSCs (ASC-ST) was collected under hypoxia conditions. Proteomics data were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and concentrations of major components were tested. After the TBI caused by an electric cortical contusion impactor, rats were injected ASC-ST through caudal veins for 7 days. The neurological functional prognosis of TBI rats was significantly improved, and the vasogenic edema of brain tissues that was measured 14 days after TBI was relieved by ASC-ST, corresponding to brain water content levels. ASC-ST ameliorated TBI-induced neuroinflammatory environments that caused the edema, the apoptosis of the neural cells, and the nerve fiber damage by increasing the number of M2 phenotypes present while reducing the number of M1 phenotype microglia present. Furthermore, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels were reduced, whereas transforming growth factor-beta (TGF-β) and tumor necrosis factor-stimulated gene 6 protein (TSG-6) levels were increased after secretome treatment. Altogether, ASC-ST is capable of improving neural functioning by modulating TBI-induced neuroinflammation and its related secondary insults. ASC-ST may be one of the most promising candidates for regulating the secondary inflammatory reactions of central nervous systems for clinical use.

Topics: Adipocytes; Animals; Apoptosis; Brain; Brain Edema; Brain Injuries, Traumatic; Cell Adhesion Molecules; Cell Differentiation; Cell Hypoxia; Culture Media, Conditioned; Disease Models, Animal; Gene Expression Regulation; Inflammation; Injections, Intravenous; Interleukin-6; Male; Mesenchymal Stem Cells; Microglia; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Macrophages (Mϕ) have been reported to downmodulate the cytotoxicity of natural killer (NK) cell against solid tumor cells. However, the collaborative role between NK cells and Mϕ remains underappreciated, especially in hematological cancers, such as chronic myeloid leukemia (CML). We observed a higher ratio of innate immune cells (Mϕ and NK) to adaptive immune cells (T and B cells) in CML bone marrow aspirates, prompting us to investigate the roles of NK and Mϕ in CML. Using coculture models simulating the tumor inflammatory environment, we observed that Mϕ protects CML from NK attack only when CML was itself mycoplasma-infected and under chronic infection-inflammation condition. We found that the Mϕ-protective effect on CML was associated with the maintenance of CD16 level on the NK cell membrane. Although the NK membrane CD16 (mCD16) was actively shed in Mϕ + NK + CML trioculture, the NK mCD16 level was maintained, and this was independent of the modulation of sheddase by tissue inhibitor of metalloproteinase 1 or inhibitory cytokine transforming growth factor beta. Instead, we found that this process of NK mCD16 maintenance was conferred by Mϕ in a contact-dependent manner. We propose a new perspective on anti-CML strategy through abrogating Mϕ-mediated retention of NK surface CD16.

Topics: Adaptive Immunity; B-Lymphocytes; Cell Differentiation; Cell Line, Tumor; Cell Survival; Coculture Techniques; Cytokines; Cytotoxicity, Immunologic; GPI-Linked Proteins; Humans; Inflammation; Interleukin-8; Killer Cells, Natural; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Macrophages; Mycoplasma; Receptors, IgG; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta

Aortic root aneurysm formation is a cardinal feature of Marfan syndrome (MFS) and likely TGF-β driven via Smad (canonical) and ERK (non-canonical) signalling. The current study assesses human MFS vascular smooth muscle cell (SMC) phenotype, focusing on individual contributions by Smad and ERK, with Notch3 signalling identified as a novel compensatory mechanism against TGF-β-driven pathology. Although significant ERK activation and mixed contractile gene expression patterns were observed by traditional analysis, this did not directly correlate with the anatomic site of the aneurysm. Smooth muscle cell phenotypic changes were TGF-β-dependent and opposed by ERK in vitro, implicating the canonical Smad pathway. Bulk SMC RNA sequencing after ERK inhibition showed that ERK modulates cell proliferation, apoptosis, inflammation, and Notch signalling via Notch3 in MFS. Reversing Notch3 overexpression with siRNA demonstrated that Notch3 promotes several protective remodelling pathways, including increased SMC proliferation, decreased apoptosis and reduced matrix metalloproteinase activity, in vitro. In conclusion, in human MFS aortic SMCs: (a) ERK activation is enhanced but not specific to the site of aneurysm formation; (b) ERK opposes TGF-β-dependent negative effects on SMC phenotype; (c) multiple distinct SMC subtypes contribute to a 'mixed' contractile-synthetic phenotype in MFS aortic aneurysm; and (d) ERK drives Notch3 overexpression, a potential pathway for tissue remodelling in response to aneurysm formation.

Topics: Aorta; Aortic Aneurysm; Apoptosis; Cell Line; Cell Proliferation; Humans; Inflammation; Marfan Syndrome; Muscle Contraction; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Receptor, Notch3; Signal Transduction; Transforming Growth Factor beta

Partial bladder outlet obstruction (pBOO) results in bladder fibrosis that is initiated by an inflammatory cascade and the decompensation after smooth muscle hypertrophy. We have been using an animal model to develop the hypothesis that mesenchymal stem cells (MSCs) are able to mitigate this cytokine cascade and prevent bladder deterioration. We hypothesized that intraperitoneal administration of MSCs can produce the same effects as intravenously administered cells but may require higher dosing. Intraperitoneal treatment will provide insights into the mechanisms of action and may offer advantages over intravenous administration, as it will permit allow higher doses and potentially reduce systemic exposure. Rats underwent a surgical induction of pBOO and instillation of either 1 × 10

Topics: Animals; Female; Fibrosis; Gene Expression Regulation; Hypertrophy; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Injections, Intraperitoneal; Mesenchymal Stem Cell Transplantation; Muscle, Smooth; Muscular Diseases; Random Allocation; Rats; Rats, Sprague-Dawley; Smad2 Protein; Transcription Factors; Transforming Growth Factor beta; Urinary Bladder Neck Obstruction; Urodynamics

Type 2 inflammation and eosinophilic infiltration are prominent pathologic features of chronic rhinosinusitis with nasal polyps (CRSwNP). The purpose of the present study was to determine the roles of Tregs in controlling type 2 inflammation and inhibiting eosinophilic infiltration in CRSwNP. A total of 134 nasal polyps, 67 ostiomeatal complex from chronic rhinosinusitis (CRS) and 62 normal nasal tissues from controls were collected to study the enumeration and function of Tregs cells and the expressions of cytokine profiles via immunofluorescence staining, flow cytometry, qRT-PCR, ELISA, and/or H&E staining. The effects of Tregs on type2 and type3 inflammations were determined in an eosinophilic chronic sinusitis (ECRS) mice model. It was confirmed that the CRSwNP displayed the features of Th2 and Th17 cells-mediated inflammation, accompanying by an increased level of eosinophilic infiltration and the eosinophil cationic protein (ECP), with a decreased frequency of Treg cells. Furthermore, the percentages of CD4+CD25+CD127lowTreg and CD4+CD25+Foxp3+Treg were only decreased in the polyps of CRSwNP but not in the paired peripheral blood. The CRSwNP possessed the decreased Nrp1+Tregs, Helios+Treg, and low TGF-β and interleukin (IL)-10 expressions in Tregs. The ECRS mice showed similar inflammatory characteristics to CRSwNP patients. The adoptive transfer of CD4+CD25+Foxp3+ Treg cells significantly decreased the inflammatory cytokines, eosinophilic chemotactic factors in the mucosa of the ECRS mice without alteration of the immune balance in the peripheral blood and spleen. In conclusion, CRSwNP showed high type 2 and type3 inflammation and defective Tregs. The induced regulatory T cell (iTreg) may correct the imbalance between immune tolerance and effect via limiting the eosinophil recruitment of mucosa in CRSwNP.

Topics: Adult; Animals; Asian People; CD4 Antigens; Chronic Disease; Eosinophils; Female; Forkhead Transcription Factors; Gene Expression Regulation; Humans; Inflammation; Interleukin-10; Male; Mice, Inbred BALB C; Nasal Mucosa; Nasal Polyps; Rhinitis; Sinusitis; T-Lymphocytes, Regulatory; Th17 Cells; Th2 Cells; Transforming Growth Factor beta

Regulatory T (Treg) cells integrate diverse environmental signals to modulate their function for optimal suppression. Translational regulation represents a favorable mechanism for Treg cell environmental sensing and adaptation. In this study, we carry out an unbiased screen of the Treg cell translatome and identify serum/glucocorticoid-regulated kinase 1 (SGK1), a known salt sensor in T cells, as being preferentially translated in activated Treg cells. We show that high salt (HS) drives thymic Treg cells to adopt a T helper type 17 (Th17)-like phenotype and enhances generation of Th17-like induced Treg cells in a SGK1-dependent manner, all the while maintaining suppressive function. Salt-mediated Th17-like differentiation of Treg cells was evident in mice fed with HS diet or injected with HS-preconditioned T cells. Overall, SGK1 enables Treg cells to adapt their function in response to environmental cues. By understanding these environmental-sensing mechanisms, we envision targeted approaches to fine-tune Treg cell function for better control of inflammation.

Topics: Animals; Cell Differentiation; Cell Polarity; Cellular Reprogramming; DNA-Binding Proteins; Forkhead Transcription Factors; Immediate-Early Proteins; Inflammation; Intestines; Kidney; Mice, Inbred C57BL; Nuclear Receptor Subfamily 1, Group F, Member 3; Phenotype; Protein Biosynthesis; Protein Serine-Threonine Kinases; RNA, Messenger; Sodium Chloride; T-Lymphocytes, Regulatory; Th17 Cells; Transcription Factors; Transforming Growth Factor beta

The transforming growth factor type-β (TGF-β) has been demonstrated to play an important role in the development of atherosclerosis through binding to the serine/threonine kinase transmembrane type I and type II receptors. However, as a key type I receptor for TGF-β, the exact role and the underlying mechanism of Activin receptor-like kinase 5 (ALK5) on macrophage activation involved in atherogenesis remain unclear. In the present study, enhanced ALK5 expression was found in bone marrow derived macrophages (BMDMs) upon OX-LDL stimulation tested by RT-PCR and Western blot, which was further verified by co-immunofluorescence staining. Next, the loss-of-function of ALK5 used AdshALK5 transfection was performed to test the effect of ALK5 on macrophage activation. We observed that ALK5 silencing inhibited pro-inflammatory but promoted anti-inflammatory macrophage markers expression. Moreover, decreased foam cell formation was found in ALK5 knockdown macrophages accompanied by increased cholesterol efflux. Mechanistically, ALK5 knockdown significantly increased KLF4 expression that was responsible for the attenuated macrophage activation induced by ALK5 knockdown. Collectively, these findings suggested that neutralization of ALK5 may act as a promising strategy for the management of atherosclerosis.

Topics: Animals; Atherosclerosis; Cells, Cultured; Foam Cells; Inflammation; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lipoproteins, LDL; Macrophage Activation; Macrophages; Mice; Mice, Knockout, ApoE; Phosphorylation; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Signal Transduction; Transforming Growth Factor beta

Imbalance of the gut microbial community promotes inflammation and colorectal cancer (CRC). Previously, we demonstrated that freeze-dried Parabacteroides distasonis (Pd) suppressed obesity-driven colorectal tumorigenesis in mice. Here, we investigated if Pd could suppress the development of colon tumors in mice independent of obesity. Six-week-old male A/J mice were assigned to receive: (i) chow diet (CTR); (ii) chow with 0.04% wt/wt freeze-dried Pd (Pd-Early) or (iii) chow diet before switching to 0.04% Pd diet (Pd-Late). Mice remained on diet for 25 weeks with the switch for Pd-Late mice occurring after 19 weeks. All mice received 6 weekly injections of the colon carcinogen azoxymethane (AOM; 10 mg/kg I.P.) starting after 1 week on diet. Colon tumors were observed in 77, 55 and 40% in CTR, Pd-Early and Pd-Late mice, respectively (X2 = 0.047). Colonic expression of toll-like receptor 4, IL-4 and TNF-α was 40% (P < 0.01), 58% (P = 0.05) and 55% (P < 0.001) lower, respectively, in Pd-Early compared with CTR mice. Pd-Late mice displayed a 217% (P = 0.05) and 185% (P < 0.001) increase in colonic IL-10 and TGF-β expression, respectively, compared with CTR mice and similar increases in protein abundances were detected (47-145%; P < 0.05). Pd-Early and Pd-Late mice both demonstrated increased colonic expression of the tight junction proteins Zonula occludens-1 (P < 0.001) and occludin (P < 0.001) at the transcript (2-3-fold; P < 0.01) and protein level (30-50%; P < 0.05) relative to CTR. Our results support a protective role for Pd in colonic tumorigenesis and maintenance of intestinal epithelial barrier in AOM-treated mice.

Topics: Animals; Azoxymethane; Bacteroidetes; Carcinogenesis; Colon; Colonic Neoplasms; Humans; Inflammation; Interleukin-4; Intestinal Mucosa; Mice; Obesity; Signal Transduction; Toll-Like Receptor 4; Transforming Growth Factor beta

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide and the majority of HCC patients occur with a background of hepatic fibrosis and cirrhosis. We have previously reported the hepatoprotective effects of steamed and freeze-dried mature silkworm larval powder (SMSP) in a chronic ethanol-treated rat model. Here, we assessed the anti-fibrotic and anti-carcinogenic effects of SMSP on diethylnitrosamine (DEN)-treated rats. Wistar rats were intraperitoneally injected with DEN once a week for 12 or 16 weeks with or without SMSP administration (0.1 and 1 g/kg). SMSP administration significantly attenuated tumor foci formation and proliferation in the livers of the rats treated with DEN for 16 weeks. SMSP administration also inhibited hepatic fibrosis by decreasing the levels of collagen fiber and the expression of pro-collagen I and alpha-smooth muscle actin (α-SMA). Moreover, SMSP supplementation improved the major parameters of fibrosis such as transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), tumor necrosis factor-alpha (TNF-α), plasminogen activator inhibitor-1 (PAI-1), and collagen type I (Col1A1) in the livers from the rats treated with DEN for 16 weeks. As s possible mechanisms, we investigated the effects of SMSP on the TGF-β and signal transducer and activator of transcription 3 (STAT3)-mediated signaling cascades, which are known to promote hepatic fibrosis. We found that SMSP treatment inhibited the activation of TGF-β and the phosphorylation of STAT3 pathway in DEN-treated rats. Moreover, SMSP administration suppressed the expressions of the target genes of TGF-β and STAT3 induced by DEN treatment. Our findings provide experimental evidences that SMSP administration has inhibitory effects of hepatic fibrosis and HCC induced by DEN in vivo and could be a promising strategy for the prevention or treatment of hepatic fibrosis and hepatocellular carcinogenesis.

Topics: Animals; Bombyx; Carcinogenesis; Carcinoma, Hepatocellular; Cell Proliferation; Diethylnitrosamine; Freeze Drying; Inflammation; Liver Cirrhosis; Liver Neoplasms; Male; Phosphorylation; Powders; Rats, Wistar; Signal Transduction; STAT3 Transcription Factor; Transforming Growth Factor beta

Dilated cardiomyopathy (DCM) is among the most common cardiac diseases in dogs. Its pathogenesis is not fully understood, but myocardial remodeling and inflammation are suspected to be involved. The present study aimed to characterize the pathological processes in canine DCM, investigating morphological changes in association with the expression of relevant cytokines and remodeling markers. The myocardium of 17 dogs with DCM and 6 dogs without cardiac diseases was histologically evaluated, and selected cases were further examined by immunohistochemistry, morphometry, and reverse transcription quantitative PCR. In DCM, the myocardium exhibited subtle but statistically significant diffuse quantitative changes. These comprised increased interstitial collagen deposition and macrophage numbers, as well as an overall reduced proportion of contractile tissue. This was accompanied by a significant increase in myocardial transcription of intracellular adhesion molecule (ICAM) 1, inflammatory cytokines, and remodeling enzymes. Laser microdissection showed that cardiomyocytes transcribed most relevant markers including ICAM-1, tumor necrosis factor α, transforming growth factor β (TGF-β), matrix metalloproteinase 2 (MMP-2), tissue inhibitor of MMP (TIMP) 1 and TIMP-2. In addition, there were multifocal cell-rich lesions characterized by fibrosis, neovascularization, macrophage infiltration, and cardiomyocyte degeneration. In these, macrophages were often found to express ICAM-1, TGF-β, and vascular endothelial growth factor; the former two were also expressed by cardiomyocytes. These results characterize the diffuse myocardial remodeling processes that occur in DCM. The observed multifocal cell-rich lesions might result from reduced tissue perfusion. Macrophages and cardiomyocytes seem to actively contribute to the remodeling processes, which ultimately lead to cardiac dilation and dysfunction. The precise role of the involved cells and the factors initiating the remodeling process still needs to be identified.

Topics: Animals; Biomarkers; Cardiomyopathy, Dilated; Collagen; Cytokines; Dog Diseases; Dogs; Fibrosis; Immunohistochemistry; Inflammation; Intercellular Adhesion Molecule-1; Macrophages; Matrix Metalloproteinase 2; Myocardium; Myocytes, Cardiac; Neovascularization, Pathologic; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Ventricular Remodeling

Restoration of kidney tubular epithelium following sublethal injury sequentially involves partial epithelial-mesenchymal transition (pEMT), proliferation, and further redifferentiation into specialized tubule epithelial cells (TECs). Because the immunosuppressant cyclosporine-A produces pEMT in TECs and inhibits the peptidyl-prolyl isomerase (PPIase) activity of cyclophilin (Cyp) proteins, we hypothesized that cyclophilins could regulate TEC phenotype. Here we demonstrate that in cultured TECs, CypA silencing triggers loss of epithelial features and enhances transforming growth factor β (TGFβ)-induced EMT in association with upregulation of epithelial repressors Slug and Snail. This pro-epithelial action of CypA relies on its PPIase activity. By contrast, CypB emerges as an epithelial repressor, because CypB silencing promotes epithelial differentiation, prevents TGFβ-induced EMT, and induces tubular structures in 3D cultures. In addition, in the kidneys of CypB knockout mice subjected to unilateral ureteral obstruction, inflammatory and pro-fibrotic events were attenuated. CypB silencing/knockout leads to Slug, but not Snail, downregulation. CypB support of Slug expression depends on its endoplasmic reticulum location, where it interacts with calreticulin, a calcium-buffering chaperone related to Slug expression. As CypB silencing reduces ionomycin-induced calcium release and Slug upregulation, we suggest that Slug expression may rely on CypB modulation of calreticulin-dependent calcium signaling. In conclusion, this work uncovers new roles for CypA and CypB in modulating TEC plasticity and identifies CypB as a druggable target potentially relevant in promoting kidney repair.

Topics: Animals; Basigin; Calcium; Cell Line; Cyclophilins; Endoplasmic Reticulum; Epithelial Cells; Fibrosis; Gene Silencing; Humans; Inflammation; Ionomycin; Kidney Tubules; Mice; Phenotype; Protein Transport; Smad Proteins; Snail Family Transcription Factors; Thapsigargin; Transforming Growth Factor beta; Ureteral Obstruction

Metabolic syndrome (MetS) profoundly changes the contents of mesenchymal stem cells and mesenchymal stem cells-derived extracellular vesicles (EVs). The anti-inflammatory TGF-β (transforming growth factor-β) is selectively enriched in EVs from Lean but not from MetS pigs, but the functional impact of this endowment remains unknown. We hypothesized that Lean-EVs more effectively induce regulatory T cells in injured kidneys. Five groups of pigs (n=7 each) were studied after 16 weeks of diet-induced MetS and unilateral renal artery stenosis (RAS; MetS+RAS). Two groups of MetS+RAS were treated 4 weeks earlier with an intrarenal injection of either Lean-EVs or MetS-EVs. MetS+RAS had lower renal volume, renal blood flow, and glomerular filtration rate than MetS pigs. Compared with Lean-EVs, MetS-EVs were less effective in improving renal function and decreasing tubular injury and fibrosis in MetS+RAS. Lean-EVs upregulated TGF-β expression in stenotic kidney and increased regulatory T cells numbers more prominently. Furthermore, markedly upregulated anti-inflammatory M2 macrophages reduced proinflammatory M1 macrophages, and CD8

Topics: Animals; Coculture Techniques; Cytokines; Dietary Carbohydrates; Dietary Fats; Extracellular Vesicles; Female; Inflammation; Infusions, Intra-Arterial; Metabolic Syndrome; MicroRNAs; Monocytes; Random Allocation; Renal Artery; Renal Artery Obstruction; Renal Circulation; Renal Insufficiency, Chronic; Signal Transduction; Swine; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Topics: Animals; Biomarkers; Biopsy; Disease Models, Animal; Extracellular Matrix Proteins; Fibrosis; Gene Knockdown Techniques; Inflammation; Kidney Diseases; Male; Mice; NF-kappa B; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

Langerhans cell histiocytosis (LCH) lesions contain myeloid lineage 'LCH' cells. Regulatory T cells (Tregs) are also enriched within lesions, although their role in LCH pathogenesis is unknown. LCH cells are thought to produce the transforming growth factor beta (TGF-β) within lesions, however whether Tregs contribute is unestablished. Using flow cytometry, we analyzed relative frequencies of live Tregs from LCH patients and identified CD56 expression and TGF-β production by lesion Tregs. While CD56

Topics: Adolescent; Adult; Aged; CD56 Antigen; CD8-Positive T-Lymphocytes; Child; Child, Preschool; Female; Forkhead Transcription Factors; Histiocytosis, Langerhans-Cell; Humans; Infant; Inflammation; Langerhans Cells; Male; Middle Aged; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Myostatin (MSTN), a family member of the transforming growth factor (TGF)-β super family, has been detected in the tubuli of pig kidney, but its role in the human kidney is not known. In this study we observed upregulation of MSTN mRNA (~8 to 10-fold increase) both in the glomeruli and tubulointerstitium in diabetic nephropathy (DN). In DN, immunoreactive MSTN was mainly localized in the tubuli and interstitium (∼4-8 fold increase), where it colocalized in CD45

Topics: Cell Line; Cell Proliferation; Diabetic Nephropathies; Epithelial Cells; Gene Expression Regulation; Glucose; Humans; Inflammation; Kidney; Kidney Tubules; Leukocyte Common Antigens; Myostatin; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta

Inflammatory bowel disease (IBD) is a multifactorial intestinal disorder characterized by chronic intestinal inflammation. The etiology of IBD is still unclear, although genetic, environmental and host factors have been associated to the disease. Extra-virgin olive oil (EVO) is a central component of the Mediterranean diet and it decreases chronic inflammation by interfering with arachidonic acid and NF-κB signaling pathways. Specifically, the different components of EVO are able to confer advantages in terms of health in their site of action. For instance, oleic acid displays a protective effect in liver dysfunction and gut inflammation, whereas phenolic compounds protect colon cells against oxidative damage and improve the symptoms of chronic inflammation in IBD. Given the biological properties of EVO, we investigated whether its administration is able to confer protection in a mouse model of dextrane sodium sulfate (DSS)-induced colitis. Four EVO cultivars from the Apulian Region of Italy, namely Ogliarola (Cima di Bitonto), Coratina, Peranzana and Cima di Mola, respectively, were used. Administration of EVO resulted in reduced body weight loss in our colitis model. Furthermore, mice treated with Ogliarola, Coratina and Cima di Mola EVO displayed a reduction of rectal bleeding and IL-1β, TGFβ, IL-6 gene expression levels. Furthermore, Ogliarola, Coratina and Peranzana EVO administration ameliorated intestinal permeability and histopathological features of inflammation. Our data further validate the well-known positive effects of EVO supplementation in promoting human health and suggest the bona fide contribution of EVO in preventing onset and reducing progression of intestinal inflammation.

Topics: Administration, Oral; Animals; Body Weight; Colitis; Dextran Sulfate; Diet, Mediterranean; Dietary Supplements; Disease Models, Animal; Gene Expression; Inflammation; Interleukin-1beta; Interleukin-6; Intestinal Mucosa; Italy; Male; Mice, Inbred C57BL; Olive Oil; Permeability; Transforming Growth Factor beta

Galectin-3 (formerly known as Mac-2), encoded by the. This study reveals a prominent protective role for galectin-3 in regulating macrophage polarization and invasive capacity and, therefore, delaying plaque progression.

Topics: Animals; Atherosclerosis; Crosses, Genetic; Female; Galectin 3; Humans; Inflammation; Macrophages; Male; Matrix Metalloproteinase 12; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Knockout, ApoE; Middle Aged; Plaque, Atherosclerotic; Signal Transduction; Transforming Growth Factor beta

Proper regulation of innate immune response is important for individual health. The NF-κB signaling pathway plays crucial roles in innate immunity and inflammation, and its aberrant activation is implicated in diverse diseases and disorders. In this study, we report that calmodulin-like 6 (CALML6), a member of the EF-hand protein family, is a negative regulator of the NF-κB signaling pathway. CALML6 attenuated TNF-stimulated phosphorylation of proteins downstream of TGF-β-activated kinase 1 (TAK1) and inhibited TAK1-induced NF-κB activation. Further studies showed that CALML6 interacted with TAK1 and recruited the deubiquitylating enzyme cylindromatosis to repress the K63-linked polyubiquitination of TAK1. CALML6 transgenic mice had higher tolerances to lethal LPS treatment in vivo. These findings suggest that CALML6 is a negative regulator of the NF-κB signaling pathway, which is important for maintaining the balance of the innate immune response.

Topics: Animals; Calcium-Binding Proteins; Calmodulin; Disease Models, Animal; Homeostasis; Humans; Immunity, Innate; Inflammation; MAP Kinase Kinase Kinases; Mice; Mice, Transgenic; NF-kappa B; Phosphorylation; Protein Binding; Sepsis; Signal Transduction; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Ubiquitination

Chronic kidney disease (CKD) is a global nephrotic syndrome characterized by chronic inflammation, oxidative stress and fibrosis in the kidney. Isoliquiritigenin (ISL), a flavonoid from licorice, has historically been reported to inhibit innate immune responses to inflammation and fibrosis in vivo. However, the effect of ISL on CKD progression is largely unknown.. In this study, we employed the inflammatory and fibrotic models of LPS/TGF-β-induced bone marrow-derived macrophages (BMDM) in vitro and unilateral ureteral obstruction (UUO) model in vivo to explore the potential effects and mechanism of ISL on renal inflammation and fibrosis.. Our results manifest that ISL improved UUO-induced renal dysfunction and reduced tubular damage with a significantly downregulated mRNA expression and secretion of IL-1β, IL-6, TNF-α and MCP-1 in vitro and in vivo. It is worth noting that ISL can strongly inhibit the mRNA and protein expression of Mincle (macrophage-induced c-type lectin) in BMDM and UUO. ISL inhibited the phosphorylation of Syk and NF-kappa B and simultaneously reduced the expression of α-SMA and Col III in vivo and in vitro. More interestingly, when dealing with TDB, a ligand of Mincle, it revealed significant reversal of protein expression levels as that observed with ISL. The expressions of IL-1β, IL-6, TNF-α, iNOS, p-Syk, p-NF-kappa B, α-SMA and FN in BMDM inflammatory model were significantly upregulated with TDB treatment. This confirms that ISL inhibits inflammation and fibrosis of macrophage by suppressing Mincle/Syk/NF-kappa B signaling pathway.. To conclude, ISL protects UUO-induced CKD by inhibiting Mincle-induced inflammation and suppressing renal fibrosis, which might be a specific renal protective mechanism of ISL, making it a novel drug to ameliorate CKD.

Topics: Administration, Oral; Animals; Cells, Cultured; Chalcones; Dose-Response Relationship, Drug; Fibrosis; Inflammation; Kidney; Lectins, C-Type; Lipopolysaccharides; Macrophages; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Molecular Structure; NF-kappa B; Protective Agents; Signal Transduction; Structure-Activity Relationship; Syk Kinase; Transforming Growth Factor beta; Ureteral Obstruction

FOXP3-expressing regulatory T (Treg) cells safeguard immunological tolerance. Treg cells can be generated during thymic development (called thymic Treg [tTreg] cells) or derived from mature conventional CD4

Topics: Biomarkers; Cells, Cultured; Cytokines; Forkhead Transcription Factors; Humans; Immune Tolerance; Inflammation; Lymphocyte Activation; Membrane Glycoproteins; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Topics: Coronavirus Infections; COVID-19; Fibrosis; Humans; Immunotherapy; Inflammation; Lung; Pandemics; Pneumonia, Viral; Transforming Growth Factor beta

Topics: Animals; Bone Regeneration; Extracellular Matrix; Inflammation; Macrophages; Mice; Mice, SCID; Tissue Scaffolds; Transforming Growth Factor beta

Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease characterized by fat accumulation and inflammation in liver. Yet, the mechanistic insight and diagnostic and therapeutic options of NASH remain incompletely understood. This study tested the roles of cysteine protease cathepsin B (CatB) in mouse NASH development. Immunoblot revealed increased liver CatB expression in NASH mice. Fructose-palmitate-cholesterol diet increased body weight gain, liver to body weight ratio, blood fasting glucose, plasma total cholesterol and alanine transaminase levels, and liver triglyceride, but decreased plasma high-density lipoprotein in wild-type mice. All these changes were blunted in CatB-deficient (Ctsb

Topics: Animals; Cadherins; Cathepsin B; Cell Polarity; Diet, High-Fat; Inflammation; Lipid Metabolism; Liver; Liver Cirrhosis; Macrophages; Male; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Weight Gain

Topics: Animals; Cardiovascular Diseases; Humans; Inflammation; Kidney Failure, Chronic; Muscle, Skeletal; Myostatin; Renal Insufficiency, Chronic; Sarcopenia; Signal Transduction; Transforming Growth Factor beta

Helminthic infection and the parallel host immune reactions are the results of a protracted dynamic co-interaction between the host and worms. An assessment of the effect of Toxocara canis infection on arthritis in rats stimulated by Freund's complete adjuvant (FCA) was the main purpose of the investigation. An arthritis model was established by the administration of 0.1 mL FCA in the palmar surface. Cytokine assessment, evaluating oedema and the use of a rheumatoid arthritis (RA) score provided evidence of the protective effects of T canis against adjuvant-induced arthritis (AIA). The cytokines TGF-β, IFN-ɣ, IL-10 and IL-17 were measured to assess the anti-inflammatory effect of T canis infection. Besides, arthritis swelling findings were evaluated in rat paws. The data showed that T canis infection significantly modulated the immune response by alleviating inflammatory cytokines and increasing TGF-β as an anti-inflammatory cytokine. Evaluations of arthritis swelling showed low severity and faster recuperation. These findings suggest that the products derived from T canis eggs might be a potential therapeutic candidate to treat autoimmune diseases like the arthritis.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Cytokines; Female; Freund's Adjuvant; Inflammation; Injections, Intradermal; Joints; Larva; Male; Random Allocation; Rats; Rats, Wistar; Toxocara canis; Transforming Growth Factor beta

The tumour microenvironment is rich in multiple cells that influence cancer development. Among them, macrophages are the most abundant immune cells, which secrete factors involved in carcinogenesis. Since protein-bound polysaccharides (PBP) from the. 4T1 cells were cultured in conditioned media (CM) collected after: stimulation of the macrophages with PBP (CM-PBP) or incubation of non-treated macrophages (CM-NT). A co-cultured model of both cell lines was also employed to investigate the crosstalk between the cells. Cell viability was measured using the MTT assay. The levels of cytokines and chemokines were determined by ELISA methods. Commercial assay kits were used to assess the activity of both arginase 1 and inducible nitric oxide synthase (iNOS) and the level of cell migration.. The results revealed that CM-NT promotes proliferation and migration of 4T1 cells, and increases the secretion of pro-angiogenic factors (VEGF, MCP-1) by cancer cells. In contrast, CM-PBP inhibits 4T1 cell growth and migration, decreases the secretion of pro-angiogenic factors (VEGF, MCP-1) and upregulates the production of pro-inflammatory mediators (IL-6, TNF-α) with certain anti-tumoral properties Moreover, PBP-treated CM significantly decreases the level of M2 macrophage markers (arginase 1 activity, IL-10 and TGF-β concentrations), but upregulates iNOS activity and IL-6 and TNF-α production, which are M1 cell markers.. The results suggest that PBP suppress the favourable tumour microenvironment by inhibiting the crosstalk between 4T1 cells and macrophages through the regulation of production of angiogenic and inflammatory mediators, and modulating the M1/M2 macrophage subtype.

Topics: Animals; Arginase; Cell Movement; Cell Proliferation; Cell Survival; Chemokine CCL2; Chemokines; Coculture Techniques; Culture Media, Conditioned; Inflammation; Interleukin-10; Interleukin-6; Mice; Neovascularization, Pathologic; Nitric Oxide Synthase Type II; Polyporaceae; Polysaccharides; RAW 264.7 Cells; Transforming Growth Factor beta; Triple Negative Breast Neoplasms; Tumor Microenvironment; Tumor Necrosis Factor-alpha; Tumor-Associated Macrophages; Vascular Endothelial Growth Factor A

The growth arrest and DNA damage-inducible beta (Gadd45β) protein have been associated with various cellular functions, but its role in progressive renal disease is currently unknown. Here, we examined the effect of Gadd45β deletion on cell proliferation and apoptosis, inflammation, and renal fibrosis in an early chronic kidney disease (CKD) mouse model following unilateral ureteral obstruction (UUO). Wild-type (WT) and Gadd45β-knockout (KO) mice underwent either a sham operation or UUO and the kidneys were sampled eight days later. A histological assay revealed that ablation of Gadd45β ameliorated UUO-induced renal injury. Cell proliferation was higher in Gadd45β KO mouse kidneys, but apoptosis was similar in both genotypes after UUO. Expression of pro-inflammatory cytokines after UUO was down-regulated in the kidneys from Gadd45β KO mice, whereas UUO-mediated immune cell infiltration remained unchanged. The expression of pro-inflammatory cytokines in response to LPS stimulation decreased in bone marrow-derived macrophages from Gadd45β KO mice compared with that in WT mice. Importantly, UUO-induced renal fibrosis was ameliorated in Gadd45β KO mice unlike in WT mice. Gadd45β was involved in TGF-β signalling pathway regulation in kidney fibroblasts. Our findings demonstrate that Gadd45β plays a crucial role in renal injury and may be a therapeutic target for the treatment of CKD.

Topics: Animals; Antigens, Differentiation; Apoptosis; Biomarkers; Biopsy; Cell Line; Cell Proliferation; Cytokines; Disease Models, Animal; Disease Susceptibility; Fibrosis; Gene Deletion; Immunohistochemistry; Inflammation; Inflammation Mediators; Kidney Diseases; Male; Mice; Mice, Knockout; Renal Insufficiency, Chronic; Transforming Growth Factor beta; Ureteral Obstruction

Septic arthritis is a condition of bone disorder caused predominantly by Staphylococcus aureus. Following the bacterial entry activated immune cells specially macrophages and dendritic cells release pro-inflammatory mediators such as IL-6, TNF-α, IL-1β etc., which not only create an inflammatory microenvironment but also play crucial roles in the proliferation of different CD+ T cell subsets. Among them, Th17 and Tregs are of major concern in recent times because of their potential roles in regulating the ongoing inflammation in many diseases including experimental arthritis. But the downstream signalling mechanism of these cells in regulating the severity of inflammation in case of septic arthritis is not known yet. So, here we have established a murine model of S. aureus induced septic arthritis and kept the animal upto 15 days post-infection. To examine the signalling mechanism, Th17 and Treg cells were isolated from blood, spleen and synovial joints of control and infected mice and observed the expression of JNK, NFκB and RANKL in the lysate of isolated Th17 and Tregs. We have also estimated the levels of serum IL-21 and TGF-β. NFκB, JNK and RANKL expression was found to be higher at 3 and 15 days post-infection along with serum IL-21 levels. On the other hand, maximum TGF-β level was observed at 9 days post-infection along with increased Treg population. In conclusion it was hypothesized that bone resorption is related with downstream signalling pathways of Th17 cells, which stimulate osteoclast generation via NFκB/JNK-RANKL axis and helps in the persistence of the disease.

Topics: Animals; Arthritis, Experimental; Arthritis, Infectious; Gene Expression Regulation; Humans; Inflammation; Interleukin-1beta; Joints; MAP Kinase Kinase 4; Mice; Osteoclasts; RANK Ligand; Signal Transduction; Staphylococcal Infections; Staphylococcus aureus; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Chronic idiopathic urticaria (CIU) is an unfavorable skin condition which could be maintained for six weeks or longer time. Gremlin1 (GREM1) was recently applied in treatments of many diseases. However, the possible regulatory mechanism of GREM1 in CIU remained unclear. This study aimed to explore the regulatory effects of GREM1 on the inflammatory response and vascular permeability mediated by mast cells of CIU via TGF-β signaling pathway. Initially, microarray analysis was used to identify CIU-related differentially expressed genes and the potential mechanism of this gene. A mouse model of CIU was established. To explore the functional role of GREM1 in CIU, the modeled mice were then injected with GREM1-siRNA, SRI-011381 (the activator of TGF-β signaling pathway), or both, followed by serum test, and immunoglobulin detection. The levels of inflammatory factors and tryptase, β-hexosaminase, histamine in the serum were detected. Besides, vascular endothelial cell permeability and the target relation between GREM1 and TGF-β were also examined. Mice injected with SRI-011381 exhibited higher levels of tryptase, β-hexosaminase, histamine, inflammation-related factors and increased vascular endothelial cell permeability, while GREM1-silenced mice yet expressed opposite tendency. Silencing of GREM1 was demonstrated to inhibit the TGF-β signaling pathway. Taken together, our results demonstrated that down-regulation of GREM1 could potentially impede inflammatory response and vascular permeability by suppressing TGF-β signaling pathway. GREM1 may promote the development of prognosis management and therapeutic treatment in CIU.

Topics: Animals; Cells, Cultured; Chronic Urticaria; Disease Models, Animal; Down-Regulation; Endothelial Cells; Female; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Male; Mast Cells; Mice; RNA, Small Interfering; Signal Transduction; Transforming Growth Factor beta

Liver disease is common and often life-threatening. Sinomenine (SIN) is an active ingredient extracted from . In vivo experiments, mice were randomly divided into six groups (n=10): control group, model group, SIN (25 mg/kg) group, SIN (50 mg/kg) group, SIN (100 mg/kg) group and SIN (100 mg/kg) + SRI-011381 group. Alanine transaminases (ALT), aspartate transaminases (AST) and alkaline phosphatase (ALP) were detected. The pathological lesion was measured by HE staining. Apoptosis was measured by TUNEL staining. In vitro experiments, BRL-3A cells were treated with APAP (7.5 mM) and then subjected to various doses of SIN (10, 50 and 100 μg/mL) at 37°C for 24 h. Inflammatory factors and oxidative stress index were measured by ELISA. The expression of proteins was detected by Western blot.. The results showed that compared with the control group, the levels of ALT, AST and ALP in the serum of APAP-induced mice were significantly increased, followed by liver histological damage and hepatocyte apoptosis. Besides, APAP reduced the activity of SOD and GSH-Px, while increasing the content of MDA and LDH. Notably, APAP also promoted the expression of NLRP3, ASC, caspase-1 and IL-1β. Interestingly, SIN treatment dose-dependently reduced APAP-induced liver injury and oxidative stress, inhibited the activation of NLRP3 inflammasomes, and reduced the levels of inflammatory cytokines. In vitro studies have shown that SIN treatment significantly reduced the viability of BRL-3A cells and oxidative stress and inflammation. In addition, the Western blotting analysis showed that SIN inhibited the activation of TGF-β/Smad pathway in a dose-dependent manner in vitro and in vivo. These effects were significantly reversed by TGF-β/Smad activator SRI-011381 or TGF-β overexpression.. The study indicates that SIN attenuates APAP-induced acute liver injury by decreasing oxidative stress and inflammatory response via TGF-β/Smad pathway in vitro and in vivo.

Topics: Acetaminophen; Animals; Apoptosis; Cells, Cultured; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Inflammation; Mice; Mice, Inbred C57BL; Morphinans; Oxidative Stress; Smad Proteins; Structure-Activity Relationship; Transforming Growth Factor beta

Signaling of 17β-estradiol (estrogen) through its two nuclear receptors, α and β (ERα, ERβ), is an important mechanism of transcriptional regulation. Although ERs are broadly expressed by cells of the immune system, the mechanisms by which they modulate immune responses remain poorly understood. ERβ-specific signaling is reduced in patients with chronic inflammatory diseases, including systemic lupus erythematosus and inflammatory bowel disease, and our previous work suggests that dysregulation of ERβ-specific signaling contributes to enhanced intestinal inflammation in female SAMP/YitFC mice, a spontaneous model of Crohn's disease-like ileitis. The present study builds on these prior observations to identify a nonredundant, immunoprotective role for ERβ-specific signaling in TGF-β-dependent regulatory T cell (Treg) differentiation. Using a strain of congenic SAMP mice engineered to lack global expression of ERβ, we observed dramatic, female-specific exacerbation of intestinal inflammation accompanied by significant reductions in intestinal Treg frequency and function. Impaired Treg suppression in the absence of ERβ was associated with aberrant overexpression of

Topics: Adolescent; Adult; Animals; Crohn Disease; Disease Models, Animal; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Female; Glucocorticoids; Humans; Ileitis; Inflammation; Inflammatory Bowel Diseases; Intestines; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Signal Transduction; T-Lymphocytes, Regulatory; Transcription Factors; Transforming Growth Factor beta; Young Adult

Macrophages in lung, including resident alveolar macrophages (AMs) and interstitial macrophages (IMs), and monocyte-derived macrophages, play important roles in pulmonary fibrosis (PF), but mechanisms underlying their differential regulation remain unclear. Recombination signal-binding protein Jκ (RBP-J)-mediated Notch signaling regulates macrophage development and phenotype. Here, using bleomycin-induced fibrosis model combined with myeloid-specific RBP-J disruption (RBP-J

Topics: Animals; Bodily Secretions; Histocompatibility Antigens Class II; Immunoglobulin J Recombination Signal Sequence-Binding Protein; Inflammation; Macrophages, Alveolar; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Monocytes; Myofibroblasts; Pulmonary Fibrosis; Receptors, Notch; Signal Transduction; Transforming Growth Factor beta

The transcription factor forkhead box P3 (FOXP3) is essential for the development of regulatory T cells (Tregs) and their function in immune homeostasis. Previous studies have shown that in natural Tregs (nTregs), FOXP3 can be regulated by polyubiquitination and deubiquitination. However, the molecular players active in this pathway, especially those modulating FOXP3 by deubiquitination in the distinct induced Treg (iTreg) lineage, remain unclear. Here, we identify the ubiquitin-specific peptidase 44 (USP44) as a novel deubiquitinase for FOXP3. USP44 interacts with and stabilizes FOXP3 by removing K48-linked ubiquitin modifications. Notably, TGF-β induces USP44 expression during iTreg differentiation. USP44 co-operates with USP7 to stabilize and deubiquitinate FOXP3. Tregs genetically lacking USP44 are less effective than their wild-type counterparts, both in vitro and in multiple in vivo models of inflammatory disease and cancer. These findings suggest that USP44 plays an important role in the post-translational regulation of Treg function and is thus a potential therapeutic target for tolerance-breaking anti-cancer immunotherapy.

Topics: Forkhead Transcription Factors; Humans; Inflammation; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Ubiquitin Thiolesterase; Ubiquitin-Specific Peptidase 7

Non-alcoholic steatohepatitis (NASH) is characterized by lipotoxicity, inflammation and fibrosis, ultimately leading to end-stage liver disease. The molecular mechanisms promoting NASH are poorly understood, and treatment options are limited. Here, we demonstrate that hepatic expression of bone morphogenetic protein 8B (BMP8B), a member of the transforming growth factor beta (TGFβ)-BMP superfamily, increases proportionally to disease stage in people and animal models with NASH. BMP8B signals via both SMAD2/3 and SMAD1/5/9 branches of the TGFβ-BMP pathway in hepatic stellate cells (HSCs), promoting their proinflammatory phenotype. In vivo, the absence of BMP8B prevents HSC activation, reduces inflammation and affects the wound-healing responses, thereby limiting NASH progression. Evidence is featured in primary human 3D microtissues modelling NASH, when challenged with recombinant BMP8. Our data show that BMP8B is a major contributor to NASH progression. Owing to the near absence of BMP8B in healthy livers, inhibition of BMP8B may represent a promising new therapeutic avenue for NASH treatment.

Topics: Animals; Bone Morphogenetic Proteins; Carbon Tetrachloride Poisoning; Diet, High-Fat; Diet, Western; Hepatic Stellate Cells; Humans; Inflammation; Liver Regeneration; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Recombinant Proteins; Smad Proteins; Transforming Growth Factor beta; Wound Healing

Acute lung injury (ALI), a common condition in critically ill patients, has limited treatments and high mortality. Aging is a risk factor for ALI. Sirtuins (SIRTs), central regulators of the aging process, decrease during normal aging and in aging-related diseases. We recently showed decreased SIRT7 expression in lung tissues and fibroblasts from patients with pulmonary fibrosis compared to controls. To gain insight into aging-related mechanisms in ALI, we investigated the effects of SIRT7 depletion on lipopolysaccharide (LPS)-induced inflammatory responses and endothelial barrier permeability in human primary pulmonary endothelial cells. Silencing SIRT7 in pulmonary artery or microvascular endothelial cells attenuated LPS-induced increases in ICAM1, VCAM1, IL8, and IL6 and induced endomesenchymal transition (EndoMT) with decreases in VE-Cadherin and PECAM1 and increases in collagen, alpha-smooth muscle actin, TGFβ receptor 1, and the transcription factor Snail. Loss of endothelial adhesion molecules was accompanied by increased F-actin stress fibers and increased endothelial barrier permeability. Together, these results show that an aging phenotype induced by SIRT7 deficiency promotes EndoMT with impaired inflammatory responses and dysfunction of the lung vascular barrier.

Topics: Adult; Animals; Bleomycin; Capillary Permeability; Cell Membrane Permeability; Cells, Cultured; Endothelial Cells; Epithelium; Gene Expression Regulation; Gene Silencing; Humans; Inflammation; Inflammation Mediators; Lipopolysaccharides; Lung; Mice, Inbred C57BL; NF-kappa B; Pulmonary Fibrosis; RNA, Messenger; Signal Transduction; Sirtuins; Transforming Growth Factor beta

The Gas6-TAM (Tyro3, Axl, Mer) ligand-receptor system is believed to promote central nervous system (CNS) (re)myelination and glial cell development. An additional important function of Gas6-TAM signalling appears to be the regulation of immunity and inflammation, which remains to be fully elucidated in the CNS. Here, we characterised the expression of TAM receptors and ligands in individual CNS glial cell types, observing high expression of Gas6 and the TAM receptors, Mer and Axl, in microglia, and high expression of Tyro3 in astrocytes. We also investigated the effect of Gas6 on the inflammatory cytokine response in the optic nerve and in mixed glial cell cultures from wildtype and single TAM receptor knockout mice. In wildtype and Mer-deficient cultures, Gas6 significantly stimulated the expression of the anti-inflammatory/pro-repair cytokines interleukin 10 (IL-10) and transforming growth factor β (TGF-β), whereas this effect was absent in either Tyro3 or Axl knockout cultures. Furthermore, Gas6 caused upregulation of myelin basic protein (MBP) expression in optic nerves, which was blocked by a neutralising antibody against IL-10. In conclusion, our data show that microglia are both a major source of Gas6 as well as an effector of Gas6 action in the CNS through the upregulation of anti-inflammatory and pro-repair mediators. Furthermore, the presence of both Axl and Tyro3 receptors appears to be necessary for these effects of Gas6. In addition, IL-10, alongside suppressing inflammation and immunity, mediates the pro-myelinating mechanism of Gas6 action in the optic nerve. Therefore, Gas6 may present an attractive target for novel therapeutic interventions for demyelinating as well as neuroinflammatory disorders of the CNS.

Topics: Animals; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Interleukin-10; Mice; Neuroglia; Transforming Growth Factor beta; Up-Regulation; White Matter

Idiopathic pulmonary fibrosis is a debilitating lung disease. CD26/DPP4 plays promotive roles in pulmonary damage and fibrosis. This study aimed to explore the roles of vildagliptin in bleomycin-induced pulmonary fibrosis, and to address its ameliorative effect on the extracellular matrix (ECM).. Idiopathic pulmonary fibrosis mice models were induced by intratracheal injection of bleomycin. DPP4 activity was evaluated, and the fibrosis was investigated by Hematoxylin-eosin, Masson's trichrome staining and hydroxyproline assay. Expression of extracellular matrix proteins including α-SMA, collagen IV, collagen I, FN and TGF-β were analyzed by immunochemistry and western blot. Percentages of the numbers of monocytes, leukocytes, basophils and lymphocytes were classified, and inflammatory factors in plasma as well as lung tissues were examined by enzyme-linked immunosorbent assay and western blot. The influences of vildagliptin on TGF-β1-induced cell proliferation, differentiation and inflammatory factors in MRC-5 cells were detected.. Vildagliptin effectively attenuated inflammation and fibrosis in bleomycin-induced pulmonary tissue via inhibiting the activity of CD26/DPP4. extracellular matrix proteins were suppressed by vildagliptin. Thus, lung tissue fibrosis was efficiently alleviated by vildagliptin.. As an inhibitor of CD26/DPP4, Vildagliptin could be a promising therapeutic candidate for idiopathic pulmonary fibrosis.

Topics: Actins; Animals; Bleomycin; Cell Line; Cell Survival; Collagen; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Extracellular Matrix; Fibronectins; Humans; Inflammation; Lung; Male; Mice, Inbred C57BL; Pulmonary Fibrosis; Transforming Growth Factor beta; Vildagliptin

The study aimed to investigate the potential attenuation effect of chitosan in liver ischemia/reperfusion injury (I/R), and its relevant protective mechanisms. Chitosan (200 mg/kg) has been administered orally for 30 days, later animals underwent liver 45 min ischemia and reperfusion for 60 min. Following treatment with chitosan, the levels of serum aminotransferases and lactate dehydrogenase were significantly reduced. Similarly, hepatic (GSH, SOD, CAT, GST and GPx) were enhanced, and the level of tissue malondialdehyde (MDA) was decreased. In addition, inflammatory cytokinesis (TNF-α and TGF-β) have recorded a significant decrease in their mRNA expression and protein levels using qPCR and ELISA respectively. Marked reduction of apoptosis has been indicated by the elevation in BCL2, and decreasing in BAX, Caspace-3 and Cytochrome-c expression levels, which furthermore confirmed by DNA fragmentation assay. The enhancement of the previous parameters resulted in a marked improvement in the liver architectures after chitosan administration. In conclusion, chitosan has proved its efficiency as an anti-inflammatory and antioxidant agent through its inhibitory effect of cytokines and reducing ROS respectively. In addition, chitosan could modulate the changes in histological structure and alleviate apoptosis induced by liver I/R, which recommend it as an efficient agent for protection against liver I/R injury.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Aspartate Aminotransferases; bcl-2-Associated X Protein; Caspase 3; Chitosan; Cytokines; Inflammation; Liver; Liver Diseases; Male; Malondialdehyde; Oxidative Stress; Protective Agents; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Regulatory T cells (Tregs) and transforming growth factor β (TGF-β) are believed to play key roles in both postoperative pro-inflammatory and anti-inflammatory responses of malignancies. Recombinant human thrombomodulin (rTM) is implied to inhibit the interaction between TGF-β and Tregs. The aim of this study is to evaluate the antitumor effects of rTM against gastrointestinal tumors under systemic inflammation. Mice were subjected to cecal ligation and puncture and percutaneous allogeneic tumor implantation. rTM were introduced by percutaneous injection into the abdominal cavity. The effects of rTM were evaluated by weight of implanted tumor, proportion of Tregs in peripheral blood lymphocytes (PBL) and tumor infiltrating lymphocytes (TIL) and temporal evaluation of serum cytokines. The effect of rTM was also evaluated on the in vitro differentiation of naïve T cells into induced Tregs induced by TGF-β and interleukin (IL) -2. rTM significantly inhibited the proliferation of the implanted tumor cells in an inflammation-dependent manner. rTM also reduced the fractions of regulatory T cells and induced regulatory T cells among both PBL and TIL. Temporal evaluation of serum cytokine levels in the model mice showed that rTM significantly suppressed the increases in the serum levels of IL-2 and TGF-β. An in vitro differentiation assay revealed that rTM inhibited the differentiation of naïve T cells into Tregs triggered by IL-2- and TGF-β. rTM has suppressive effects on inflammation-induced gastrointestinal tumor growth by suggestively affecting differentiation of Tregs.

Topics: Animals; Cell Differentiation; Cell Line, Tumor; Disease Models, Animal; Female; Gastrointestinal Neoplasms; Inflammation; Mice; Mice, Inbred BALB C; Peritonitis; Recombinant Proteins; T-Lymphocytes, Regulatory; Thrombomodulin; Transforming Growth Factor beta

Unresolved inflammation can lead to tissue fibrosis and impaired organ function. Macrophage-myofibroblast transition (MMT) is one newly identified mechanism by which ongoing chronic inflammation causes progressive fibrosis in different forms of kidney disease. However, the mechanisms underlying MMT are still largely unknown. Here, we discovered a brain-specific homeobox/POU domain protein Pou4f1 (Brn3a) as a specific regulator of MMT. Interestingly, we found that Pou4f1 is highly expressed by macrophages undergoing MMT in sites of fibrosis in human and experimental kidney disease, identified by coexpression of the myofibroblast marker, α-SMA. Unexpectedly, Pou4f1 expression peaked in the early stage in renal fibrogenesis in vivo and during MMT of bone marrow-derived macrophages (BMDMs) in vitro. Mechanistically, chromatin immunoprecipitation (ChIP) assay identified that Pou4f1 is a Smad3 target and the key downstream regulator of MMT, while microarray analysis defined a Pou4f1-dependent fibrogenic gene network for promoting TGF-β1/Smad3-driven MMT in BMDMs at the transcriptional level. More importantly, using two mouse models of progressive renal interstitial fibrosis featuring the MMT process, we demonstrated that adoptive transfer of TGF-β1-stimulated BMDMs restored both MMT and renal fibrosis in macrophage-depleted mice, which was prevented by silencing Pou4f1 in transferred BMDMs. These findings establish a role for Pou4f1 in MMT and renal fibrosis and suggest that Pou4f1 may be a therapeutic target for chronic kidney disease with progressive renal fibrosis.

Topics: Animals; Female; Fibrosis; Gene Regulatory Networks; Humans; Inflammation; Kidney; Kidney Diseases; Macrophages; Male; Mice; Mice, Inbred C57BL; Myofibroblasts; Signal Transduction; Smad3 Protein; Transcription Factor Brn-3A; Transforming Growth Factor beta; Transforming Growth Factor beta1; Urinary Tract

TNF-related apoptosis-inducing ligand (TRAIL) has attracted attention not only as an anti-cancer agent, but also as a potential treatment for diabetes. Animal studies have shown that TRAIL delivery ameliorated glucose control in type 1 and type 2 diabetes. It is currently unknown whether TRAIL positive effects are maintained in more severe forms of type 2 diabetes, and whether they include renoprotection. Our study aimed at evaluating TRAIL effects in a severe form of type 2 diabetes with nephropathy.. A total of 20 db/db mice were treated with saline or TRAIL twice per week for 12 weeks. In parallel, renal tubular epithelial cells were cultured with TGF-β1 in the presence and absence of TRAIL, with and without silencing TRAIL-specific receptor (DR5) and leptin receptor.. TRAIL did not improve glucose control, but it significantly reduced circulating interleukin (IL)-6 and resistin. In the kidney, TRAIL treatment significantly ameliorated glomerular and tubular morphology with an improvement in kidney function, but no effect on proteinuria. Our in vitro studies on TGF-β1-treated cells, showed that by binding to DR5, TRAIL rescued normal tubular cell morphology, increasing E-cadherin and reducing α-smooth muscle actin (SMA) expression, with no effects on cell viability. Interestingly, both in vivo and in vitro, TRAIL reduced the accumulation of the autophagy substrate p62.. Our data confirm TRAIL protective effects against organ damage and shed light on to promising anti-fibrotic actions, which are independent of glucose control. TRAIL anti-fibrotic actions might be due to the rescue of autophagy in diabetes.

Topics: Animals; Body Weight; Diabetic Nephropathies; Epithelial-Mesenchymal Transition; Feeding Behavior; Fibrosis; Gene Expression Regulation; Gene Silencing; Glucose; Humans; Inflammation; Kidney; Kidney Tubules; Male; Mice; Protein Binding; Rats; Receptors, Leptin; Receptors, TNF-Related Apoptosis-Inducing Ligand; Sequestosome-1 Protein; TNF-Related Apoptosis-Inducing Ligand; Transforming Growth Factor beta

Angiogenesis is one of the hallmarks of cancer. We hypothesized that intra-tumoral angiogenesis correlates with inflammation and metastasis in breast cancer patients. To test this hypothesis, we generated an angiogenesis pathway score using gene set variation analysis and analyzed the tumor transcriptome of 3999 breast cancer patients from The Cancer Genome Atlas Breast Cancer (TCGA-BRCA), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), GSE20194, GSE25066, GSE32646, and GSE2034 cohorts. We found that the score correlated with expression of various angiogenesis-, vascular stability-, and sphingosine-1-phosphate (S1P)-related genes. Surprisingly, the angiogenesis score was not associated with breast cancer subtype, Nottingham pathological grade, clinical stage, response to neoadjuvant chemotherapy, or patient survival. However, a high score was associated with a low fraction of both favorable and unfavorable immune cell infiltrations except for dendritic cell and M2 macrophage, and with Leukocyte Fraction, Tumor Infiltrating Lymphocyte Regional Fraction and Lymphocyte Infiltration Signature scores. High-score tumors had significant enrichment for unfavorable inflammation-related gene sets (interleukin (IL)6, and tumor necrosis factor (TNF)α- and TGFβ-signaling), as well as metastasis-related gene sets (epithelial mesenchymal transition, and Hedgehog-, Notch-, and WNT-signaling). High score was significantly associated with metastatic recurrence particularly to brain and bone. In conclusion, using the angiogenesis pathway score, we found that intra-tumoral angiogenesis is associated with immune reaction, inflammation and metastasis-related pathways, and metastatic recurrence in breast cancer.

Topics: Breast Neoplasms; Dendritic Cells; Epithelial-Mesenchymal Transition; Female; Humans; Inflammation; Interferon-gamma; Interleukin-6; Leukocytes; Lymphocytes, Tumor-Infiltrating; Lysophospholipids; Macrophages; Neoplasm Recurrence, Local; Neovascularization, Pathologic; Signal Transduction; Sphingosine; Transforming Growth Factor beta

Protease-activated receptor (PAR)-1 has emerged as a key profibrotic player in various organs including kidney. PAR-1 activation leads to deposition of extracellular matrix (ECM) proteins in the tubulointerstitium and induction of epithelial-mesenchymal transition (EMT) during renal fibrosis. We tested the anti-fibrotic potential of vorapaxar, a clinically approved PAR-1 antagonist for cardiovascular protection, in an experimental kidney fibrosis model of unilateral ureteral obstruction (UUO) and an AKI-to-chronic kidney disease (CKD) transition model of unilateral ischemia-reperfusion injury (UIRI), and dissected the underlying renoprotective mechanisms using rat tubular epithelial cells. PAR-1 is activated mostly in the renal tubules in both the UUO and UIRI models of renal fibrosis. Vorapaxar significantly reduced kidney injury and ameliorated morphologic changes in both models. Amelioration of kidney fibrosis was evident from down-regulation of fibronectin (Fn), collagen and α-smooth muscle actin (αSMA) in the injured kidney. Mechanistically, inhibition of PAR-1 inhibited MAPK ERK1/2 and transforming growth factor-β (TGF-β)-mediated Smad signaling, and suppressed oxidative stress, overexpression of pro-inflammatory cytokines and macrophage infiltration into the kidney. These beneficial effects were recapitulated in cultured tubular epithelial cells in which vorapaxar ameliorated thrombin- and hypoxia-induced TGF-β expression and ECM accumulation. In addition, vorapaxar mitigated capillary loss and the expression of adhesion molecules on the vascular endothelium during AKI-to-CKD transition. The PAR-1 antagonist vorapaxar protects against kidney fibrosis during UUO and UIRI. Its efficacy in human CKD in addition to CV protection warrants further investigation.

Topics: Animals; Biomarkers; Cell Hypoxia; Endothelial Cells; Epithelial Cells; Epithelial-Mesenchymal Transition; Extracellular Matrix Proteins; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Inflammation; Kidney; Kidney Tubules; Lactones; Macrophages; Mice, Inbred BALB C; Mice, Inbred C57BL; Oxidative Stress; Pyridines; Rats; Reactive Oxygen Species; Receptor, PAR-1; Reperfusion Injury; Smad3 Protein; Thrombin; Transforming Growth Factor beta; Up-Regulation; Ureteral Obstruction

Growth factors and cytokines mediate complex interactions between cells within the breast tumour microenvironment. In advanced cancer, an excess of regulatory T (T. We used 3D breast tumour models to determine morphological alterations, and the levels of secreted transforming growth factor-β (TGFβ) and induced cytokines. 3D luminal phenotype models and basal phenotype models were generated by culturing NK cells and CD4. We identified that an interleukin-6 (IL6)-chemokine axis associated with TGFβ is primarily responsible for differences detected between breast cancer models, with luminal and basal phenotype tumours responding differentially to immune mediation. Identified cytokines are implicated in facilitating tumour cell subversion of immune cell function to promote an invasive phenotype. Moreover, the disruption of the extracellular matrix and failure to form well-differentiated tumour masses/networks is indicative of enhanced malignancy. Tumour cells are implicated in promoting a pro-inflammatory microenvironment to attenuate NK cell function and in inducing a pro-tumorigenic profile that is facilitated by T

Topics: Breast Neoplasms; Cell Culture Techniques; Cell Shape; Female; Humans; Inflammation; Inflammation Mediators; MCF-7 Cells; Models, Biological; Principal Component Analysis; Transforming Growth Factor beta

Calcific aortic valve disease (CAVD) is the result of maladaptive fibrocalcific processes leading to a progressive thickening and stiffening of aortic valve (AV) leaflets. CAVD is the most common cause of aortic stenosis (AS). At present, there is no effective pharmacotherapy in reducing CAVD progression; when CAVD becomes symptomatic it can only be treated with valve replacement. Inflammation has a key role in AV pathological remodeling; hence, anti-inflammatory therapy has been proposed as a strategy to prevent CAVD. Cyclooxygenase 2 (COX-2) is a key mediator of the inflammation and it is the target of widely used anti-inflammatory drugs. COX-2-inhibitor celecoxib was initially shown to reduce AV calcification in a murine model. However, in contrast to these findings, a recent retrospective clinical analysis found an association between AS and celecoxib use. In the present study, we investigated whether variations in COX-2 expression levels in human AVs may be linked to CAVD. We extracted total RNA from surgically explanted AVs from patients without CAVD or with CAVD. We found that COX-2 mRNA was higher in non-calcific AVs compared to calcific AVs (0.013 ± 0.002 vs. 0.006 ± 0.0004;

Topics: Aged; Aged, 80 and over; Animals; Aortic Valve; Aortic Valve Stenosis; Apoptosis; Calcinosis; Celecoxib; Cyclooxygenase 2; Female; Gene Expression Regulation; Humans; Inflammation; Male; Mice; Middle Aged; RNA, Messenger; Transforming Growth Factor beta

The mesenchymal stromal cells (MSCs) residing within the stromal component of visceral adipose tissue appear to be greatly affected by obesity, with impairment of their functions and presence of senescence. To gain further insight into these phenomena, we analyzed the changes in total proteome content and secretome of mouse MSCs after a high-fat diet (HFD) treatment compared to a normal diet (ND). In healthy conditions, MSCs are endowed with functions mainly devoted to vesicle trafficking. These cells have an immunoregulatory role, affecting leukocyte activation and migration, acute inflammation phase response, chemokine signaling, and platelet activities. They also present a robust response to stress. We identified four signaling pathways (TGF-β, VEGFR2, HMGB1, and Leptin) that appear to govern the cells' functions. In the obese mice, MSCs showed a change in their functions. The immunoregulation shifted toward pro-inflammatory tasks with the activation of interleukin-1 pathway and of Granzyme A signaling. Moreover, the methionine degradation pathway and the processing of capped intronless pre-mRNAs may be related to the inflammation process. The signaling pathways we identified in ND MSCs were replaced by MET, WNT, and FGFR2 signal transduction, which may play a role in promoting inflammation, cancer, and aging.

Topics: Aging; Animals; Diet, High-Fat; Granzymes; HMGB1 Protein; Inflammation; Interleukin-1; Intra-Abdominal Fat; Leptin; Mesenchymal Stem Cells; Methionine; Mice; Obesity; Proteome; Proto-Oncogene Proteins c-met; Receptor, Fibroblast Growth Factor, Type 2; RNA Precursors; RNA Processing, Post-Transcriptional; Secretory Vesicles; Signal Transduction; Transforming Growth Factor beta; Vascular Endothelial Growth Factor Receptor-2; Wnt Signaling Pathway

Pro-inflammatory biomarkers are well-established contributors to insulin resistance and represent valid targets for diabetes management and prevention. Yet, little is known whether nutrition could play a role in modulating various aspects of immune-inflammatory responses. Our aim is to assess the effect of isocaloric animal and plant protein dietary interventions on selected biomarkers representing various immune-inflammatory pathways.. We enrolled 37 participants with type 2 diabetes (age 64 ± 6 years, body mass index 30.2 ± 3.6 kg/m. Chemerin and progranulin concentrations decreased following AP and PP diets. TGF-β1 increased in AP and decreased in PP, whereas calprotectin increased in PP and decreased in AP. No statistically significant differences in the concentrations of IL-6, TNF-α, suPAR, lactoferrin and GDF-15 could be seen in either of the protein diet arms.. These results suggest that both AP and PP diets may effectively reduce the levels of the pro-inflammatory adipokines chemerin and progranulin. The effects on the additional immune-inflammatory biomarkers seem to be more complex.. NCT02402985 (ww.clinicaltrials.gov).

Topics: Adipokines; Aged; Animal Proteins, Dietary; Biomarkers; Diabetes Mellitus, Type 2; Diet, High-Protein; Female; Humans; Inflammation; Leukocyte L1 Antigen Complex; Male; Middle Aged; Plant Proteins, Dietary; Transforming Growth Factor beta

Chronic idiopathic urticaria (CIU) is a polyetiological dermatologic disease. Reports have stated that some microRNAs (miRNAs) have their roles to play in inflammatory response. In this present study, we aim to investigate whether miR-194 has an effect on attenuating inflammatory response and human dermal microvascular endothelial cells (HDMECs) permeability of CIU mast cells through TGF-β/SMAD pathway by binding to thrombospondin 1 (THBS1). The Gene Expression Omnibus database was used to obtain the CIU-related microarray data, and then the analysis of differentially expressed genes was conducted and the miRNA regulated by THBS1 was predicted. After transfection of different mimic, inhibitor, or small interfering RNA, the effect of miR-194 on inflammatory reaction, mast cell degranulation, histamine release rate, HDMECs permeability, and the expression of THBS1, interferon γ (IFN-γ), TGF-β, Smad3, and interleukin 4 (IL-4) were detected. THBS1 was verified to be the miR-194 target. After transfected with overexpressed miR-194 and si-THBS1, the degranulation rate, histamine release rate, and HDMECs permeability were significantly reduced, while the expression of IFN-γ was higher, and the expression of THBS1, TGF-β, Smad3, IL-4 was significantly lower, accompanied with alleviated inflammatory reaction. Our study provides evidence that miR-194 negatively modulates THBS1 and inhibits the activation of TGF-β/SMAD pathway, thereby alleviating the inflammatory response and HDMECs permeability of mast cells in CIU.

Topics: Adult; Capillary Permeability; Chronic Urticaria; Endothelial Cells; Female; Histamine; Humans; Immunoglobulin G; Immunoglobulin M; Inflammation; Male; Mast Cells; Microcirculation; MicroRNAs; Skin; Smad Proteins; Thrombospondin 1; Transforming Growth Factor beta; Young Adult

Postoperative cognitive dysfunction (POCD) is one of the common postoperative complications, which is more common in aged patients. POCD mainly manifests as cognitive function changes after surgery, such as memory decline and inattention. In some severe cases, patients may suffer from personality changes and (or) social behavior decline. The aim of the current study is to confirm the effect and elucidate the mechanism of bone marrow mesenchymal stem cells (BMSCs) in postoperative central inflammatory mice.. Mice were randomly assigned to four groups: sham, sham+BMSCs, model, and BMSCs group. In the model group, mice were intraperitoneally injected 8 mg/kg per day lipopolysaccharide for 5 days. In sham+BMSCs and BMSCs group, BMSCs (1 × 10. In the model group, transforming growth factor β (TGF-β) protein expression was significantly increased, compared with that in the sham group. BMSCs were treated into postoperative central inflammatory mice, which resulted in a decreased of TGF-β protein expression. TGF-β and smad2 protein expression were suppressed, and apoptosis rate and inflammation were inhibited in coculture with BMSCs. The suppression of TGF-β inhibited the effects of BMSCs on apoptosis rate and inflammation in postoperative central inflammatory through a smad2 signaling pathway. The promotion of TGF-β reduced the effects of BMSCs on apoptosis rate and inflammation in postoperative central inflammatory through a smad2 signaling pathway.. The present study demonstrates that BMSCs regulates TGF-β to adjust neuroinflammation in postoperative central inflammatory mice.

Topics: Animals; Apoptosis; Behavior, Animal; Bone Marrow Cells; Cell Differentiation; Cell Survival; Cognitive Dysfunction; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Inflammation; Lipopolysaccharides; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Neurons; Postoperative Period; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta

IL-17A is abundant in scleroderma but its role in fibrogenesis is controversial. We interrogated the role of IL-17A in extracellular matrix deposition and inflammation by investigating its effects on keratinocytes and fibroblasts cross-talk and in organotypic skin cultures. Keratinocyte-conditioned media of resting, IL-17A-, and/or transforming growth factor-β-primed primary keratinocytes were used to stimulate healthy donors and scleroderma fibroblasts. Alternatively, organotypic cultures of full human skin were challenged with these cytokines. Keratinocyte-conditioned media tilted the balance of col-I to matrix metalloproteinase-1 production by fibroblasts in favor of matrix metalloproteinase-1, significantly more so in healthy donors than in scleroderma, resulting in enhanced extracellular matrix turnover, further increased by IL-17A. In organotypic skin, transforming growth factor-β induced an extensive pro-fibrotic gene signature, including the enhanced expression of several collagen genes associated with Wnt signaling. IL-17A strongly promoted the expression of pro-inflammatory genes, with no direct effects on collagen genes, and attenuated Wnt signaling induced by transforming growth factor-β. In this model, at the protein level, IL-17A significantly decreased col-I production. Our data strongly support a pro-inflammatory and antifibrogenic activity of IL-17A in the context of keratinocyte-fibroblast interaction and in full skin. These data help in directing and interpreting targeted therapeutic approaches in scleroderma.

Topics: Cells, Cultured; Collagen Type I; Extracellular Matrix; Fibroblasts; Fibrosis; Gene Expression Regulation; Gene Regulatory Networks; Humans; Inflammation; Interleukin-17; Keratinocytes; Matrix Metalloproteinase 1; Organ Culture Techniques; Scleroderma, Localized; Scleroderma, Systemic; Skin; Transforming Growth Factor beta; Wnt Signaling Pathway

Here, we have investigated the therapeutic potency of EW-7197, a transforming growth factor-β type I receptor kinase inhibitor, against postsurgical adhesion band formation. Our results showed that this pharmacological inhibitor prevented the frequency and the stability of adhesion bands in mice model. We have also shown that downregulation of proinflammatory cytokines, reduce submucosal edema, attenuation of proinflammatory cell infiltration, inhibition of oxidative stress, decrease in excessive collagen deposition, and suppression of profibrotic genes at the site of surgery are some of the mechanisms by which EW-7197 elicits its protective responses against adhesion band formation. These results clearly suggest that EW-7197 has novel therapeutic properties against postsurgical adhesion band formation with clinically translational potential of inhibiting key pathological responses of inflammation and fibrosis in postsurgery patients.

Topics: 3T3 Cells; Aniline Compounds; Animals; Apoptosis; Fibroblasts; Gene Expression Regulation; Inflammation; Mice; Oxidative Stress; Random Allocation; Tissue Adhesions; Transforming Growth Factor beta; Triazoles

Atrial fibrillation (AF) is the most common type of heart arrhythmia. Currently, the pathogenesis of AF is not fully understood yet. A growing body of evidence highlighted the strong association between inflammation and the pathogenesis of AF. C-reactive protein (CRP) is an inflammation marker with increased expression in AF. Therefore, the aim of this study was to determine if CRP promotes inflammation, which may sequentially mediate the onset of AF and the concurrent atrial fibrosis, through TLR4/NF-κB/TGF-β pathway. HL-1 cells were treated with either 25 or 50 μg/ml recombinant human CRP. TGF-β1 and NF-κB inhibitors were given either solely or together to the 50 μg/ml CRP-treated cells. Cell proliferation, apoptosis, the expression of apoptotic factors and TLR4, IL-6, TGF-β1, Smad2, and the phosphorylation of Smad2 were determined. Data showed that CRP induced dose-dependent inhibition on cell proliferation and promoted cell apoptosis, which was induced through both intrinsic and extrinsic pathways. Such effects were reversed by inhibiting TGF-β1 and/or NF-κB. Inhibition of TGF-β1 and/or NF-κB also reduced the expression of TLR4 and IL-6. Inhibition of NF-κB alone weakened the expression of TGF-β1 and phosphorylation of Smad2. Our study demonstrated that CRP is not only a marker, but also an important mediator in the induction of inflammation and likely the pathogenesis of AF. We for the first time reported CRP-induced activation and cross-talk between TLR4 and NF-κB/TGF-β1 signaling pathway in a cardiomyocyte model. Reducing CRP and targeting TLR4/NF-κB/TGF-β1 pathway may provide new insights in the therapeutic interventions to inflammation-induced AF.

Topics: Atrial Fibrillation; C-Reactive Protein; Cell Line; Gene Expression Regulation; Humans; Inflammation; NF-kappa B; Signal Transduction; Toll-Like Receptor 4; Transforming Growth Factor beta

Th17 cells are essential for the pathogenesis of inflammatory and autoimmune diseases. In the presence of TGF-β, the differentiation of Th17 cells can be induced by inflammatory cytokines, especially IL-6, which is mainly produced by antigen presenting cells (APCs); or IL-21, which is derived from T cells. IL-21 is required for IL-6-induced Th17 cell differentiation. However, the key regulators and underlying mechanisms for IL-21-induced Th17 differentiation is still elusive. Here we show that SMAD4 is a key regulator in IL-21-induced Th17 differentiation. SMAD4 deficient naïve T cells can differentiate into Th17 cells in the absence of TGF-β signaling, and these Th17 cells are pathogenic during EAE. SMAD4 represses Rorc mRNA transcription to constrain IL-21-induced Th17 differentiation in the absence of TGF-β signaling. While in the presence of TGF-β, SMAD4 losses its suppressive ability due to the degradation of SKI. Mutation of Y429A or A432E on SMAD4 disrupts the interaction of SKI from SMAD4 and eliminates SMAD4 mediated suppression of Th17 differentiation. SMAD4 is indispensable for SKI binding to Rorc promoter region to regulate Th17 differentiation. Moreover, activin can induce Th17 differentiation in combination with IL-21, and the process is also subjected to the control of SKI and SMAD4. This study therefore elucidates critical mechanism for IL-21-induced Th17 differentiation to indicate SKI and SMAD4 as potential therapeutic targets for treating autoimmune diseases.

Topics: Animals; Autoimmune Diseases; Cell Differentiation; Cytokines; Inflammation; Interleukins; Mice; Mice, Inbred C57BL; Signal Transduction; Smad4 Protein; Th17 Cells; Transforming Growth Factor beta

We hypothesize that altered intensities of a few morphogenic pathways account for most/all the phenotypes of aging. Investigating this has revealed a novel approach to rejuvenate multiple mammalian tissues by defined pharmacology. Specifically, we pursued the simultaneous youthful in vivo calibration of two determinants: TGF-beta which activates ALK5/pSmad 2,3 and goes up with age, and oxytocin (OT) which activates MAPK and diminishes with age. The dose of Alk5 inhibitor (Alk5i) was reduced by 10-fold and the duration of treatment was shortened (to minimize overt skewing of cell-signaling pathways), yet the positive outcomes were broadened, as compared with our previous studies. Alk5i plus OT quickly and robustly enhanced neurogenesis, reduced neuro-inflammation, improved cognitive performance, and rejuvenated livers and muscle in old mice. Interestingly, the combination also diminished the numbers of cells that express the CDK inhibitor and marker of senescence p16 in vivo. Summarily, simultaneously re-normalizing two pathways that change with age in opposite ways (up vs. down) synergistically reverses multiple symptoms of aging.

Topics: Aging; Animals; Brain; Cognition; Inflammation; Liver; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Muscle, Skeletal; Neurogenesis; Oxytocin; Psychomotor Performance; Receptor, Transforming Growth Factor-beta Type I; Rejuvenation; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

There is considerable evidence that implicates dysregulation of type I interferon signalling (or type I IFN signature) in the pathogenesis of systemic sclerosis (SSc). Interferon regulatory factor 7 (IRF7) has been recognised as a master regulator of type I IFN signalling. The objective of this study was to elucidate the role of IRF7 in dermal fibrosis and SSc pathogenesis.. SSc and healthy control skin biopsies were investigated to determine IRF7 expression and activation. The role of IRF7 in fibrosis was investigated using IRF7 knockout (KO) mice in the bleomycin-induced and TSK/+mouse models. In vitro experiments with dermal fibroblasts from patients with SSc and healthy controls were performed.. IRF7 expression was significantly upregulated and activated in SSc skin tissue and explanted SSc dermal fibroblasts compared with unaffected, matched controls. Moreover, IRF7 expression was stimulated by IFN-α in dermal fibroblasts. Importantly, IRF7 co-immunoprecipitated with Smad3, a key mediator of transforming growth factor (TGF)-β signalling, and IRF7 knockdown reduced profibrotic factors in SSc fibroblasts. IRF7 KO mice demonstrated attenuated dermal fibrosis and inflammation compared with wild-type mice in response to bleomycin. Specifically, hydroxyproline content, dermal thickness as well as Col1a2, ACTA2 and interleukin-6 mRNA levels were significantly attenuated in IRF7 KO mice skin tissue. Furthermore, IRF7 KO in TSK/+mice attenuated hydroxyproline content, subcutaneous hypodermal thickness, Col1a2 mRNA as well as α-smooth muscle actin and fibronectin expression.. IRF7 is upregulated in SSc skin, interacts with Smad3 and potentiates TGF-β-mediated fibrosis, and therefore may represent a promising therapeutic target in SSc.

Topics: Animals; Bleomycin; Disease Models, Animal; Fibroblasts; Fibrosis; Humans; Inflammation; Interferon Regulatory Factor-7; Mice; Mice, Knockout; Scleroderma, Systemic; Signal Transduction; Skin; Smad3 Protein; Transforming Growth Factor beta; Up-Regulation

Anoplocephala perfoliata is the commonest equine tapeworm, the adult parasites are attached in groups close to the ileocaecal valve causing marked inflammatory pathology. This work aimed to characterize the nature of the in vivo mucosal immune response to A perfoliata, and to investigate the role of A perfoliata excretory-secretory components in modulating in vitro immune responses. Real-time PCR detected elevation of IL13 and TGFβ transcription in early-stage A perfoliata infection. In late-stage infection, IL-13, IL4 and Ifn transcripts were reduced while the regulatory cytokines, TGFβ, IL10 and the transcription factor FOXP3 were increased in tissue close to the site of A perfoliata attachment; indicating downregulation of T-cell responses to A perfoliata. In vitro, A perfoliata excretory-secretory products induced apoptosis of the Jurkat T-cell line and premature cell death of ConA stimulated equine peripheral blood leucocytes. Analysis of cytokine transcription patterns in the leucocyte cultures showed a marked inhibition of IL-1 and IL-2 suggesting that a lack of T-cell growth factor transcription underlies the mechanism of the induced equine T-cell death. These preliminary findings suggest A perfoliata may have the ability to down-regulate host T-cell responses.

Topics: Animals; Cecum; Cestoda; Cestode Infections; Forkhead Transcription Factors; Horse Diseases; Horses; Inflammation; Interleukin-1; Interleukin-10; Interleukin-13; Interleukin-2; Interleukin-4; Mucous Membrane; T-Lymphocytes; Transforming Growth Factor beta

Diet has been suggested to be a potential environmental risk factor for the increasing incidence of autoimmune diseases, yet the underlying mechanisms remain elusive. Here, we show that high glucose intake exacerbated autoimmunity in mouse models of colitis and experimental autoimmune encephalomyelitis (EAE). We elucidated that high amounts of glucose specifically promoted T helper-17 (Th17) cell differentiation by activating transforming growth factor-β (TGF-β) from its latent form through upregulation of reactive oxygen species (ROS) in T cells. We further determined that mitochondrial ROS (mtROS) are key for high glucose-induced TGF-β activation and Th17 cell generation. We have thus revealed a previously unrecognized mechanism underlying the adverse effects of high glucose intake in the pathogenesis of autoimmunity and inflammation.

Topics: Animals; Autoimmunity; Cell Differentiation; Cells, Cultured; Diet; Disease Models, Animal; Eating; Encephalomyelitis, Autoimmune, Experimental; Glucose; Humans; Inflammation; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Multiple Sclerosis; Reactive Oxygen Species; Th17 Cells; Transforming Growth Factor beta

Peritoneal fibrosis (PF) represents a long-term complication of peritoneal dialysis (PD), affecting peritoneal membrane (PM) integrity and function. Understanding the mechanisms underlying PF development in an uremic environment aiming alternative therapeutic strategies for treating this process is of great interest. The aim of this study was to analyze the effects of tamoxifen (TAM) and recombinant BMP7 (rBMP7) in an experimental model of PF developed in uremic rats.. To mimic the clinical situation of patients on long-term PD, a combo model, characterized by the combination of PF and CKD with severe uremia, was developed in Wistar rats. PF was induced by intraperitoneal (IP) injections of chlorhexidine gluconate (CG), and CKD was induced by an adenine-rich diet. Uremia was confirmed by severe hypertension, increased blood urea nitrogen (BUN> 120 mg/dL) and serum creatinine levels (> 2 mg/dL). Uremic rats with PF were treated with TAM (10 mg/Kg by gavage) or BMP7 (30 μg/Kg, IP). Animals were followed up for 30 days.. CG administration in uremic rats induced a striking increase in PM thickness, neoangiogenesis, demonstrated by increased capillary density, and failure of ultrafiltration capacity. These morphological and functional changes were blocked by TAM or rBMP7 treatment. In parallel, TAM and rBMP7 significantly ameliorated the PM fibrotic response by reducing α-SMA, extracellular matrix proteins and TGF-ß expression. TAM or rBMP7 administration significantly inhibited peritoneal Smad3 expression in uremic rats with PF, prevented Smad3 phosphorylation, and induced a remarkable up-regulation of Smad7, an intracellular inhibitor of TGFβ/Smad signaling, contributing to a negative modulation of profibrotic genes. Both treatments were also effective in reducing local inflammation, possibly by upregulating IκB-α expression in the PM of uremic rats with PF. In vitro experiments using primary peritoneal fibroblasts activated by TGF-ß confirmed the capacity of TAM or rBMP7 in blocking inflammatory mediators, such as IL-1ß expression.. In conclusion, these findings indicate important roles of TGF-ß/Smad signaling in PF aggravated by uremia, providing data regarding potential therapeutic approaches with TAM or rBMP7 to block this process.

Topics: Animals; Bone Morphogenetic Protein 7; Cells, Cultured; Disease Models, Animal; Inflammation; Male; Peritoneal Fibrosis; Peritoneum; Rats; Rats, Wistar; Recombinant Proteins; Renal Insufficiency, Chronic; Smad7 Protein; Tamoxifen; Transforming Growth Factor beta; Uremia

Corneal lymphangiogenesis plays a key role in diverse pathological conditions of the eye. Here, we demonstrate that a versatile extracellular matrix protein, transforming growth factor-β induced protein (TGFBIp), promotes lymphatic sprouting in corneal lymphangiogenesis. TGFBIp is highly up-regulated in inflamed mouse corneas. Immunolocalization of TGFBIp is detected in infiltrating macrophages in inflamed mouse corneas. Subconjunctival injection of liposomal clodronate can significantly reduce macrophage infiltration in inflamed mouse cornea, and decrease the expression of TGFBIp and areas of corneal lymphangiogenesis and angiogenesis after corneal suture placement. In brief, these results indicate that the up-regulation of TGFBIp in sutured cornea correlates with macrophage infiltration. Although TGFBIp alone cannot significantly stimulate corneal lymph vessel ingrowth in vivo, it can enhance the effect of vascular endothelial growth factor-C in promoting corneal lymphangiogenesis. The in vitro results show that TGFBIp promotes migration, tube formation and adhesion of human lymphatic endothelial cells (HLECs), but it has no effect on HLECs' proliferation. We also find that the in vitro effect of TGFBIp is mediated by the integrin α5β1-FAK pathway. Additionally, integrin α5β1 blockade can significantly inhibit lymphatic sprouting induced by TGFBIp. Taken together, these findings reveal a new molecular mechanism of lymphangiogenesis in which the TGFBIp-integrin pathways plays a pivotal role in lymphatic sprouting.

Topics: Animals; Cornea; Endothelial Cells; Extracellular Matrix Proteins; Focal Adhesion Protein-Tyrosine Kinases; Humans; Inflammation; Integrin alpha5beta1; Lymphangiogenesis; Macrophages; Male; Mice, Inbred C57BL; Models, Biological; Sutures; Transforming Growth Factor beta; Up-Regulation; Vascular Endothelial Growth Factor C

Skeletal muscle injury presents a challenging traumatological dilemma, and current therapeutic options remain mediocre. This study was designed to delineate if engraftment of mesenchymal stem cells derived from umbilical cord Wharton's jelly (uMSCs) could aid in skeletal muscle healing and persuasive molecular mechanisms. We established a skeletal muscle injury model by injection of myotoxin bupivacaine (BPVC) into quadriceps muscles of C57BL/6 mice. Post BPVC injection, neutrophils, the first host defensive line, rapidly invaded injured muscle and induced acute inflammation. Engrafted uMSCs effectively abolished neutrophil infiltration and activation, and diminished neutrophil chemotaxis, including Complement component 5a (C5a), Keratinocyte chemoattractant (KC), Macrophage inflammatory protein (MIP)-2, LPS-induced CXC chemokine (LIX), Fractalkine, Leukotriene B4 (LTB4), and Interferon-γ, as determined using a Quantibody Mouse Cytokine Array assay. Subsequently, uMSCs noticeably prevented BPVC-accelerated collagen deposition and fibrosis, measured by Masson's trichrome staining. Remarkably, uMSCs attenuated BPVC-induced Transforming growth factor (TGF)-β1 expression, a master regulator of fibrosis. Engrafted uMSCs attenuated TGF-β1 transmitting through interrupting the canonical Sma- And Mad-Related Protein (Smad)2/3 dependent pathway and noncanonical Smad-independent Transforming growth factor beta-activated kinase (TAK)-1/p38 mitogen-activated protein kinases signaling. The uMSCs abrogated TGF-β1-induced fibrosis by reducing extracellular matrix components including

Topics: Animals; Fibrosis; Humans; Inflammation; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Neutrophil Infiltration; Neutrophils; Signal Transduction; Transforming Growth Factor beta; Umbilical Cord

To investigate the role of microRNA (miR)‑519d‑3p in postoperative epidural scar formation and its regulation of the bone morphogenetic protein and activin membrane‑bound inhibitor (BAMBI), miR‑519d‑3p and BAMBI expression levels in the lumbar disc of patients who had undergone laminectomy were detected with reverse transcription‑quantitative polymerase chain reaction and western blotting. The results demonstrated that miR‑519d‑3p expression was significantly increased, whereas BAMBI expression was sharply reduced in the lumbar discs of patients suffering from epidural scars. Subsequently, the miR‑519d‑3p mimic was transfected into primary fibroblasts isolated from epidural scar tissues. Flow cytometric and Cell Countin Kit‑8 analyses indicated that overexpression of miR‑519d‑3p promoted the proliferation of fibroblasts, the production of tumor necrosis factor‑α and interleukin (IL)‑1α, and the expression of type I collagen (col I), α‑smooth muscle actin (α‑SMA) and fibronectin (FN). Downregulation of miR‑519d‑3p by the miR‑519d‑3p antagomir transfection had the opposite effect. Bioinformatics and luciferase reporter gene analyses demonstrated that BAMBI is a target gene of miR‑519d‑3p: miR‑519d‑3p directly binds to the 3'‑untranslated region of BAMBI mRNA and suppressed BAMBI protein expression. Finally, the pcDNA‑BAMBI vector and BAMBI small interfering RNA were respectively transfected into primary fibroblasts to overexpress and knockdown the BAMBI gene. It was demonstrated that BAMBI overexpression suppressed fibroblast proliferation, TNF‑α and IL‑1α production, and the expression of col I, α‑SMA and FN proteins, whereas, BAMBI knockdown had the opposite effect. In conclusion, it was noted that BAMBI is a target of miR‑519d‑3p and miR‑519d‑3p promotes transforming growth factor β/mothers against decapentaplegic homolog 9‑mediated postoperative epidural scar formation via suppression of BAMBI.

Topics: Adult; Cell Proliferation; Cells, Cultured; Cicatrix; Down-Regulation; Female; Fibroblasts; Humans; Inflammation; Male; Membrane Proteins; MicroRNAs; Middle Aged; Postoperative Period; Smad Proteins; Transforming Growth Factor beta; Up-Regulation

Asthma is a common obstructive airway disease characterized by inflammation and remodeling with a progressive decline in lung function. Fangxiao Formula (FXF) is an herbal medicine that has achieved significant clinical benefits toward asthma patients, but the relevant mechanism has not yet been clarified. The aim of this study was to determine the inhibitory effects of FXF on airway inflammation and remodeling, and investigate the activities of TGF‑β/Smads signaling pathway in the rat asthma model. Rats were sensitized by ovalbumin (OVA) for six weeks to establish the asthma experimental model. OVA-challenged animals were randomly divided into 5 groups and received different concentrations of FXF or dexamethasone. The animals in blank control group received saline only. Lung tissues were collected and analyzed for determining the inflammatory cells infiltration, HE and PAS staining, airway wall thickness and collagen deposition. The productions of inflammatory cytokine productions were analyzed by ELISA in the bronchoalveolar lavage (BAL) fluid. Immunohistochemical analysis was performed to measure the expression of α-SMA and PCNA in lung tissue after the treatment of FXF. The levels of TGF-β were assessed by both immunohistology and western blotting, and the expression of p-Smad2/3 proteins were determined by western blotting analysis. Our results indicated that FXF attenuated the infiltration of inflammatory cells, decreased the production of Th2 cytokines and simultaneously increased the levels of Th1 cytokine in the asthma rat model. In addition, FXF reduced allergen-induced increased airway wall thickness, goblet cell hyperplasia and collagen deposition. Furthermore, the expression levels of TGF-β and p-Smad3 were obviously reduced after the treatment of FXF. These results indicate that FXF alleviates airway inflammation and remodeling by restoring the balance of Th1/Th2 cytokines and the TGF-β/Smad-3 pathway, therefor providing potential therapeutic approach for asthmatic patients.

Topics: Airway Remodeling; Animals; Asthma; Bronchoalveolar Lavage Fluid; Collagen; Cytokines; Disease Models, Animal; Drugs, Chinese Herbal; Hyperplasia; Inflammation; Lung; Male; Proliferating Cell Nuclear Antigen; Rats, Sprague-Dawley; Signal Transduction; Smad3 Protein; Th1 Cells; Th2 Cells; Transforming Growth Factor beta

Fibrosis is the most important pathologic condition involved in undesirable outcomes of dacryocystorhinostomy. A number of biochemical factors are currently known to have an effect on wound healing by promoting excessive scarring. Isoforms of transforming growth factor β (TGF-β1) are considered the 'main' pro-fibrotic factor, but wound healing is also affected by other cytokines such as connective tissue growth factor (CTGF), which stimulates fibrosis, and fibroblast growth factor (FGF-2), which acts as antagonist to it.. To investigate correlations between endoscopic endonasal dacryocystorhinostomy outcomes and certain mediators of fibrosis.. The study included 45 cases of endoscopic endonasal dacryocystorhinostomy. The patients were grouped according to surgery outcome: patients with unsuccessful surgical treatment were assigned to group 1 (n=10); patients with successful surgical treatment - to group 2 (n=34). One patient was excluded from the study. Full-layer biopsy specimen were taken from patients' nasal mucosa before the surgery. TGF-β1, TGF-β2, TGF-β3, CTGF, FGF-2 concentrations were evaluated using ELISA and normalized by total protein concentration.. Surgical failure was observed in 10 cases (22.72%). CTGF concentration was significantly correlated with negative outcome (p<0.05) and was elevated in most specimen obtained from group 1. No significant correlation was noted between the concentrations of other evaluated cytokines in nasal mucosa specimens and the surgical outcome.. The study found a correlation between CTGF concentration in nasal mucosa and dacryocystorhinostomy outcome, which supports the hypothesis suggested by several authors linking dacryocystorhinostomy failure with chronic inflammation in nasal mucosa.. Введение. Фиброз является наиболее важным патологическим состоянием, приводящим к неудачному результату оперативного вмешательства при дакриоцисториностомии. В настоящее время известно множество биохимических факторов, оказывающих влияние на течение процесса заживления, активность которых может являться причиной избыточного рубцевания. 'Центральными' медиаторами фиброза считаются изоформы трансформирующего фактора роста (TGF-β), но в процессе заживления ран также участвуют и другие цитокины, такие как фактор роста соединительной ткани (CTGF), обладающий профибротическим действием, и фактор роста фибробластов (FGF-2), обладающий антифибротическим действием. Цель исследования - изучить корреляцию результата эндоназальной эндоскопической дакриоцисториностомии с концентрацией некоторых медиаторов фиброза. Материал и методы. В исследование было включено 45 случаев эндоназальной эндоскопической дакриоцисториностомии. В соответствии с результатом оперативного вмешательства пациентов разделили на две группы: в 1-ю группу (n=10) вошли пациенты с неблагоприятным результатом операции; во 2-группу (n=34) - пациенты с благоприятным результатом. Из исследования исключен 1 пациент. До начала оперативного вмешательства осуществляли забор полнослойных биоптатов слизистой оболочки полости носа. Исследование концентрации цитокинов TGF-β1, TGF-β2, TGF-β3, CTGF, FGF-2 выполняли методом твердофазного иммуноферментного анализа (ELISA) с последующей нормировкой показателей по содержанию общего белка. Результаты. Неблагоприятный результат оперативного вмешательства наблюдали в 10 (22,72%) случаях. Концентрация цитокина CTGF повышена у большинства пациентов 1-й группы и статистически значимо коррелировала с неблагоприятным результатом хирургического вмешательства (p<0,05). Корреляции между результатом оперативного вмешательства и содержанием других исследованных цитокинов в образцах слизистой оболочки полости носа не обнаружено. Заключение. В настоящем исследовании выявлена корреляция между концентрацией цитокина CTGF в слизистой оболочке полости носа и результатом эндоназальной эндоскопической дакриоцисториностомии; это поддерживает выдвинутую рядом авторов гипотезу, что хроническое воспаление в полости носа обусловливает неблагоприятный результат оперативного вмешательства.

Topics: Cytokines; Dacryocystorhinostomy; Fibrosis; Humans; Inflammation; Transforming Growth Factor beta

Semen induces post-coital inflammation of the endometrium in several species. Post-coital inflammation is proposed to alter the endometrial environment of early pregnancy, mediate embryonic development and modulate the maternal immune response to pregnancy. In cattle, it is common for pregnancies to occur in the absence of whole semen due to the high utilization of artificial insemination. Here, we have utilized a cell culture system to characterize semen-induced expression of inflammatory mediators in bovine endometrial cells and test the efficacy of transforming growth factor beta as the active agent in mediating any such change. We hypothesize that seminal plasma-derived transforming growth factor beta increases the expression of inflammatory mediators in bovine endometrial cells. Initially, we describe a heat-labile cytotoxic effect of seminal plasma on BEND cells, and a moderate increase in IL1B and IL6 expression. In addition, we show that transforming growth factor beta is present in bovine semen and can increase the expression of endometrial IL6, whereas blocking transforming growth factor beta in semen ameliorates this effect. However, intra-uterine infusion of seminal plasma, sperm or transforming growth factor beta did not alter the endometrial expression of inflammatory mediators. We conclude that bovine semen can modulate endometrial gene expression in vitro, which is partially due to the presence of transforming growth factor beta. It is likely that additional, unidentified, bioactive molecules in semen can alter the endometrial environment. Characterizing bioactive molecules in bovine semen may lead to the development of additives to improve artificial insemination in domestic species.

Topics: Animals; Cattle; Cytokines; Endometrium; Female; Gene Expression Regulation; Inflammation; Inflammation Mediators; Insemination, Artificial; Male; Pregnancy; Semen; Transforming Growth Factor beta

Solid tumour growth is the consequence of a complex interplay between cancer cells and their microenvironment. Recently, a new global transcriptomic immune classification of solid tumours has identified six immune subtypes (ISs) (C1-C6). Our aim was to specifically characterise ISs in colorectal cancer (CRC) and assess their interplay with the consensus molecular subtypes (CMSs).. Clinical and molecular information, including CMSs and ISs, were obtained from The Cancer Genome Atlas (TCGA) (N = 625). Immune cell populations, differential gene expression and gene set enrichment analysis were performed to characterise ISs in the global CRC population by using CMSs.. Only 5 ISs were identified in CRC, predominantly C1 wound healing (77%) and C2 IFN-γ dominant (17%). CMS1 showed the highest proportion of C2 (53%), whereas C1 was particularly dominant in CMS2 (91%). CMS3 had the highest representation of C3 inflammatory (7%) and C4 lymphocyte depleted ISs (4%), whereas all C6 TGF-β dominant cases belonged to CMS4 (2.3%). Prognostic relevance of ISs in CRC substantially differed from that reported for the global TCGA, and ISs had a greater ability to stratify the prognosis of CRC patients than CMS classification. C2 had higher densities of CD8, CD4 activated, follicular helper T cells, regulatory T cells and neutrophils and the highest M1/M2 polarisation. C2 had a heightened activation of pathways related to the immune system, apoptosis and DNA repair, mTOR signalling and oxidative phosphorylation, whereas C1 was more dependent of metabolic pathways.. The correlation of IS and CMS allows a more precise categorisation of patients with relevant clinical and biological implications, which may be valuable tools to improve tailored therapeutic interventions in CRC patients.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Aged; CD8-Positive T-Lymphocytes; Cell Proliferation; Colorectal Neoplasms; Epithelial-Mesenchymal Transition; Female; Genes, MHC Class I; Humans; Inflammation; Interferon-gamma; Lymphocytes; Macrophages; Male; Microsatellite Instability; Monocytes; Neovascularization, Pathologic; Prognosis; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins p21(ras); Receptors, Antigen, T-Cell; Signal Transduction; Th1 Cells; Th17 Cells; Th2 Cells; Transforming Growth Factor beta; Tumor Microenvironment; Wnt Signaling Pathway; Wound Healing

Enhancing the therapeutic efficacy of drugs for inflammatory diseases is of high demand. One possible approach is targeting drugs to the extracellular matrix of the inflamed area. Here, we target collagens in the matrix, which are inaccessible in most tissues yet are exposed to the bloodstream in the inflamed area because of vascular hyperpermeability. We conferred collagen affinity to anti-tumor necrosis factor-α (α-TNF) antibody by conjugating a collagen-binding peptide (CBP) derived from the sequence of decorin. CBP-α-TNF accumulated in the inflamed paw of the arthritis model, and arthritis development was significantly suppressed by treatment with CBP-α-TNF compared with the unmodified antibody. Similarly, CBP-anti-transforming growth factor-β (α-TGF-β) accumulated in the inflamed lung of pulmonary fibrosis model and significantly suppressed pulmonary fibrosis compared with the unmodified antibody. Together, collagen affinity enables the anticytokine antibodies to target arthritis and pulmonary fibrosis accompanied by inflammation, demonstrating a clinically translational approach to treat inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Antibodies; Collagen; Humans; Inflammation; Lung; Mice, Inbred BALB C; Mice, Inbred C57BL; Molecular Targeted Therapy; Peptide Fragments; Pulmonary Fibrosis; Sialoglycoproteins; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The present study was designed to investigate the protective effect of moracin on primary culture of nucleus pulposus cells in intervertebral disc and explore the underlying mechanism. Moracin treatment significantly inhibited the LPS-induced inflammatory cytokine accumulation (IL-1β, IL-6 and TNF-α) in nucleus pulposus cells. And moracin also dramatically decreased MDA activity, and increased the levels of SOD and CAT induced by LPS challenge. Moreover, the expressions of Nrf-2 and HO-1 were decreased and the protein levels of p-NF-κBp65, p-IκBα, p-smad-3 and TGF-β were increased by LPS challenge, which were significantly reversed after moracin treatments. Moracin treatments also decreased the levels of matrix degradation enzymes (MMP-3, MMP-13) as indicated by RT-PCR analysis. However, Nrf-2 knockdown abolished these protective effects of moracin. Together, our results demonstrated the ability of moracin to antagonize LPS-mediated inflammation in primary culture of nucleus pulposus in intervertebral disc by partly regulating the Nrf2/HO-1 and NF-κB/TGF-β pathway in nucleus pulposus cells.

Topics: Benzofurans; Heme Oxygenase (Decyclizing); Humans; Inflammation; Lipopolysaccharides; Matrix Metalloproteinase 13; Matrix Metalloproteinase 3; NF-E2-Related Factor 2; NF-kappa B; Nucleus Pulposus; Stilbenes; Transforming Growth Factor beta

Environmental triggers acting at the intestinal barrier are thought to contribute to the initiation of autoimmune disorders. The transforming growth factor beta inhibitor Smad7 determines the phenotype of CD4

Topics: Animals; Autoimmunity; CD4-Positive T-Lymphocytes; Cell Differentiation; Central Nervous System; Disease Models, Animal; Encephalomyelitis; Encephalomyelitis, Autoimmune, Experimental; Gastrointestinal Microbiome; Gene Expression Regulation; Humans; Immune Tolerance; Inflammation; Intestines; Mice; Mice, Transgenic; Multiple Sclerosis; Signal Transduction; Smad7 Protein; Spinal Cord; Transforming Growth Factor beta

The purpose of this study is to reveal the participation of different regulatory cytokines within the process of pseudoexfoliation (PEX).. Our study included 140 patients referred to cataract surgery with early and late stage of pseudoexfoliation syndrome (XFS) or pseudoexfoliation glaucoma (XFG). Humor and serum levels of cytokines: transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), IL-8 and interferon-inducible T cell alpha chemoattractant (ITAC) were measured in a sample using high sensitivity enzyme-linked immunoabsorbent assay (ELISA) kit.. Our results indicate that profibrotic action induced by increasing TGF-β and PDGF locally activates fibrous tissue production in the early XFS with a prolonged effect of PDGF (late XFS) and finally (XFG stage) it is dominantly controlled by EGF and IGF. ITAC overrides angiogenetic effects of IL-8 in XFG.. Based on our findings, local chronic inflammation in the eye is accompanied by the secretion of different profibrotic cytokines (TGF-β, PDGF, EGF, IGF, IL-8) without angiogenesis due to effects of ITAC.

Topics: Cytokines; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Exfoliation Syndrome; Humans; Inflammation; Neovascularization, Physiologic; Platelet-Derived Growth Factor; Transforming Growth Factor beta

Systemic sclerosis is a multisystem inflammatory and vascular lesion leading to extensive tissue fibrosis. A reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor, DZ2002, modulates the pathologic processes of various inflammatory diseases and autoimmune diseases. This study is designed to investigate the therapeutic potentiality of DZ2002 for experimental systemic sclerosis models.. The anti-inflammatory and anti-fibrotic features of DZ2002 and its mechanisms were investigated in a bleomycin (BLM)-induced dermal fibrosis mice model. The effects of DZ2002 on expression of extracellular matrix components and TGF-β signaling in human dermal fibroblasts were analyzed. Simultaneously, the effects of DZ2002 on macrophage activation and endothelial cell adhesion molecule expression were also evaluated.. DZ2002 significantly attenuated dermal fibrosis in BLM-induced mice. Consistently, DZ2002 inhibited the expression of various molecules associated with dermal fibrosis, including transforming growth factor β1, connective tissue growth factor, tumor necrosis factor-α, interferon-γ, IL-1β, IL-4, IL-6, IL-10, IL-12p40, IL-17A, and monocyte chemotactic protein 1 in the lesional skin of BLM-induced mice. Furthermore, DZ2002 decreased the proportion of macrophages, neutrophils, and T cells (especially T helper cells) in the skin tissue of BLM-induced mice. In addition, DZ2002 attenuated both M1 macrophage and M2 macrophage differentiation in vivo and in vitro. Importantly, DZ2002 directly reversed the profibrotic phenotype of transforming growth factor-β1-treated dermal fibroblasts and suppressed ICAM-1, VCAM-1, VEGF, bFGF, and ET-1 expression in endothelial cells. Finally, our investigations showed that DZ2002 relieved systemic sclerosis by regulating fibrosis TGF-β/Smad signaling pathway.. DZ2002 prevents the development of experimental dermal fibrosis by reversing the profibrotic phenotype of various cell types and would be a potential drug for the treatment of systemic sclerosis.

Topics: Adenine; Animals; Bleomycin; Butyrates; Cell Line; Cells, Cultured; Dermis; Disease Models, Animal; Female; Fibroblasts; Fibrosis; Gene Expression; Humans; Inflammation; Macrophages; Mice, Inbred C57BL; Scleroderma, Systemic; THP-1 Cells; Transforming Growth Factor beta; Vascular Diseases; Vascular Endothelial Growth Factor A

Topics: Animals; Arginine; Dietary Supplements; Female; Fibrosis; Glutamine; Immunohistochemistry; Inflammation; Intestinal Diseases; Intestinal Mucosa; Radiation Injuries, Experimental; Rats; Rats, Wistar; Transforming Growth Factor beta; Valerates

Pitavastatin inhibits 3 hydroxy 3 methyl glutaryl coenzyme A (HMGCoA) reductase enzyme, preventing cholesterol synthesis along with elevating high density apolipoprotein A1 (Apo-A1). The present study was designed to evaluate cardioprotective potential of pitavastatin at 1 mg/kg/day and 3 mg/kg/day dose for 14 days in low dose isoproterenol (ISO) (5 mg/kg/day for 7 consecutive days) induced myocardial damage. ISO administration induced significant reduction in endogenous antioxidant enzymes like reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and raised thiobarbituric acid reactive substances (TBARS) indicating activated lipid peroxidation. Along with this, a significant increase in level of cardiac injury biomarkers vie, creatine kinase (CK-MB), lactate dehydrogenase (LDH), aspartate amino transferase (AST), tumor necrosis factor (TNF-α) and transforming growth factor (TGF-β) as well as brain natriuretic peptide (BNP). Histological examination also revealed marked myocardial tissue damage in ISO treated rats. However, pretreatment with pitavastatin (3 mg/kg/day) significantly maintained nearly normal levels of cardiac biomarkers and oxidant antioxidant status as well as lipid peroxidation in ISO induced MI rats. Cardiac histological assessment and infarct size assessment also showed marked reduction in myocardial architecture alteration including infarct size as well as collagen deposition by pitavastatin that strongly supported biochemical findings. These observations strongly corroborate that pitavastatin prevents myocardial damages via up regulation of endogenous oxidants along with its hypocholesterolemic activity.

Topics: Animals; Antioxidants; Aspartate Aminotransferases; Catalase; Collagen; Creatine Kinase, MB Form; Free Radicals; Glutathione; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Isoproterenol; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Myocardial Infarction; Myocardium; Natriuretic Peptide, Brain; Quinolines; Rats; Rats, Wistar; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Clinical manifestations of skin fibrosis are very variable and ambiguous, making its management quite critical and challenging. The lack of appropriate established pharmacological interventions make its treatment even more complicated. Intricate details of the underlying pathogenesis are thus imperative to further explore different treatment possibilities. Of note, the TGF-β/Smad signaling axis and epithelial to mesenchymal transition (EMT) are the principal offenders in this fibrotic disorder.. Our current study is aimed at demonstrating the antifibrotic and anti-inflammatory potential of nimbolide, a triterpene derived from Indian traditional plant neem, in a murine model of Bleomycin-induced scleroderma.. Male C57BL/6 mice were administered with Bleomycin injections subcutaneously, daily for 28 days, at a constant site on the dorsum of the mice. Treatment with nimbolide lasted from day 1 to day 28. At the time of study termination, the injected sites were collected and stored suitably to conduct further molecular experiments and protein expression studies.. The results of our study show that nimbolide can significantly intervene in the TGF-β/Smad signaling axis and the consequent EMT process, thus attenuating deposition of extracellular matrix. Nimbolide also profoundly caused the regression of established inflammation-driven fibrosis, thus demonstrating both antifibrotic and anti-inflammatory activities. Another commendable finding of this study is that nimbolide was able to decrease the levels of LOXL2, a collagen cross-linker, which is aberrantly expressed in scleroderma. Although further mechanistic studies are required, our study displays nimbolide for the first time as a potent antifibrotic agent which can be used as a pharmacological intervention for the treatment of scleroderma.

Topics: Amino Acid Oxidoreductases; Animals; Anti-Inflammatory Agents; Bleomycin; Disease Models, Animal; Epithelial-Mesenchymal Transition; Fibrosis; Inflammation; Limonins; Male; Mice; Mice, Inbred C57BL; Scleroderma, Localized; Signal Transduction; Skin; Smad Proteins; Transforming Growth Factor beta

Pancreatic ductal adenocarcinoma (PDAC) is poorly responsive to therapies and histologically contains a paucity of neoplastic cells embedded within a dense desmoplastic stroma. Within the stroma, cancer-associated fibroblasts (CAF) secrete tropic factors and extracellular matrix components, and have been implicated in PDAC progression and chemotherapy resistance. We recently identified two distinct CAF subtypes characterized by either myofibroblastic or inflammatory phenotypes; however, the mechanisms underlying their diversity and their roles in PDAC remain unknown. Here, we use organoid and mouse models to identify TGFβ and IL1 as tumor-secreted ligands that promote CAF heterogeneity. We show that IL1 induces LIF expression and downstream JAK/STAT activation to generate inflammatory CAFs and demonstrate that TGFβ antagonizes this process by downregulating IL1R1 expression and promoting differentiation into myofibroblasts. Our results provide a mechanism through which distinct fibroblast niches are established in the PDAC microenvironment and illuminate strategies to selectively target CAFs that support tumor growth. SIGNIFICANCE: Understanding the mechanisms that determine CAF heterogeneity in PDAC is a prerequisite for the rational development of approaches that selectively target tumor-promoting CAFs. Here, we identify an IL1-induced signaling cascade that leads to JAK/STAT activation and promotes an inflammatory CAF state, suggesting multiple strategies to target these cells

Topics: Animals; Apoptosis; Cancer-Associated Fibroblasts; Carcinoma, Pancreatic Ductal; Cell Proliferation; Female; Humans; Inflammation; Interleukin-1; Janus Kinase 1; Mice; Mice, Nude; Mutation; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Signal Transduction; STAT1 Transcription Factor; Transforming Growth Factor beta; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Recently, hepatic sinusoidal obstruction syndrome (HSOS) caused by herbal preparations containing pyrrolizidine alkaloids (PAs), such as Gynura Rhizoma (Tusanqi), has gained global attention. However, the lack of a reliable and reproducible animal model has greatly hampered mechanistic studies. Therefore, we aimed to establish a reproducible HSOS mouse model and investigate the hepatotoxic mechanism. The model was established by intragastrical administration of Gynura Rhizoma extract, i.e., 1.0 g extract/kg per day (equal to 16.7 g crude drug/kg per day based on extraction rate and 49.1 mg PA/kg per day based on the total PA content in the extract determined) for 40 successive days. Then, the mice were sacrificed, and their blood samples and livers were collected for analyses. Using hematoxylin-eosin (HE) and Masson staining, scanning electron microscopy imaging, clinical biomarkers, and other assays, we showed that the HSOS was successfully induced in our mouse model. Furthermore, we detected the key factors involved in liver fibrosis in the mice, revealing significantly increased hydroxyproline concentration; elevated expression of α-smooth muscle actin (α-SMA) and fibrosis-related genes such as Collagen-1, Collagen-3, Mmp2, Mmp13, Timp1, Timp3, and Activin, upregulated Smad3 phosphorylation, and increased serum TGF-β levels. Moreover, pro-inflammatory cytokines, including Tnf-α, Il-1β, and Il-6, were also increased in the model. All these results demonstrate the key roles of the TGF-β-Smad3 and inflammatory signaling pathways in this Gynura Rhizoma-induced HSOS mouse model, suggesting that blockade of fibrosis and/or inflammation should be an effective treatment for HSOS.

Topics: Animals; Disease Models, Animal; Drugs, Chinese Herbal; Hepatic Veno-Occlusive Disease; Inflammation; Interleukin-1beta; Interleukin-6; Liver; Liver Cirrhosis; Male; Mice, Inbred C57BL; Pyrrolizidine Alkaloids; RNA, Messenger; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Up-Regulation

Topics: Animals; Cadmium; Cell Proliferation; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Female; Glucose; Inflammation; Lipid Metabolism; Liver; Metallothionein; Mice; Oxidative Stress; Transforming Growth Factor beta

The present study aimed to explore the underlying mechanisms of bone morphogenetic protein 2 (BMP2) in alleviating intervertebral disc degeneration (IDD). A rat puncture IDD model was constructed, and the rats were randomly divided into six groups: Control; IDD (model); IDD+PBS [containing 1010 adeno‑associated virus serotype 2 (AAV)]; and IDD + AAV2‑BMP2 (106, 108 and 1010). IL‑1β was used to treat primary nucleus pulposus (NP) cells to mimic IDD in vitro. The effects of BMP2 in IDD were determined by magnetic resonance imaging (MRI), hematoxylin and eosin staining and Alcian Blue staining in vivo. The levels of collagen II, aggrecan, transcription factor SOX9 (SOX9) and matrix metalloproteinase 13 (MMP‑13) were examined using western blot analysis and reverse transcription quantitative polymerase chain reaction (RT‑qPCR) in NP tissues and cells. The expression of C‑telopeptide of type II collagen (CTX‑II) in the sera or cell supernatants was determined by ELISA. In addition, the levels of phosphorylation of phosphoinositide 3‑kinase (PI3K) and protein kinase B (Akt), and the levels of apoptosis‑associated proteins and apoptosis ratio of NP cells were also determined by western blot analysis and flow cytometry, respectively. LY29400, an inhibitor of PI3K, was used to additionally confirm the signal pathway mechanism of BMP2 treatment in IDD. BMP2 significantly extended the interval between discs and alleviated the fibrous ring rupture and the decrease in the levels of glycoproteins in IDD rats, as determined by MRI and histological staining. Additionally, BMP2 treatment significantly upregulated the levels of collagen II, aggrecan and SOX9, but downregulated the levels of MMP‑13 and CTX‑II in IDD rats and NP cells in a dose‑dependent manner. Concurrently, recombinant human (rh)BMP2 pretreatment also significantly decreased the apoptosis ratio of interleukin (IL)‑1β‑treated NP cells via downregulating the level of cleaved caspase‑3 and upregulating the level of uncleaved poly (adenosine 5'‑diphosphate‑ribose) polymerase. It was demonstrated that rhBMP2 also significantly decreased the inflammatory response in NP tissues and cells, based on levels of IL‑6, TNF‑α and IL‑10. In addition, rhBMP2 inhibited cell apoptosis via upregulating the phosphorylation levels of the PI3K/Akt signaling pathway, and LY29400 pretreatment inhibited the effects of BMP2 in IL‑1β treated NP cells. BMP2 alleviated IDD via the PI3K/Akt signaling pathway by inhibiting NP cell apopt

Topics: Animals; Apoptosis; Biomarkers; Bone Morphogenetic Protein 2; Cytokines; Extracellular Matrix; Inflammation; Inflammation Mediators; Intervertebral Disc Degeneration; Male; Nucleus Pulposus; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Rats, Inbred Lew; Recombinant Proteins; Transforming Growth Factor beta

We assessed the roles of Smad7 in skin inflammation and wound healing using genetic and pharmacological approaches. In K5.TGFβ1/K5.Smad7 bigenic (double transgenic) mice, Smad7 transgene expression reversed transforming growth factor (TGF)-β1 transgene-induced inflammation, fibrosis, and subsequent epidermal hyperplasia and molecularly abolished TGF-β and NF-κB activation. Next, we produced recombinant human Smad7 protein with a Tat-tag (Tat-Smad7) that rapidly enters cells. Subcutaneous injection of Tat-Smad7 attenuated infiltration of F4/80

Topics: Animals; Carcinogenesis; Gene Expression Regulation, Neoplastic; Guinea Pigs; Humans; Inflammation; Keratinocytes; Mice; Mice, Transgenic; Neoplasms, Experimental; Phenotype; RNA, Neoplasm; Skin; Skin Neoplasms; Smad7 Protein; Transforming Growth Factor beta; Wound Healing

Tissue inhibitor of metalloproteinase (TIMP)-3 is a natural inhibitor of a range of enzymes that degrade connective tissue and are involved in the pathogenesis of conditions such as arthritis and cancer. We describe here the engineering of TIMP-3 using a novel drug-delivery system known as the 'LAP technology'. This involves creating therapeutic proteins in fusion with the latency-associated peptide (LAP) from the cytokine TGF-? to generate proteins that are biologically inactive until cleavage of the LAP to release the therapy. LAP-TIMP-3 was successfully expressed in mammalian cells and the presence of the LAP resulted in a 14-fold increase in the quantity of recombinant TIMP-3 produced. LAP-TIMP-3 was latent until release from the LAP by treatment with matrix metalloproteinase when it could inhibit proteases of the adamalysins and adamalysins with thrombospondin motifs families, but not matrix metalloproteinases, indicating that this version of TIMP-3 is a more specific inhibitor than the native protein. There was sufficient protease activity in synovial fluid from human joints with osteoarthritis to release TIMP-3 from the LAP fusion. These results demonstrate the potential for development of TIMP-3 as a novel therapy for conditions where upregulation of catabolic enzymes are part of the pathology.

Topics: Aged; Aged, 80 and over; Animals; Cartilage; Cattle; Cytokines; Female; Humans; Inflammation; Male; Middle Aged; Osteoarthritis; Peptides; Protein Precursors; Recombinant Fusion Proteins; Recombinant Proteins; Synovial Fluid; Tissue Inhibitor of Metalloproteinase-3; Transforming Growth Factor beta

Matrix metalloproteinases (MMPs) are a family of endopeptidases collectively able to degrade the components of the extracellular matrix (ECM), with important roles in many biological processes, such as embryogenesis, normal tissue remodelling, angiogenesis and wound healing. New views on the function of MMPs reveal that they regulate inflammatory response and therefore might represent an early step in the evolution of the immune system. MMPs can affect the activity of cytokines involved in inflammation including TGF-β and TNF-α. MMPs are widely distributed in all kingdoms of life and have likely evolved from a single-domain protein which underwent successive rounds of duplications. In this study, we focused on the Ciona robusta (formerly known as Ciona intestinalis) MMP gelatinase homologue. Gene organization, phylogenetic analysis and 3D modeling supported the closest correlation of C. robusta gelatinase with the human MMP-9. Real-time PCR analysis and zymographic assay showed a prompt expression induced by LPS inoculation and an upregulation of enzymatic activity. Furthermore, we showed that before of the well-known increase of TGF-β and TNF-α levels, a MMP-9like boost occurred, suggesting a possible involvement of MMP-9like in regulating inflammatory response in C. robusta.

Topics: Animals; Ciona intestinalis; Gelatinases; Inflammation; Lipopolysaccharides; Matrix Metalloproteinases; Models, Molecular; Phylogeny; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Thymic stromal lymphopoietin (TSLP) mediates immune reaction in patients with asthma. Matrix metalloproteinase (MMP), connective tissue growth factor (CTGF), and transforming growth factor-β (TGF-β) are inflammatory mediators whose responses to the anti-TSLP antibody are unknown. This study examined the effect of an anti-TSLP antibody on MMP, CTGF, TGF-β, and airway structural changes in airway remodeling in asthma.. Mice were randomly divided into phosphate-buffered-saline-challenged (PBS), ovalbumin-challenged (OVA), and ovalbumin-challenged with anti-TSLP antibody (OVA + anti-TSLP) groups. Airway responsiveness and serum ovalbumin-specific immunoglobulin E were measured. Differential cell counts and MMP-2 and MMP-9 were evaluated in bronchoalveolar lavage fluid (BALF). Airway structural changes were quantified using morphometric analysis and presentation by immunohistochemistry staining. Lung CTGF, TGF-β, and TSLP were analyzed using western blot.. Airway responsiveness was significantly lower in OVA + anti-TSLP and PBS groups than in OVA group. Airway structural changes exhibited less smooth muscle thickness in OVA + anti-TSLP and PBS groups than in OVA group. MMP-2 and MMP-9 in BALF and CTGF, TGF-β, and TSLP in lungs significantly decreased in OVA + anti-TSLP and PBS groups compared with OVA group.. Anti-TSLP antibody exerts the preventive effect of decreasing airway structural changes through reduction of MMP, TGF-β, and CTGF in airway remodeling of asthma.

Topics: Airway Remodeling; Animals; Antibodies, Monoclonal; Asthma; Connective Tissue Growth Factor; Cytokines; Disease Models, Animal; Female; Immunoglobulin E; Inflammation; Lung; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Methacholine Chloride; Mice; Mice, Inbred BALB C; Ovalbumin; Plethysmography; Thymic Stromal Lymphopoietin; Transforming Growth Factor beta

To identify single-cell transcriptional signatures of dendritic cells (DCs) that are associated with autoimmunity, and determine whether those DC signatures are correlated with the clinical heterogeneity of autoimmune disease.. Blood-derived DCs were single-cell sorted from the peripheral blood of patients with rheumatoid arthritis, systemic lupus erythematosus, or type 1 diabetes as well as healthy individuals. DCs were analyzed using single-cell gene expression assays, performed immediately after isolation or after in vitro stimulation of the cells. In addition, protein expression was measured using fluorescence-activated cell sorting.. CD1c+ conventional DCs and plasmacytoid DCs from healthy individuals exhibited diverse transcriptional signatures, while the DC transcriptional signatures in patients with autoimmune disease were altered. In particular, distinct DC clusters, characterized by up-regulation of TAP1, IRF7, and IFNAR1, were abundant in patients with systemic autoimmune disease, whereas DCs from patients with type 1 diabetes had decreased expression of the regulatory genes PTPN6, TGFB, and TYROBP. The frequency of CD1c+ conventional DCs that expressed a systemic autoimmune profile directly correlated with the extent of disease activity in patients with rheumatoid arthritis (Spearman's r = 0.60, P = 0.03).. DC transcriptional signatures are altered in patients with autoimmune disease and are associated with the level of disease activity, suggesting that immune cell transcriptional profiling could improve our ability to detect and understand the heterogeneity of these diseases, and could guide treatment choices in patients with a complex autoimmune disease.

Topics: Adaptor Proteins, Signal Transducing; Arthritis, Rheumatoid; ATP Binding Cassette Transporter, Subfamily B, Member 2; Autoimmune Diseases; Case-Control Studies; Dendritic Cells; Diabetes Mellitus, Type 1; Flow Cytometry; Gene Expression Profiling; Humans; Inflammation; Interferon Regulatory Factor-7; Lupus Erythematosus, Systemic; Membrane Proteins; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Receptor, Interferon alpha-beta; Severity of Illness Index; Single-Cell Analysis; Transforming Growth Factor beta; Up-Regulation

Glucocorticosteroids are the most efficacious anti-inflammatory agents and the gold standard treatment in Duchenne muscular dystrophy (DMD). However, their chronic use may lead to severe side effects. We evaluated the use of a novel injectable steroidal nano-drug in mdx mouse model of DMD by comparing the efficacy of nano-liposomes remotely loaded with the steroid prodrug, methylprednisolone hemisuccinate (MPS) with the same steroid as-is, in short (4-weeks) and long-term (58-weeks) treatments. Liposomal-MPS was selectively targeted to the mouse diaphragm, the most dystrophic muscle at early stage of the disease. The bioactivity of the steroidal nano-drug was evidenced by a significant decreased serum TGF-β and reduced diaphragm macrophage infiltration after short-term treatment. In the long-term, the treatment with liposomal-MPS not only demonstrated improved muscle strength and mobility it also induced lower tibia and lumbar vertebrae osteoporosis indicating much lower bone related adverse effects.

Topics: Animals; Creatine Kinase; Disease Models, Animal; Immunohistochemistry; Inflammation; Liposomes; Male; Mice; Mice, Inbred mdx; Muscle Strength; Muscular Dystrophy, Duchenne; Steroids; Transforming Growth Factor beta

In this study, pirfenidone's role about reducing tracheal stenosis by suppressing fibrosis and inflammation was examined.. Tracheotomy was performed on 14 rats, and their cannulas were fixed to tracheotomy area by stoma suture. Two working groups were established. Rats in the first group were given 15 mg/kg/day (1 mL pirfenidone solution) pirfenidone intraperitoneally for 10 days. In the second group as a control group, 1 mL saline solution was applied intraperitoneally. Ten days later, rats were decanulated and kept alive for 3 more weeks. Anesthetized rats were sacrificed on day 30. All rat tracheas were resected between the first and seventh rings. Epithelial damage, inflammation, and fibrosis were determined histopathologically; diameters of intratracheal lumen and their mucosal thickness parameters were determined histomorphometrically; and TGFβ-1 (the growth factor beta), TNFα (tumor necrosis factor alpha), and IL-1β (Interleukin-1 beta) values were determined immunohistochemically.. According to the parameters of the control group, fibrosis; diameters of intratracheal lumen; and values of TGFβ-1, TNFα, and IL-1β were found to be statistically significant.. In our study, it was found that pirfenidone reduces fibrosis and narrowing of intratracheal lumen diameter significantly.. NA Laryngoscope, 129:E178-E186, 2019.

Topics: Animals; Fibrosis; Immunohistochemistry; Inflammation; Interleukin-1beta; Pyridones; Rats; Rats, Sprague-Dawley; Tracheal Stenosis; Tracheotomy; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Renal fibrosis is a key pathological feature and final common pathway leading to end-stage kidney failure in many chronic kidney diseases. Myofibroblast is the master player in renal fibrosis. However, myofibroblasts are heterogeneous. Recent studies show that bone marrow-derived macrophages transform into myofibroblasts by transforming growth factor (TGF)-β-induced macrophage-myofibroblast transition (MMT) in renal fibrosis.. TGF-β signaling was redirected by inhibition of β-catenin/T-cell factor (TCF) to increase β-catenin/Foxo in bone marrow-derived macrophages. A kidney fibrosis model of unilateral ureteral obstruction was performed in EGFP bone marrow chimera mouse. MMT was examined by flow cytometry analysis of GFP+F4/80+α-SMA+ cells from unilateral ureteral obstruction (UUO) kidney, and by immunofluorescent staining of bone marrow-derived macrophages in vitro. Inflammatory and anti-inflammatory cytokines were analysis by enzyme-linked immunosorbent assay.. Inhibition of β-catenin/TCF by ICG-001 combined with TGF-β1 treatment increased β-catenin/Foxo1, reduced the MMT and inflammatory cytokine production by bone marrow-derived macrophages, and thereby, reduced kidney fibrosis in the UUO model.. Our results demonstrate that diversion of β-catenin from TCF to Foxo1-mediated transcription not only inhibits the β-catenin/TCF-mediated fibrotic effect of TGF-β, but also enhances its anti-inflammatory action, allowing therapeutic use of TGF-β to reduce both inflammation and fibrosis at least partially by changing the fate of bone marrow-derived macrophages.

Topics: Animals; Anti-Inflammatory Agents; beta Catenin; Cytokines; Disease Models, Animal; Fibrosis; Inflammation; Kidney; Macrophages; Male; Mice; Mice, Inbred C57BL; Signal Transduction; Transforming Growth Factor beta; Ureteral Obstruction

Elevated plasma homocysteine (Hcy) concentration is considered as the diagnostic criteria of Hyperhomocysteinemia (HHcy), which is associated with the inflammatory response and blood-brain barrier disruption. Previous studies have proposed that HHcy with hypertension was associated with the brain injury by enhancing the cerebrovascular permeability, however, the immune mechanism remains obscure. The purpose of the study is to explore the immunomodulatory mechanism of brain injury in spontaneously hypertensive rats (SHRs) induced by HHcy.. Sixty SHRs were randomly assigned to three groups: SHR-C (control group), SHR-M (methionine group) and SHR-T (treatment group). Physical examination of body weight, systolic blood pressure (SBP) and plasma Hcy content was measured every 4 weeks. Besides, T-helper cell 17 and regulatory T cells (Treg)-related inflammatory cytokines (interleukin [IL]-6, IL-17, IL-10, and transforming growth factor beta [TGF-β]) and genes (RORγt and FoxP3) were detected by enzyme-linked immunosorbent assay, quantitative polymerase chain reaction , Western blot, and immunohistochemistry.. High methionine diet could cause weight loss, SBP rising, and plasma Hcy content significantly elevated. IL-16 and IL-17A levels in peripheral blood and in brain tissue both lifted, while IL-10 and TGF-β levels dropped; RORγt expression raised in brain, nevertheless, FoxP3 levels were the opposite. After the intervention with vitamin B6, B12, and folic acid in SHR-T group, these trends would be eased or completely changed. Furthermore, brain tissue slices showed that IL-17-positive cells tended to decrease, and IL-10-positive cells increased in SHR-T group, which was reversed in SHR-M group.. HHcy may promote inflammation that can lead to brain lesions and down-regulate immune response to protect the brain.

Topics: Animals; Blood-Brain Barrier; Brain Injuries; Forkhead Transcription Factors; Homocysteine; Humans; Hyperhomocysteinemia; Immunomodulation; Inflammation; Interleukin-10; Interleukin-17; Interleukin-6; Methionine; Nuclear Receptor Subfamily 1, Group F, Member 3; Rats; Rats, Inbred SHR; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Malignant mesothelioma is an aggressive fibrous tumor, predominantly of the pleura, with a very poor prognosis. Cell-matrix interactions are recognized important determinants of tumor growth and invasiveness but the role of the extracellular matrix in mesothelioma is unknown. Mesothelioma cells synthesize collagen as well as transforming growth factor-beta (TGF-β), a key regulator of collagen production. This study examined the effect of inhibiting collagen production on mesothelioma cell proliferation in vitro and tumor growth in vivo. Collagen production by mesothelioma cells was inhibited by incubating cells in vitro with the proline analogue thiaproline (thiazolidine-4-carboxylic acid) or by oral administration of thiaproline in a murine tumor model. Cell cytotoxicity was measured using neutral red uptake and lactate dehydrogenase assays. Proliferation was measured by tritiated thymidine incorporation, and inflammatory cell influx, proliferation, apoptosis and angiogenesis in tumors examined by immunohistochemical labelling. Tumor size was determined by tumor weight and collagen production was measured by HPLC. Thiaproline at non-toxic doses significantly reduced basal and TGF-β-induced collagen production by over 50% and cell proliferation by over 65%. In vivo thiaproline administration inhibited tumor growth at 10 days, decreasing the median tumor weight by 80%. The mean concentration of collagen was 50% lower in the thiaproline-treated tumors compared with the controls. There were no significant differences in vasculature or inflammatory cell infiltration but apoptosis was increased in thiaproline treated tumors at day 10. In conclusion, these observations strongly support a role for collagen in mesothelioma growth and establish the potential for inhibitors of collagen synthesis in mesothelioma treatment.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Collagen; Disease Models, Animal; Extracellular Matrix; Female; Humans; Inflammation; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Mice; Mice, Inbred CBA; Pleural Neoplasms; Thiazolidines; Transforming Growth Factor beta

Topics: Acute Kidney Injury; Animals; Animals, Newborn; Antioxidants; Body Weight; Cell Proliferation; Disease Models, Animal; Female; Glomerular Filtration Rate; Hyperoxia; Inflammation; Interleukin-6; Kidney Cortex; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Organ Size; Oxygen; Regeneration; Smad2 Protein; STAT3 Transcription Factor; Transforming Growth Factor beta

Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been widely used in spine fusion surgery. However, high doses of rhBMP-2 delivered with absorbable collagen sponge (ACS) have led to inflammation-related adverse conditions. Polyelectrolyte complex (PEC) control release carrier can substantially reduce the rhBMP-2 dose and complication without compromising fusion. The molecular events underlying controlled release and their effects on spinal fusion remain unknown. In this study, a rabbit interbody spinal fusion chamber was designed to provide a controlled environment for profiling molecular events during the fusion process. Study groups included Group 1, PEC with 100 μg rhBMP-2; Group 2, ACS with 100 μg rhBMP-2; Group 3, ACS with 300 μg rhBMP-2; Group 4, autologous bone graft; and Group 5, empty chamber. Manual palpation, microcomputed tomography, and histological analysis showed that Group 1 and 3 achieved bone fusion, while the other groups showed no signs of fusion. Gene expression profiling showed robust induction of osteogenic markers in Groups 1 and 3, with modulated early induction of inflammatory genes in the PEC group. Delivery of 100 μg rhBMP-2 with ACS (Group 2) resulted in less upregulation of osteogenic genes, increased inflammatory genes expression, and upregulation of osteoclastic genes compared to Group 1. These results suggest that the manner of BMP-2 release at the interbody spinal defect site could dictate the balance of

Topics: Animals; Biomarkers; Bone Morphogenetic Protein 2; Bone Regeneration; Delayed-Action Preparations; Gene Expression Regulation; Humans; Implants, Experimental; Inflammation; Osteoclasts; Osteogenesis; Polyelectrolytes; Rabbits; Recombinant Proteins; Seroma; Spinal Cord; Spinal Fusion; Transforming Growth Factor beta; X-Ray Microtomography

Mutations in extracellular matrix and smooth muscle cell contractile proteins predispose to thoracic aortic aneurysms in Marfan syndrome (MFS) and related disorders. These genetic alterations lead to a compromised extracellular matrix-smooth muscle cell contractile unit. The abnormal aortic tissue responds with defective mechanosensing under hemodynamic stress. Aberrant mechanosensing is associated with transforming growth factor-beta (TGF-β) hyperactivity, enhanced angiotensin-II (Ang-II) signaling, and perturbation of other cellular signaling pathways. The downstream consequences include enhanced proteolytic activity, expression of inflammatory cytokines and chemokines, infiltration of inflammatory cells in the aortic wall, vascular smooth muscle cell apoptosis, and medial degeneration. Mouse models highlight aortic inflammation as a contributing factor in the development of aortic aneurysms. Anti-inflammatory drugs and antioxidants can reduce aortic oxidative stress that prevents aggravation of aortic disease in MFS mice. Targeting TGF-β and Ang-II downstream signaling pathways such as ERK1/2, mTOR, PI3/Akt, P38/MAPK, and Rho kinase signaling attenuates disease pathogenesis. Aortic extracellular matrix degradation and medial degeneration were reduced upon inhibition of inflammatory cytokines and matrix metalloproteinases, but the latter lack specificity. Treating inflammation associated with aortic aneurysms in MFS and related disorders could prove to be beneficial in limiting disease pathogenesis.

Topics: Animals; Aortic Aneurysm, Thoracic; Inflammation; Marfan Syndrome; Mice; Transforming Growth Factor beta

Osteoarthritis (OA) is a conversant joint disease, which seriously threatens the health of the elderly, and even leads to disability. Long non-coding RNA-activated by transforming growth factor beta (lncRNA-ATB) has been reported in diverse cancers. However, the functions of lncRNA-ATB in OA remain uninvestigated. The current study aimed to explore the impacts of lncRNA-ATB on lipopolysaccharide (LPS)-induced inflammatory injury in ATDC5 cells and to uncover the underlying mechanism. LPS-induced ATDC5 cell injury model was constructed, and the effects of lncRNA-ATB on LPS-injured cells were explored via analyzing cell viability, apoptosis, iNOS, COX-2, and inflammatory cytokines (IL-6 and TNF-α). Subsequently, the relationship between lncRNA-ATB and microRNA (miR)-223 was detected, and whether miR-223 was involved in modulating LPS-induced cells injury in ATDC5 cells was investigated. Finally, MyD88/NF-κB and p38MAPK pathways were assessed to explore the underlying mechanism. Results showed that LPS repressed cell viability, induced apoptosis, and promoted iNOS, COX-2, IL-6 and TNF-α expression. Additionally, we observed that lncRNA-ATB expression was down-regulated in LPS-injured cells, and lncRNA-ATB overexpression significantly alleviated LPS-induced inflammatory injury in ATDC5 cells. Interesting results revealed that miR-223 expression was down-regulated by lncRNA-ATB and miR-223 overexpression declined the protective effect of lncRNA-ATB on LPS-injured ATDC5 cells. Further, the signaling pathway experiments showed that lncRNA-ATB inhibited MyD88/NF-κB and p38MAPK pathways by down-regulating miR-223 in LPS-injured cells. These data demonstrated that lncRNA-ATB protected ATDC5 cells against LPS-induced inflammatory injury by repressing MyD88/NF-κB and p38MAPK pathways, which was mediated by down-regulation of miR-223.

Topics: Aged; Animals; Anti-Inflammatory Agents; Apoptosis; Cell Line; Chondrocytes; Cyclooxygenase 2; Disease Models, Animal; Humans; Inflammation; Interleukin-6; Lipopolysaccharides; Mice; MicroRNAs; Nitric Oxide Synthase Type II; Osteoarthritis; RNA, Long Noncoding; Signal Transduction; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Pulmonary hypertension (PH) is a life-threatening lung disease. PH with concomitant lung diseases, e.g., idiopathic pulmonary fibrosis, is associated with poor prognosis. Development of novel therapeutic vasodilators for treatment of these patients is a key imperative. We evaluated the efficacy of dual activation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) using an active, small-molecule phosphodiesterase (PDE4)/PDE5 dual inhibitor (Compound A). Compound A increased both cAMP and cGMP levels in WI-38 lung fibroblasts and suppressed the expressions of type-1 collagen α1 chain and fibronectin. Additionally, compound A reduced right ventricular weight/left ventricular weight+septal weight ratio, brain natriuretic peptide expression levels in right ventricle, C─C motif chemokine ligand 2 expression levels in lung, and plasma surfactant protein D. Our data indicate that dual activation of cAMP/cGMP pathways may be a novel treatment strategy for PH.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cells, Cultured; Collagen Type I; Collagen Type I, alpha 1 Chain; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Epithelium; Fibronectins; Gene Expression Regulation; Humans; Hypertension, Pulmonary; Inflammation; Lung; Monocrotaline; Phosphodiesterase 5 Inhibitors; Rats, Wistar; Transforming Growth Factor beta

This study aims to explore the roles of miR-145/TGFBR2 axis in sepsis-induced acute lung injury. Here, RNA-sequencing assay showed that miR-145 was significantly decreased in exosomes from sepsis patient blood samples. And miR-145 was decreased but TGFBR2 was increased in LPS-treated mice lung tissues or BEAS-2B cells in a time-dependent manner. Mechanistically, TGFBR2 was identified as a direct target of miR-145 and the downstream effector Smad3 was also suppressed in BEAS-2B cells with miR-145 overexpression. Pre-injection or post-injection of miR-145 agomir following LPS treatment attenuated LPS-induced inflammation, characterized as the downregulation of IL-2 and TNF-α secretion and ameliorate sepsis, and prolonged the overall survival of septic mice with lung injury. Additionally, TGFBR2 overexpression partially abrogated miR-145-mediated inhibition on LPS-induced inflammation and sepsis-induced acute lung injury. Importantly, TGF-β (Transforming growth factor-β) and miR-145 level displayed a negative correlation in sepsis patients. Thus, these results suggest that miR-145 could ameliorate sepsis-induced lung injury via inhibiting TGFBR2 signaling.

Topics: Acute Lung Injury; Animals; Cell Line; Down-Regulation; Humans; Inflammation; Interleukin-2; Mice; MicroRNAs; Receptor, Transforming Growth Factor-beta Type II; Sepsis; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

Topics: Animals; Blood Glucose; Chemokine CCL2; Collagen Type IV; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dianthus; Disease Models, Animal; Fibrosis; Humans; Inflammation; Insulin; Insulin Resistance; Intercellular Adhesion Molecule-1; Kidney; Mesangial Cells; Mice; Phytotherapy; Plant Extracts; Protective Agents; Signal Transduction; Transforming Growth Factor beta

There is a major unmet clinical need to identify pathways in inflammatory bowel disease (IBD) to classify patient disease activity, stratify patients that will benefit from targeted therapies such as anti-tumor necrosis factor (TNF), and identify new therapeutic targets. In this study, we conducted global transcriptome analysis to identify IBD-related pathways using colon biopsies, which highlighted the coagulation gene pathway as one of the most enriched gene sets in patients with IBD. Using this gene-network analysis across 14 independent cohorts and 1800 intestinal biopsies, we found that, among the coagulation pathway genes, plasminogen activator inhibitor-1 (PAI-1) expression was highly enriched in active disease and in patients with IBD who did not respond to anti-TNF biologic therapy and that PAI-1 is a key link between the epithelium and inflammation. Functionally, PAI-1 and its direct target, the fibrinolytic protease tissue plasminogen activator (tPA), played an important role in regulating intestinal inflammation. Intestinal epithelial cells produced tPA, which was protective against chemical and mechanical-mediated colonic injury in mice. In contrast, PAI-1 exacerbated mucosal damage by blocking tPA-mediated cleavage and activation of anti-inflammatory TGF-β, whereas the inhibition of PAI-1 reduced both mucosal damage and inflammation. This study identifies an immune-coagulation gene axis in IBD where elevated PAI-1 may contribute to more aggressive disease.

Topics: Animals; Biological Factors; Blood Coagulation; Cell Proliferation; Citrobacter; Colitis; Colon; Cytokines; Inflammation; Inflammatory Bowel Diseases; Interleukin-17; Intestinal Mucosa; Mice; Plasminogen Activator Inhibitor 1; Severity of Illness Index; Small Molecule Libraries; Th17 Cells; Tissue Plasminogen Activator; Transcription, Genetic; Transforming Growth Factor beta

The hypoglycemic drugs dipeptidyl peptidase-4 (DPP-4) inhibitors have proven protective effects on diabetic kidney disease, including renal fibrosis. Although NOD-like receptor protein 3 (NLRP3) inflammasome activation is known to play an important role in the progression of renal fibrosis, the impact of DPP-4 inhibition on NLRP3-mediated inflammation while ameliorating renal fibrosis has not been fully elucidated. Here, we report that the renoprotective effect of gemigliptin is associated with a reduction in NLRP3-mediated inflammation in a murine model of renal fibrosis.. We examined the effects of gemigliptin on renal tubulointerstitial fibrosis induced in mice by unilateral ureteral obstruction (UUO). Using immunohistochemical and Western blot analysis, we quantitated components of the NLRP3 inflammasome in kidneys with and without gemigliptin treatment, and. Immunohistological examination revealed that gemigliptin ameliorated UUO-induced tubular atrophy and renal fibrosis. Gemigliptin-treated kidneys showed a reduction in levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and interleukin-1β, which had all been markedly increased by UUO. In line with the. The present study shows that activation of the NLRP3 inflammasome contributes to UUO-induced renal fibrosis and the renoprotective effect of gemigliptin is associated with attenuation of NLRP3 inflammasome activation.

Topics: Administration, Oral; Animals; Cell Line; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Down-Regulation; Fibrosis; Humans; Inflammasomes; Inflammation; Kidney Tubules, Proximal; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Piperidones; Protective Agents; Pyrimidines; Signal Transduction; Transforming Growth Factor beta; Ureteral Obstruction

Nε-(carboxymethyl)lysine (CML), which is a compound produced when food is processed, has aroused concern in recent years because of its potentially dangerous effects. This study aimed to investigate the mechanism of free CML-induced toxic injury in mice. The inflammatory cytokine tumor necrosis factor-α, transforming growth factor-β, vascular cell adhesion molecule-1 mRNA expression levels of CML-infected mice liver and kidney tissues significantly increased. While CML receptor-receptor for advanced glycation end products (RAGE) protein expression in male mice liver tissue had a more significant change than the control group, there was no significant difference in other dose groups compared with the control group. In conclusion, the foodborne free CML can be induced by oxidative stress and immune response to liver and kidney tissue injury in mice. Additionally, the free CML may also bind to RAGE, which activates the downstream inflammatory pathway.

Topics: Animals; Female; Inflammation; Kidney; Liver; Lysine; Male; Mice; Oxidative Stress; Receptor for Advanced Glycation End Products; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Diabetic nephropathy (DN) is an important factor leading to end-stage kidney disease that affects diabetes mellitus patients globally. Our previous transcriptome sequencing has identified a large group of differentially expressed long noncoding RNA (lncRNA) in early development of DN. On basis of this, we aimed to investigate the function of lncRNA NONHSAG053901 in DN pathogenesis. In this study, we revealed that the expression of NONHSAG053901 was drastically elevated in both DN mouse model and mesangial cells (MCs). It was found that overexpression of NONHSAG053901 remarkably promoted inflammation, fibrosis and proliferation in MCs. Consistently, further investigations suggested that the stimulation of NONHSAG053901 on proinflammatory cytokines via direct binding to early growth response protein 1 (Egr-1). Interaction between Egr-1 and transforming growth factor β (TGF-β) could augment TGF-β function in DN inflammation. Furthermore, the effects of NONHSAG053901 on stimulation of proinflammatory cytokines were abolished by knockdown of Egr-1. These results together suggested that NONHSAG053901 promoted proinflammatory cytokines via stimulating Egr-1/TGF-β mediated renal inflammation.

Topics: Animals; Cell Proliferation; Cytokines; Diabetic Nephropathies; Disease Models, Animal; Early Growth Response Protein 1; Female; Fibrosis; Gene Expression Regulation; Inflammation; Inflammation Mediators; Kidney; Mesangial Cells; Mice; Protein Binding; RNA, Long Noncoding; Streptozocin; Transforming Growth Factor beta

Diabetic individuals are at considerable risk for invasive infection by Staphylococcus aureus, however, the mechanisms underlying this enhanced susceptibility to infection are unclear. We observed increased mortality following i.v. S. aureus infection in diabetic mice compared with nondiabetic controls, correlating with increased numbers of low-density neutrophils (LDNs) and neutrophil extracellular traps (NETs). LDNs have been implicated in the inflammatory pathology of diseases such as lupus, given their release of large amounts of NETs. Our goal was to describe what drives LDN increases during S. aureus infection in the diabetic host and mechanisms that promote increased NET production by LDNs. LDN development is dependent on TGF-β, which we found to be more activated in the diabetic host. Neutralization of TGF-β, or the TGF-β-activating integrin αvβ8, reduced LDN numbers and improved survival during S. aureus infection. Targeting S. aureus directly with MEDI4893*, an α toxin-neutralizing monoclonal antibody, blocked TGF-β activation, reduced LDNs and NETs, and significantly improved survival. A comparison of gene and protein expression in high-density neutrophils and LDNs identified increased GPCRs and elevated phosphatase and tensin homolog (PTEN) in the LDN subset. Inhibition of PTEN improved the survival of infected diabetic mice. Our data identify a population of neutrophils in infected diabetic mice that correlated with decreased survival and increased NET production and describe 3 therapeutic targets, a bacterial target and 2 host proteins, that prevented NET production and improved survival.

Topics: Animals; Antibodies, Monoclonal, Humanized; Broadly Neutralizing Antibodies; Cell Separation; Diabetes Mellitus, Experimental; Disease Models, Animal; Extracellular Traps; Female; Flow Cytometry; Immunoglobulin G; Inflammation; Integrins; Mice; Mice, Inbred C57BL; Mice, Obese; Neutrophils; Risk Factors; Signal Transduction; Staphylococcal Infections; Staphylococcus aureus; Streptozocin; Transforming Growth Factor beta

Renal interstitial fibrosis is a common pathological feature in progressive kidney diseases currently lacking effective treatment. Nicotinamide (NAM), a member of water-soluble vitamin B family, was recently suggested to have a therapeutic potential for acute kidney injury (AKI) in mice and humans. The effect of NAM on chronic kidney pathologies, including renal fibrosis, is unknown. Here we have tested the effects of NAM on renal interstitial fibrosis using in vivo and in vitro models. In vivo, unilateral urethral obstruction (UUO) induced renal interstitial fibrosis as indicated Masson trichrome staining and expression of pro-fibrotic proteins, which was inhibited by NAM. In UUO, NAM suppressed tubular atrophy and apoptosis. In addition, NAM suppressed UUO-associated T cell and macrophage infiltration and induction of pro-inflammatory cytokines, such as TNF-α and IL-1β. In cultured mouse proximal tubule cells, NAM blocked TGF-β-induced expression of fibrotic proteins, while it marginally suppressed the morphological changes induced by TGF-β. NAM also suppressed the expression of pro-inflammatory cytokines (eg MCP-1 and IL-1β) during TGF-β treatment of these cells. Collectively, the results demonstrate an anti-fibrotic effect of NAM in kidneys, which may involve the suppression of tubular injury and inflammation.

Topics: Animals; Apoptosis; Cell Line; Chemokine CCL2; Disease Models, Animal; Fibrosis; Inflammation; Interleukin-1beta; Kidney; Kidney Diseases; Kidney Tubules, Proximal; Macrophages; Male; Mice; Mice, Inbred C57BL; Niacinamide; T-Lymphocytes; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Ureteral Obstruction

We examined the effects of tadalafil, one of the phosphodiesterase type 5 (PDE5) inhibitors, in a rat model of with partial and complete unilateral ureteral obstruction (UUO).. The rats were divided into 5 groups: sham (n=6), partial unilateral ureteral obstruction (PUUO, n=6), PUUO with tadalafil treatment (PUUO+T; Cialis, 10 mg/72 h, intragastric; Lilly, Indianapolis, Indiana, USA), complete unilateral ureteral obstruction (CUUO, n=6), and CUUO with tadalafil treatment (CUUO+T).. Fifteen days after the UUO, the ureter presented changes in the layers of urothelium and significant infiltration of inflammatory cells in the PUUO and CUUO groups. Compared with the sham, PUUO and CUUO groups had severe increased inflammatory cell infiltration. The urothelial epithelium exhibited cell degeneration and loss because of the swollen, atrophic, and denuded epithelial cells in the PUUO and CUUO groups. In the PUUO+T and CUUO+T groups, the urothelium revealed less epithelial cell degeneration and loss.The expressions of α-smooth muscle actin (α-SMA) and transforming growth factor-β (TGF-β) exhibited up-regulation in the PUUO and CUUO groups. The expression of TGF-β decreased positively correlated with that of α-SMA in the tadalafil therapy groups, PUUO+T and CUUO+T.. The phosphodiesterase type 5 inhibitor's tadalafil reduced expressions of α-SMA and TGF-β in the obstructed ureters, measured by biochemical examinations. In addition, tadalafil decreased urothelium degeneration due to the decreased epithelial cell loss and inflammatory cell infiltration. Our results show that tadalafil prevents or slows down the onset of ureter inflammation and urothelial degeneration in rats with UUO.

Topics: Actins; Animals; Enzyme-Linked Immunosorbent Assay; Inflammation; Male; Phosphodiesterase 5 Inhibitors; Rats, Sprague-Dawley; Reference Values; Reproducibility of Results; Tadalafil; Transforming Growth Factor beta; Up-Regulation; Ureter; Ureteral Obstruction

Interference with autoimmune-mediated cytokine production is a key yet poorly developed approach to treat autoimmune and inflammatory diseases such as rheumatoid arthritis. Herein, we show that soluble CD83 (sCD83) enhances the resolution of autoimmune antigen-induced arthritis (AIA) by strongly reducing the expression levels of cytokines such as IL-17A, IFNγ, IL-6, and TNFα within the joints. Noteworthy, also the expression of RANKL, osteoclast differentiation, and joint destruction was significantly inhibited by sCD83. In addition, osteoclasts which were cultured in the presence of synovial T cells, derived from sCD83 treated AIA mice, showed a strongly reduced number of multinuclear large osteoclasts compared to mock controls. Enhanced resolution of arthritis by sCD83 was mechanistically based on IDO, since inhibition of IDO by 1-methyltryptophan completely abrogated sCD83 effects on AIA. Blocking experiments, using anti-TGF-β antibodies further revealed that also TGF-β is mechanistically involved in the sCD83 induced reduction of bone destruction and cartilage damage as well as enhanced resolution of inflammation. Resolution of arthritis was associated with increased numbers of regulatory T cells, which are induced in a sCD83-IDO-TGF-β dependent manner. Taken together, sCD83 represents an interesting approach for downregulating cytokine production, inducing regulatory T cells and inducing resolution of autoimmune arthritis.

Topics: Animals; Antibodies, Blocking; Antigens, CD; Arthritis, Experimental; CD83 Antigen; Cytokines; Female; Immunoglobulins; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inflammation; Joints; Membrane Glycoproteins; Mice; Signal Transduction; Solubility; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tryptophan

Topics: Animals; Dendritic Cells; Disease Models, Animal; Female; Forkhead Transcription Factors; Inflammation; Interleukin-10; Macrophages; Mice; Mice, Inbred C57BL; Th1 Cells; Th2 Cells; Transforming Growth Factor beta; Trichinella spiralis

Abnormal joint instability contributes to cartilage damage and osteophyte formation. We investigated whether controlling joint instability inhibited chronic synovial membrane inflammation and delayed osteophyte formation and examined the role of transforming growth factor-beta (TGF-β) signaling in the associated mechanism.. Rats (n = 94) underwent anterior cruciate ligament (ACL) transection. Anterior tibial instability was either controlled (CAM group) or allowed to continue (SHAM group). At 2, 4, and 8 weeks after surgery, radiologic, histopathologic, immunohistochemical, immunofluorescent, and enzyme-linked immunosorbent assay examinations were performed to evaluate osteophyte formation and TGF-β signaling.. Joint instability increased cartilage degeneration score and osteophyte formation, and cell hyperplasia and proliferation and synovial thickening were observed in the synovial membrane. Major findings were increased TGF-β expression and Smad2/3 following TGF-β phosphorylation in synovial membarene, articular cartilage, and the posterior tibial growth plate (TGF-β expression using ELISA: 4 weeks; P = 0.009, 95% CI [260.1-1340.0]) (p-Smad2/3 expression density: 4 weeks; P = 0.024, 95% CI [1.67-18.27], 8 weeks; P = 0.034, 95% CI [1.25-25.34]). However, bone morphogenetic protein (BMP)-2 and Smad1/5/8 levels were not difference between the SHAM model and the CAM model.. This study showed that the difference between anterior tibial instability caused a change in the expression level of TGF in the posterior tibia and synovial membrane, and the reaction might be consequently involved in osteophyte formation.

Topics: Animals; Anterior Cruciate Ligament Injuries; Bone Morphogenetic Protein 2; Cartilage, Articular; Cell Proliferation; Growth Plate; Inflammation; Joint Instability; Knee Joint; Models, Animal; Osteophyte; Phosphorylation; Random Allocation; Rats, Wistar; Smad2 Protein; Smad3 Protein; Suture Techniques; Synovial Membrane; Transforming Growth Factor beta

Chemerin is an adipocytokine that participates in glycolipid metabolism; however, its association with type 2 diabetes (T2DM) with lower extremity macroangiopathy (T2DM-V) has rarely been reported. This study explored the association of chemerin and inflammatory factors with body fat parameters, glucolipid metabolism, and insulin resistance (IR) in T2DM and T2DM-V. Patients were classified into normal glucose regulation (NGR), T2DM, and T2DM-V groups. Serum chemerin, glucolipid metabolic parameters, transforming growth factor (TGF)-β, interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, and fasting insulin levels were measured along with HOMA-IR, body mass index (BMI), and waist-to-stature ratio (WSR). Serum chemerin, TGF-β, IL-6, and MCP-1 levels were significantly higher in T2DM groups than in NGR group, and BMI, WSR, fasting plasma glucose (FPG), 2hPG, glycated hemoglobin (HbA1c), triglycerides (TG), and HOMA-IR were higher in T2DM-V subgroups with moderate or severe lower extremity macroangiopathy than in NGR group, simple T2DM group, and T2DM-V subgroup with mild macroangiopathy. FPG, 2hPG, HbA1c, TG, and HOMA-IR were higher in T2DM-V subgroup with severe macroangiopathy than in T2DM-V with moderate macroangiopathy (p < 0.05). In all groups, serum chemerin levels were positively correlated with BMI, WSR, FPG, 2hPG, HbA1c, fasting insulin, aspartate transaminase, TG, TGF-β, IL-6, and HOMA-IR (p < 0.05) and negatively correlated with high-density lipoprotein cholesterol [HDL-c] (p < 0.05). Multiple stepwise regression analysis showed that 2hPG, HbA1c, and HDL-c were independent predictors of serum chemerin levels (β = -0.768, -0.122, -0.115, and 3.261, respectively; p < 0.01). Collectively, chemerin, factors associated with obesity, pathological and physiological changes in glucolipid metabolism, and inflammatory factors may promote the development of T2DM macroangiopathy.

Topics: Adult; Aged; Blood Glucose; Body Height; Body Mass Index; Chemokine CCL2; Chemokines; Cholesterol, HDL; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Glucose Tolerance Test; Glycated Hemoglobin; Glycolipids; Humans; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Male; Middle Aged; Obesity; Regression Analysis; Transforming Growth Factor beta; Triglycerides; Waist-Height Ratio

Mycobacterium tuberculosis (Mtb)-derived components are usually recognized by pattern recognition receptors to initiate a cascade of innate immune responses. One striking characteristic of Mtb is their utilization of different type VII secretion systems to secrete numerous proteins across their hydrophobic and highly impermeable cell walls, but whether and how these Mtb-secreted proteins are sensed by host immune system remains largely unknown. Here, we report that MPT53 (Rv2878c), a secreted disulfide-bond-forming-like protein of Mtb, directly interacts with TGF-β-activated kinase 1 (TAK1) and activates TAK1 in a TLR2- or MyD88-independent manner. MPT53 induces disulfide bond formation at C

Topics: Animals; Antigens, Bacterial; Bacterial Proteins; Cytokines; Female; HEK293 Cells; Humans; Immunity, Innate; Inflammation; Lung; MAP Kinase Kinase Kinases; Mice; Mice, Inbred C57BL; Mice, Knockout; Mycobacterium tuberculosis; Myeloid Differentiation Factor 88; Oxidation-Reduction; Signal Transduction; Toll-Like Receptor 2; Transforming Growth Factor beta; Tuberculosis; Type VII Secretion Systems

Topics: Animals; Anti-Bacterial Agents; Bone Morphogenetic Protein 2; Bone Regeneration; Drug Delivery Systems; Hydrogels; Inflammation; Lysostaphin; Male; Mice; Mice, Inbred C57BL; Orthopedic Procedures; Prostheses and Implants; Recombinant Proteins; Staphylococcal Infections; Staphylococcus aureus; Transforming Growth Factor beta

Acute liver failure is a serious consequence of acetaminophen (APAP)-induced hepatotoxic liver injury with high rates of morbidity and mortality. Transforming growth factor beta 1 (TGFβ1) is elevated during liver injury and influences hepatocyte senescence during APAP-induced hepatotoxicity. This study investigated TGFβ1 signaling in the context of inflammation, necrotic cell death, and oxidative stress during APAP-induced liver injury. Male C57Bl/6 mice were injected with 600 mg/kg APAP to generate liver injury in the presence or absence of the TGFβ receptor 1 inhibitor, GW788388, 1 h prior to APAP administration. Acetaminophen-induced liver injury was characterized using histological and biochemical measures. Transforming growth factor beta 1 expression and signal transduction were assessed using immunohistochemistry, Western blotting and ELISA assays. Hepatic necrosis, liver injury, cell proliferation, hepatic inflammation, and oxidative stress were assessed in all mice. Acetaminophen administration significantly induced necrosis and elevated serum transaminases compared with control mice. Transforming growth factor beta 1 staining was observed in and around areas of necrosis with phosphorylation of SMAD3 observed in hepatocytes neighboring necrotic areas in APAP-treated mice. Pretreatment with GW788388 prior to APAP administration in mice reduced hepatocyte cell death and stimulated regeneration. Phosphorylation of SMAD3 was reduced in APAP mice pretreated with GW788388 and this correlated with reduced hepatic cytokine production and oxidative stress. These results support that TGFβ1 signaling plays a significant role in APAP-induced liver injury by influencing necrotic cell death, inflammation, oxidative stress, and hepatocyte regeneration. In conclusion, targeting TGFβ1 or downstream signaling may be a possible therapeutic target for the management of APAP-induced liver injury.

Topics: Acetaminophen; Animals; Antioxidants; Apoptosis; Benzamides; Cell Death; Chemical and Drug Induced Liver Injury; Glutathione; Hepatocytes; Inflammation; JNK Mitogen-Activated Protein Kinases; Liver; Liver Failure, Acute; Male; Mice; Mice, Inbred C57BL; Necrosis; Oxidative Stress; Phosphorylation; Protective Agents; Pyrazoles; Regeneration; Signal Transduction; Transforming Growth Factor beta

Topics: Adult; Aged; Blood Chemical Analysis; Body Mass Index; Clusterin; Female; Humans; Inflammation; Limit of Detection; Male; Middle Aged; Time Factors; Transforming Growth Factor beta; Waist Circumference

Resistance to immunotherapy is one of the biggest problems of current oncotherapeutics. WhileT cell abundance is essential for tumor responsiveness to immunotherapy, factors that define the T cell inflamed tumor microenvironment are not fully understood. We conducted an unbiased approach to identify tumor-intrinsic mechanisms shaping the immune tumor microenvironment(TME), focusing on pancreatic adenocarcinoma because it is refractory to immunotherapy and excludes T cells from the TME. From human tumors, we identified EPHA2 as a candidate tumor intrinsic driver of immunosuppression. Epha2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy. We found that PTGS2, the gene encoding cyclooxygenase-2, lies downstream of EPHA2 signaling through TGFβ and is associated with poor patient survival. Ptgs2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy; pharmacological inhibition of PTGS2 was similarly effective. Thus, EPHA2-PTGS2 signaling in tumor cells regulates tumor immune phenotypes; blockade may represent a novel therapeutic avenue for immunotherapy-refractory cancers. Our findings warrant clinical trials testing the effectiveness of therapies combining EPHA2-TGFβ-PTGS2 pathway inhibitors with anti-tumor immunotherapy, and may change the treatment of notoriously therapy-resistant pancreatic adenocarcinoma.

Topics: Adenocarcinoma; Animals; CD8-Positive T-Lymphocytes; Cell Line; Cyclooxygenase 2; Ephrin-A2; Female; Gene Deletion; Humans; Immunosuppression Therapy; Immunotherapy; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Pancreatic Neoplasms; Receptor, EphA2; Transforming Growth Factor beta

We have previously shown that endoplasmic reticulum stress (ER stress) represses the PTEN inducible kinase 1 (PINK1) in lung type II alveolar epithelial cells (AECII) reducing mitophagy and increasing the susceptibility to lung fibrosis. Although increased circulating mitochondrial DNA (mtDNA) has been reported in chronic lung diseases, the contribution of mitophagy in the modulation of mitochondrial DAMP release and activation of profibrotic responses is unknown. In this study, we show that ER stress and PINK1 deficiency in AECII led to mitochondrial stress with significant oxidation and damage of mtDNA and subsequent extracellular release. Extracellular mtDNA was recognized by TLR9 in AECII by an endocytic-dependent pathway. PINK1 deficiency-dependent mtDNA release promoted activation of TLR9 and triggered secretion of the profibrotic factor TGF-β which was rescued by PINK1 overexpression. Enhanced mtDNA oxidation and damage were found in aging and IPF human lungs and, in concordance, levels of circulating mtDNA were significantly elevated in plasma and bronchoalveolar lavage (BAL) from patients with IPF. Free mtDNA was found elevated in other ILDs with low expression of PINK1 including hypersensitivity pneumonitis and autoimmune interstitial lung diseases. These results support a role for PINK1 mediated mitophagy in the attenuation of mitochondrial damage associated molecular patterns (DAMP) release and control of TGF-β mediated profibrotic responses.

Topics: A549 Cells; Adult; Aged; Aged, 80 and over; Alveolar Epithelial Cells; Animals; Bronchoalveolar Lavage Fluid; Cytokines; Disease Progression; DNA, Mitochondrial; Female; Fibroblasts; Humans; Idiopathic Pulmonary Fibrosis; Inflammation; Lung; Male; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Models, Biological; Oxidation-Reduction; Protein Kinases; Toll-Like Receptor 9; Transforming Growth Factor beta; Young Adult

Obstructive nephropathy is the end result of a variety of diseases that block drainage from the kidney(s). Transforming growth factor-β1 (TGF-β1)/Smad3-driven renal fibrosis is the common pathogenesis of obstructive nephropathy. In this study, we identified petchiether A (petA), a novel small-molecule meroterpenoid from Ganoderma, as a potential inhibitor of TGF-β1-induced Smad3 phosphorylation. The obstructive nephropathy was induced by unilateral ureteral obstruction (UUO) in mice. Mice received an intraperitoneal injection of petA/vehicle before and after UUO or sham operation. An in vivo study revealed that petA protected against renal inflammation and fibrosis by reducing the infiltration of macrophages, inhibiting the expression of proinflammatory cytokines (interleukin-1β and tumour necrosis factor-α) and reducing extracellular matrix deposition (α-smooth muscle actin, collagen I and fibronectin) in the obstructed kidney of UUO mice; these changes were associated with suppression of Smad3 and NF-κB p65 phosphorylation. Petchiether A inhibited Smad3 phosphorylation in vitro and down-regulated the expression of the fibrotic marker collagen I in TGF-β1-treated renal epithelial cells. Further, we found that petA dose-dependently suppressed Smad3-responsive promoter activity, indicating that petA inhibits gene expression downstream of the TGF-β/Smad3 signalling pathway. In conclusion, our findings suggest that petA protects against renal inflammation and fibrosis by selectively inhibiting TGF-β/Smad3 signalling.

Topics: Actins; Animals; Cell Line; Collagen; Fibronectins; Fibrosis; Humans; Inflammation; Kidney; Kidney Diseases; Male; Mice, Inbred C57BL; NF-kappa B; Phosphorylation; Signal Transduction; Smad3 Protein; Terpenes; Transforming Growth Factor beta; Ureteral Obstruction

Shwachman-Diamond Syndrome (SDS) is a rare and clinically-heterogeneous bone marrow (BM) failure syndrome caused by mutations in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. Although SDS was described over 50 years ago, the molecular pathogenesis is poorly understood due, in part, to the rarity and heterogeneity of the affected hematopoietic progenitors. To address this, we used single cell RNA sequencing to profile scant hematopoietic stem and progenitor cells from SDS patients. We generated a single cell map of early lineage commitment and found that SDS hematopoiesis was left-shifted with selective loss of granulocyte-monocyte progenitors. Transcriptional targets of transforming growth factor-beta (TGFβ) were dysregulated in SDS hematopoietic stem cells and multipotent progenitors, but not in lineage-committed progenitors. TGFβ inhibitors (AVID200 and SD208) increased hematopoietic colony formation of SDS patient BM. Finally, TGFβ3 and other TGFβ pathway members were elevated in SDS patient blood plasma. These data establish the TGFβ pathway as a novel candidate biomarker and therapeutic target in SDS and translate insights from single cell biology into a potential therapy.

Topics: Adolescent; Adult; Antigens, CD34; Bone Marrow; Cell Differentiation; Cell Lineage; Child; Granulocytes; Hematopoiesis; Hematopoietic Stem Cells; Humans; Inflammation; Monocytes; Mutation; Phosphorylation; Sequence Analysis, RNA; Shwachman-Diamond Syndrome; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1; Young Adult

During Freund's adjuvant induced inflammation rat mesenteric mesothelial cells transdifferentiate into mesenchymal cell. They express macrophage markers, inflammatory cytokines (TGF-β, TNFα, IL-6), and specific receptors. When primary mesenteric cultures were treated with GM-CSF and/or TGF-β (in vitro), similar phenotypic and biological changes were induced. It seemed likely that GM-CSF receptor-ligand complex should be internalized to initiate mesothelial-macrophage transition. To follow the intracellular route of GM-CSF receptor β, we co-localized this receptor with various endocytic markers (Cav-1, EEA1, Rab7, and Rab11a), and carried out detailed immunocytochemical, statistical and biochemical analyses. Since STAT5 is one of the downstream element of GM-CSF signaling, we followed the expression and phosphorylation level of this transcription factor. Our results showed that in mesenteric mesothelial cells GM-CSF receptor β is internalized by caveolae, delivered into early endosomes where the signaling events occur, STAT5A is phosphorylated by JAK2, and then translocated into the nucleus. When dynamin-dependent endocytosis of GM-CSFR β is inhibited by dynasore, phosphorylation of STAT5A is not occurred, confirming, that the internalization of receptor β is indispensable for signal transduction. At the early time of inflammation a significant receptor recycling can be found to the plasma membrane. Later (day 8) the receptor is delivered into late endosomes, indicating that its degradation has already started, and the regeneration of mesothelial cells can start. All of these data strongly support that the internalization of GM-CSF receptor β is required and essential for signal transduction.

Topics: Animals; Caveolae; Cell Transdifferentiation; Cytokine Receptor Common beta Subunit; Disease Models, Animal; Endocytosis; Hydrazones; Inflammation; Janus Kinase 2; Macrophages; Male; Phosphorylation; Rats; Rats, Sprague-Dawley; Signal Transduction; STAT5 Transcription Factor; Transforming Growth Factor beta

Fingolimod, an oral therapy for patients with relapsing Multiple Sclerosis (MS), traps CC chemokine receptor type 7 (CCR7)-expresssing lymphocytes within lymphoid tissues in the periphery, thereby supposedly reducing the infiltration of pathogenic cells into the central nervous system. Additional immunomodulatory effects of Fingolimod, involving cell function, B and T cells interactions and cross-regulation, have scarcely been studied. The objective of this study was to assess how Fingolimod therapy affects B cells functions, namely cell migration, immunoglobullin production and T cell stimulation.. B cells from 36 patients with relapsing MS were obtained before and after 3 months Fingolimod therapy, while CD4 T cells were collected pre-treatment. Clinical follow-up was performed for 1 year. For in-vitro validation, Lymphoblastoid cell-lines from 16 patients were cultured with Fingolimod. B cell migration towards C-X-C Motif Chemokine Ligand 12 (CXCL12) was assessed using a transwell system. C-X-C chemokine receptor 4 (CXCR4) expression was assessed by flow cytometry and western blot. Plasma immunoglobullins and Brain-derived Neurotrophic Factor (BDNF) were assessed by ELISA or RT-PCR. Drug effect on interacting co-cultured B and T cells on cytokine profiles and T cell proliferation was explored by flow cytometry.. Lymphocyte count reduction did not predict clinical response of patients. Fingolimod therapy reduced CXCR4 expression and B cell migration towards CXCL12. No effect was found on immunoglobulins and BDNF. B cells from Fingolimod-treated patients induced a reduction in pro-inflammatory cytokines in T cells, while increased transforming growth factor beta (TGFβ). Fingolimod promotes anti-inflammatory cytokine profiles of B and T cells, through induction of regulatory B cells. Reduced B cell migration capacity in Fingolimod-treated patients leading to decreased cerebral inflammatory infiltration, may be part of the mechanism by which Fingolimod reduces disease activity in MS.

Topics: Adult; B-Lymphocytes; Brain-Derived Neurotrophic Factor; Cell Movement; Cell Proliferation; Chemokine CXCL12; Female; Fingolimod Hydrochloride; Follow-Up Studies; Humans; Immunosuppressive Agents; Inflammation; Interleukin-2; Male; Multiple Sclerosis, Relapsing-Remitting; Receptors, CXCR4; T-Lymphocytes; Transforming Growth Factor beta; Treatment Outcome

Extracorporeal membrane oxygenation (ECMO) could increase survival rate and neurological outcomes of cardiac arrest (CA) patients compared with conventional cardiopulmonary resuscitation (CCPR). Currently, the underlying mechanisms how ECMO improves neurological outcomes of CA patients compared with CCPR have not been revealed. A pig model of CA was established by ventricular fibrillation induction and then underwent CCPR or ECMO. Survival and hemodynamics during the 6 h after return of spontaneous circulation (ROSC) were compared. The levels of inflammatory cytokines and Ca

Topics: Animals; Arterial Pressure; Calcium-Transporting ATPases; Cardiac Output; Cardiopulmonary Resuscitation; Disease Models, Animal; Extracorporeal Membrane Oxygenation; Gene Expression Regulation; Heart Arrest; Heart Rate; Humans; Inflammation; Interleukin-1; Interleukin-10; Interleukin-1beta; Interleukin-6; Sodium-Potassium-Exchanging ATPase; Survival Analysis; Swine; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

In case of large injuries of skeletal muscles the pool of endogenous stem cells, i.e., satellite cells, might be not sufficient to secure proper regeneration. Such failure in reconstruction is often associated with loss of muscle mass and excessive formation of connective tissue. Therapies aiming to improve skeletal muscle regeneration and prevent fibrosis may rely on the transplantation of different types of stem cell. Among such cells are adipose tissue-derived stromal cells (ADSCs) which are relatively easy to isolate, culture, and manipulate. Our study aimed to verify applicability of ADSCs in the therapies of severely injured skeletal muscles. We tested whether 3D structures obtained from Matrigel populated with ADSCs and transplanted to regenerating mouse gastrocnemius muscles could improve the regeneration. In addition, ADSCs used in this study were pretreated with myoblasts-conditioned medium or anti-TGFβ antibody, i.e., the factors modifying their ability to proliferate, migrate, or differentiate. Analyses performed one week after injury allowed us to show the impact of 3D cultured control and pretreated ADSCs at muscle mass and structure, as well as fibrosis development immune response of the injured muscle.

Topics: Adipose Tissue; Animals; Antibodies; Cell Shape; Collagen; Culture Media, Conditioned; Drug Combinations; Gene Expression Regulation; Inflammation; Laminin; Male; Mice, Inbred C57BL; Muscle, Skeletal; Myoblasts; Proteoglycans; Regeneration; RNA, Messenger; Signal Transduction; Stromal Cells; Transforming Growth Factor beta

Autoimmune ovarian disease (AOD) is considered to be a major cause of premature ovarian failure (POF). The immunomodulatory properties of human amniotic epithelial cells (hAECs) have been studied in many disease models. We previously reported that hAECs restored ovarian function in chemotherapy-induced POF mice, but the immunomodulatory mechanism of hAECs is still unclear. To investigate the effect of hAECs on recipient mice, especially on regulatory Treg cells, hAECs and hAEC-conditioned medium (hAEC-CM) were intravenously injected into AOD mice immunized with zona pellucida protein 3 peptides (pZP3). Ovarian function was evaluated through estrous cycle, hormone secretion, follicle development, and cell apoptosis analysis. Immune cells including CD3, CD4, CD8 and Treg cells in the spleens were tested by flow cytometry. To elucidate the effect of hAEC-CM on macrophage function, inflammation model in vitro was established in RAW264.7 cells induced by lipopolysaccharide (LPS). hAECs and hAEC-CM regulated estrous cycles, promoted follicle development, ameliorated cell apoptosis and fibrosis in ovaries of AOD mice. In addition, hAECs significantly reversed the decrease of pZP3-induced Treg cells in the spleens. In vitro, hAEC-CM significantly inhibited the inflammatory reaction induced by LPS in RAW264.7 cells via up-regulating the expression of M2 macrophage genes. Further study demonstrated that hAEC-secreted transforming growth factor-beta and macrophage inhibitory factor played important roles in the macrophage polarization and migration under inflammatory stimulation. Taken together, hAECs restored ovarian function by up-regulating Treg cells in the spleens and reduced the inflammatory reaction via modulating the activated macrophage function in a paracrine manner in the ovaries of AOD mice.

Topics: Amnion; Animals; Apoptosis; Autoimmune Diseases; Cell Movement; Culture Media, Conditioned; Disease Models, Animal; Epithelial Cells; Female; Granulosa Cells; Humans; Immunohistochemistry; Inflammation; Intramolecular Oxidoreductases; Lipopolysaccharides; Macrophage Migration-Inhibitory Factors; Macrophages; Mice; Ovarian Diseases; Primary Ovarian Insufficiency; RAW 264.7 Cells; Spleen; Transforming Growth Factor beta; Zona Pellucida Glycoproteins

In this study, we investigated the response of myeloid-derived suppressor cells (MDSCs) during the pathogenesis of an immunoblinding disease of the cornea caused by HSV type 1 infection. We also measured the anti-inflammatory potential of in vitro-differentiated MDSCs in dampening herpetic stromal keratitis resulting from primary ocular HSV1 infection in mice. In the lymphoid organs and inflamed corneal tissues, MDSCs were phenotypically characterized as CD11b

Topics: Adoptive Transfer; Animals; CD11b Antigen; CD4-Positive T-Lymphocytes; Cell Proliferation; Female; Forkhead Transcription Factors; Herpes Simplex; Herpesvirus 1, Human; Immune Tolerance; Inflammation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Myeloid-Derived Suppressor Cells; Signal Transduction; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Immune homeostasis in the gut associated lymphoid tissues (GALT) is critical to prevent the development of inadvertent pathologies. B cells as the producers of antibodies and cytokines plays an important role in maintaining the GALT homeostasis. However, the mechanism by which B cells specifically direct their responses towards non-self-antigens and become ignorant to self-antigens in the GALT is not known. Therefore, we developed a novel mouse model by expressing Duck Egg Lysozyme (DEL) in gut epithelial cells in presence of HEL reactive B cells. Notably, we observed a transient activation and rapid deletion of self-reactive B cells in Peyers Patches and Mesenteric lymph nodes upon self-antigen exposure. The survival of self-reactive B cells upon exposure to their self-antigen was partially rescued by blocking receptor editing but could be completely rescued by stronger survival signal like ectopic expression of BCL2. Importantly, rescuing the self-reactive B cells promoted production of auto-antibodies and gut inflammation. Mechanistically, we identify a specific activation of TGFβ signaling in self-reactive B cells in the gut and a critical role of this pathway in maintaining peripheral tolerance. Collectively, our studies describe functional consequences and fate of self-reactive B cells in GALT and provide novel mechanistic insights governing self-tolerance of B cells in the gut.

Topics: Animals; Autoantigens; B-Lymphocytes; Bone Marrow; Epithelial Cells; Gastrointestinal Tract; Homeostasis; Inflammation; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Animal; Muramidase; Proto-Oncogene Proteins c-bcl-2; Transforming Growth Factor beta

Inhaled oxidative toxicants present in ambient air cause airway epithelial injury, inflammation, and airway hyperresponsiveness. Effective adaptation to such environmental insults is essential for the preservation of pulmonary function, whereas failure or incomplete adaptation to oxidative injury can render the host susceptible to the development of airway disease.. We sought to explore the mechanisms of airway adaptation to oxidative injury.. For a model to study pulmonary adaptation to oxidative stress-induced lung injury, we exposed mice to repeated nose-only chlorine gas exposures. Outcome measures were evaluated 24 hours after the last chlorine exposure. Lung mechanics and airway responsiveness to methacholine were assessed by using the flexiVent. Inflammation and antioxidant responses were assessed in both bronchoalveolar lavage fluid and lung tissue. Using both loss or gain of function and genomic approaches, we further dissected the cellular and molecular mechanisms involved in pulmonary adaptation.. Repeated exposures to oxidative stress resulted in pulmonary adaptation evidenced by abrogation of neutrophilic inflammation and airway hyperresponsiveness. This adaptation was independent of antioxidant mechanisms and regulatory T cells but dependent on residential alveolar macrophages (AMs). Interestingly, 5% of AMs expressed forkhead box P3, and depletion of these cells abolished adaptation. Results from transcriptomic profiling and loss and gain of function suggest that adaptation might be dependent on TGF-β and prostaglandin E. Pulmonary adaptation during oxidative stress-induced lung injury is mediated by a novel subset of forkhead box P3-positive AMs that limits inflammation, favoring airway adaptation and host fitness through TGF-β and prostaglandin E

Topics: Adaptation, Physiological; Animals; Chlorine; Dinoprostone; Inflammation; Irritants; Lung Injury; Macrophages, Alveolar; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Oxidative Stress; Respiratory Hypersensitivity; Transforming Growth Factor beta

Crohn's disease is an immune-mediated disease characterized by inflammation along the gastrointestinal tract. Fibrosis requiring surgery occurs in one-third of people with Crohn's disease but there are no treatments for intestinal fibrosis. Mice deficient in the SH2 domain-containing inositolpolyphosphate 5'-phosphatase (SHIP), a negative regulator of phosphatidylinositol 3-kinase (PI3K) develop spontaneous Crohn's disease-like intestinal inflammation and arginase I (argI)-dependent fibrosis. ArgI is up-regulated in SHIP deficiency by PI3Kp110δ activity. Thus, we hypothesized that SHIP-deficient mice develop fibrosis due to increased PI3Kp110δ activity. In SHIP-deficient mice, genetic ablation or pharmacological inhibition of PI3Kp110δ activity reduced intestinal fibrosis, including muscle thickening, accumulation of vimentin

Topics: Animals; Arginase; Class Ia Phosphatidylinositol 3-Kinase; Cytokines; Disease Models, Animal; Disease Susceptibility; Enzyme Activation; Fibrosis; Gene Expression; Inflammation; Intestines; Macrophages; Mice; Mice, Knockout; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; Transforming Growth Factor beta

Resveratrol is a natural polyphenol compound highly found in red wine that displays several beneficial effects on the central nervous system (CNS), preventing or slowing the progression of a wide variety of neurological diseases. Its neuroprotective role is particularly associated to modulation of antioxidant and anti-inflammatory responses in glial cells in a mechanism dependent of heme oxygenase 1 (HO-1) signaling pathway. Oligodendrocyte progenitor cells (OPC), primarily known for giving rise to mature oligodendrocytes, have emerged as dynamic cells that are also important to maintain the CNS homeostasis. In this sense, we have demonstrated that resveratrol has a protective effect on oligodendroglial functionality against lipopolysaccharide (LPS)-mediated cytotoxicity and that its glioprotective mechanism involves the nuclear factor erythroid 2-related factor 2 (Nrf2) and HO-1 pathways. LPS, through toll-like receptor 4 (TLR4), affected the release of trophic factors by OPC, including transforming growth factor beta (TGF-β), brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF), and resveratrol reestablished the trophic factor release to control levels. Additionally, resveratrol prevented the LPS-induced increase in the intracellular reactive oxygen species (ROS) as well as the decrease in glutathione (GSH) levels and in glutamate cysteine ligase (GCL) activity, through Nrf2/HO-1 signaling pathways. Resveratrol also prevented the increase of the transcriptional activities of nuclear factor κB (NFκB) and hypoxia-inducible factor 1 alpha (HIF-1α) after LPS challenge. In summary, this is the first study showing the glioprotective effect of resveratrol on oligodendroglial cells.

Topics: Animals; Animals, Newborn; Biomarkers; Brain-Derived Neurotrophic Factor; Cell Death; Cells, Cultured; Glial Cell Line-Derived Neurotrophic Factor; Glutathione; Heme Oxygenase-1; Inflammation; Lipopolysaccharides; Models, Biological; Neuroprotective Agents; NF-E2-Related Factor 2; Oligodendroglia; Rats, Wistar; Reactive Oxygen Species; Resveratrol; RNA, Messenger; Signal Transduction; Transcription Factor RelA; Transforming Growth Factor beta

Numerous growth factors, cytokine, mitogen and chemotactic factors are involved in wound healing. Even though inflammation is important for the stimulation of proliferative phase, excessive inflammation also causes impairment in wound healing. Strontium salts suppress keratinocyte-induced TNF-alpha and interleukin-1 and interleukin-6 in in vitro cultures. This study was conducted to determine the effects of administration of topical strontium chloride hexahydrate on wound healing through TNF-alpha and TGF-beta in surgical wound healing model of in-vivo rat skin.. Twenty-four rats were used in the study. After approximately 2 cm cutaneous-subcutaneous incision was horizontally carried out on the mid-neckline of the rats, the incision was again closed using 2.0 vicryl. The rats were assigned into three groups including eight rats in each group. Placebo emollient ointment and also the ointments, which were containing 5% and 10% strontium chloride hexahydrate and were prepared at the same base with placebo ointment, were administered to the groups by a blind executor twice a day for a week. At the end of seventh day, the rats were sacrificed and cutaneous and subcutaneous tissue of their wound site was resected for histopathological examination. Scoring of histopathological wound healing and scoring of tissue TNF-alpha and TGF-beta level with immunohistochemical staining were performed.. The groups, to which both 5% and 10% strontium chloride hexahydrate was administered, had lower immunohistochemical TNF-alpha levels and histopathological wound scores compared to controls, which was statistically significant (p < 0.05).. Strontium chloride hexahydrate can lead to impairment in wound healing by suppressing inflammation through TNF-alpha.

Topics: Administration, Cutaneous; Animals; Dermatologic Surgical Procedures; Female; Inflammation; Rats, Wistar; Skin; Strontium; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Wound Healing

Obesity is a multifactorial disease, associated with metabolic disorders, chronic low-grade inflammation, and impaired immunity. This study aimed to evaluate the childhood obesity-associated effects on neutrophil activation and cytokine production.. We evaluated activation and recognition markers and cytokine production in neutrophils from the peripheral blood of children with obesity and normal weight using multicolor flow cytometry.. We demonstrate a higher frequency of neutrophils in childhood obesity group (CO) compared to normal-weight group (NW). Our data showed that neutrophils from CO group are capable of antigen recognition and presentation through higher expression of TLR-4 (CD284) and HLA-DR in comparison with neutrophils from NW. On the other hand, neutrophils from CO group are faulty to deliver co-stimulatory signals, through lower expression of co-stimulatory molecules. We showed an increased expression of IL-6, IL-1β, IL-12, and TNF, and decreased expression of IL-8 and IL-10 by neutrophils from CO compared to NW, while TGF-β is equivalently expressed in neutrophils from both groups. Despite this, we observed that TGF-β/inflammatory cytokine ratio was significantly higher than the IL-10/inflammatory cytokine ratio only in CO group. Our analysis showed obesity altering the correlation profile for the expression of co-stimulatory, recognition, and activation molecules, as well as for cytokines by neutrophils, suggesting an association between lower IL-10 expression and inflammation in childhood obesity.. The unbalance between the ratio of IL-10 and TGF-β expressions, the IL-10 lower expression, and changes in correlation profile seem to contribute with an inefficient regulation of inflammatory cytokine expression in childhood obesity. However, these changes still not may be considered the sole mechanism that directs inflammation during childhood obesity, once other molecules, pathways, and cells should be evaluated.

Topics: Child; Cytokines; Female; Humans; Inflammation; Interleukin-10; Male; Neutrophils; Pediatric Obesity; Transforming Growth Factor beta

Pulmonary fibrosis is a result of an abnormal wound healing in lung tissue triggered by an excessive accumulation of extracellular matrix proteins, loss of tissue elasticity, and debit of ventilatory function. NKT cells are a major source of Th1 and Th2 cytokines and may be crucial in the polarization of M1/M2 macrophages in pulmonary fibrogenesis. Although there appears to be constant scientific progress in that field, pulmonary fibrosis still exhibits no current cure. From these facts, we hypothesized that NKT cells could influence the development of pulmonary fibrosis via modulation of macrophage activation. Wild type (WT) and NKT type I cell-deficient mice (Jα18

Topics: Animals; Bleomycin; Collagen; Cytokines; Disease Models, Animal; Galactosylceramides; Inflammation; Lung; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Natural Killer T-Cells; Phenotype; Pulmonary Fibrosis; Th1 Cells; Th2 Cells; Transforming Growth Factor beta; Vimentin

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Female; Humans; Inflammation; Intracellular Signaling Peptides and Proteins; Male; Mesangial Cells; Mice; Mice, Knockout; NF-kappa B; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

Toxoplasmosis is mostly associated with other intestinal parasitic infections especially Giardia due to shared mode of peroral infection. Toxoplasma and Giardia induce a strong T-helper 1- immune response. Our aim was to induce a protective immune response that results in significant impact on intestinal and extra-intestinal phases of Toxoplasma infection. This study was conducted in experimental animals and assessment of Giardia cyst extract effect on Toxoplasma infection was investigated by histopathological examination of small intestine and brain, Toxoplasma cyst count and iNOS staining of the brain, measurement of IFN-γ and TGF-β in intestinal tissues. Results showed that the brain Toxoplasma cyst number was decreased in mice infected with Toxoplasma then received Giardia cyst extract as compared to mice infected with Toxoplasma only. This effect was produced because Giardia cyst extract augmented the immune response to Toxoplasma infection as evidenced by severe inflammatory reaction in the intestinal and brain tissues, increased levels of IFN-γ and TGF-β in intestinal tissues and strong iNOS staining of the brain. In conclusion, Giardia cyst extract generated a protective response against T. gondii infection. Therefore, Giardia antigen will be a suitable candidate for further researches as an immunomodulatory agent against Toxoplasma infection.

Topics: Animals; Antigens, Protozoan; Brain; Female; Giardia; Giardiasis; Inflammation; Interferon-gamma; Intestine, Small; Mice; Nitric Oxide Synthase Type II; Th1 Cells; Toxoplasma; Toxoplasmosis; Toxoplasmosis, Animal; Transforming Growth Factor beta

Intraperitoneal adhesions (IA) develop as a consequence of the healing process in peritoneum injured during surgeries. IA might be formed after all types of surgical interventions regardless the surgical approach with a higher incidence in obese individuals. Here we determine the diagnostic power of TGF-β and blood inflammatory parameters in the prediction of IA in obese patients undergoing second surgical intervention.. Eighty patients were divided into groups according to body mass index (BMI) values and presence of intraperitoneal adhesions (IA). Evaluation of peritoneal adhesion index (PAI), serum TGF-β and blood inflammatory parameters was performed.. Level of TGF-β, C-reactive protein (CRP), leukocytes, neutrophil to lymphocyte ratio and platelet to lymphocyte ratio were significantly higher in obese patients while TGF-β, CRP, and leukocytes were higher in patients with IA. There was a significant correlation between PAI values and TGF-β concentration (p<0.001; r=0.869) in IA group.. The preoperative TGF-β concentration, BMI, CRP and NLR could be strong predictors of intraperitoneal adhesions in patients with the history of surgeries.

Topics: Biomarkers; Body Mass Index; C-Reactive Protein; Female; Humans; Inflammation; Lymphocytes; Male; Middle Aged; Neutrophils; Peritoneum; Tissue Adhesions; Transforming Growth Factor beta

Nuclear factor of activated T cells (NFAT)-c1 is known as a key regulator in osteoclast differentiation and immune response. This study is a follow-up to our previous study showing the antiresorptive activity of VIVIT, a peptide type NFATc1 inhibitor, using absorbable collagen sponge (ACS). This study aimed to investigate the effective concentration range of local VIVIT that suppresses early excessive osteoclast activation and inflammation induced by high-dose recombinant human bone morphogenetic protein (rhBMP)-2 and concomitantly enhances bone healing in a rat critical-sized calvaria defect model. High-dose rhBMP-2 (40 μg/defect) alone significantly increased in vivo osteoclast activation and expression of the inflammatory cytokines interleukin-1β and transforming necrosis factor-α on the scaffold at 7 days after surgery. However, rhBMP-2 had no direct effect on osteoclast activation in vitro. Osteoclast activation by rhBMP-2 was significantly suppressed by combined treatment with VIVIT at concentrations of 75 and 150 μM, but not at 15 μM, whereas suppression of inflammation occurred at all doses of VIVIT. Microcomputed tomography at 4 and 8 weeks after implantation revealed that the combination of rhBMP-2 and VIVIT at 75 μM VIVIT led to a greater bone fraction at the initial defect area, compared with rhBMP-2 alone. These findings revealed that local administration of VIVIT at certain concentrations has multiple positive effects that weaken early excessive osteoimmunological responses and enhance bone healing after rhBMP-2 administration. VIVIT has the potential to expand the therapeutic area of high-dose rhBMP-2 therapy to inflammatory bone loss. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1299-1310, 2018.

Topics: Animals; Bone and Bones; Bone Morphogenetic Protein 2; Bone Resorption; Inflammation; NFATC Transcription Factors; Oligopeptides; Osteoclasts; Osteogenesis; Rats, Sprague-Dawley; Recombinant Proteins; Signal Transduction; Transforming Growth Factor beta

The balance between pro- and anti-inflammatory signals maintains tissue homeostasis and defines the outcome of chronic inflammatory diseases such as periodontitis, a condition that afflicts the tooth-supporting tissues and exerts an impact on systemic health. The induction of tissue inflammation relies heavily on Toll-like receptor (TLR) signaling, which drives a proinflammatory pathway through recruiting myeloid differentiation primary response gene 88 (MyD88) and activating nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). TLR-induced production of proinflammatory cytokines and chemokines is reined in by anti-inflammatory cytokines, including the transforming growth factor β (TGFβ) family of cytokines. Although Smad6 is a key mediator of TGFβ-induced anti-inflammatory signaling, the exact mechanism by which TGFβ regulates TLR proinflammatory signaling in the periodontal tissue has not been addressed to date. In this study, we demonstrate for the first time that the ability of TGFβ to inhibit TLR-NFκB signaling is mediated by protein arginine methyltransferase 1 (PRMT1)-induced Smad6 methylation. Upon methylation, Smad6 recruited MyD88 and promoted MyD88 degradation, thereby inhibiting NFκB activation. Most important, Smad6 is expressed and methylated in the gingival epithelium, and PRMT1-Smad6 signaling promotes tissue homeostasis by limiting inflammation. Consistent with this, disturbance of Smad6 methylation exacerbates inflammation and bone loss in experimental periodontitis. The dissected mechanism is therapeutically important, as it highlights the manipulation of PRMT1-Smad6 signaling as a novel promising strategy to modulate the host immune response in periodontitis.

Topics: Arginine; Cells, Cultured; Gingiva; Humans; Inflammation; Methylation; Myeloid Differentiation Factor 88; NF-kappa B; Periodontitis; Protein Interaction Domains and Motifs; Protein-Arginine N-Methyltransferases; Repressor Proteins; Signal Transduction; Smad6 Protein; Transforming Growth Factor beta; Ubiquitin-Protein Ligases

The purpose of this study was to explore retina-intrinsic neuroinflammatory reactions, effects on neuronal survival, relationship with classic gliosis, and possible role of the toll-like receptor 4 (TLR4). To isolate the adult retina from the systemic immune system, a previously described large animal explant culture model was used in which full-thickness porcine retinal sheets can be kept in vitro for extended time periods. Explants were kept for 5 days in vitro (DIV) and were treated with either; lipopolysaccharide (LPS), a Toll-like receptor-4 (TLR4) inhibitor (CLI-095), LPS + CLI-095, or solvent vehicle throughout the culture period after which retinal sections were examined with hematoxylin and eosin staining and extensive immunohistochemistry. In addition, culture medium from all explant groups was assayed for a panel of cytokines at 2 and 5DIV. Compared with in vivo controls, vehicle controls (CT) as well as CLI-095 explants displayed moderate reduction of total thickness and number of retinal neurons with upregulation of glial fibrillary acidic protein (GFAP) throughout the Müller cells. In contrast, LPS and LPS + CLI-095 treated counterparts showed extensive overall thinning with widespread neuronal degeneration but only minimal signs of classical Müller cell gliosis (limited upregulation of GFAP and no downregulation of glutamine synthetase (GS). These specimens also displayed a significantly increased expression of galectin-3 and TGF-beta activated kinase 1 (TAK1). Multiplex proteomic analysis of culture medium at 2DIV revealed elevated levels of IL-1β, IL-6, IL-4 and IL-12 in LPS-treated explants compared to CLI-095 and CT counterparts. LPS stimulation of the isolated adult retina results in substantial neuronal cell death despite only minimal signs of gliosis indicating a retina-intrinsic neuroinflammatory response directly related to the degenerative process. This response is characterized by early upregulation of several inflammatory related cytokines with subsequent upregulation of Galectin-3, TLR4 and TAK1. Pharmacological block of TLR4 does not attenuate neuronal loss indicating that LPS induced retinal degeneration is mediated by TLR4 independent neuroinflammatory pathways.

Topics: Animals; Cell Survival; Cells, Cultured; Cytokines; Disease Models, Animal; Galectin 3; Glial Fibrillary Acidic Protein; Gliosis; Glutamate-Ammonia Ligase; Inflammation; Lipopolysaccharides; Nerve Degeneration; Proteomics; Retinal Degeneration; Retinal Neurons; Swine; Toll-Like Receptor 4; Transforming Growth Factor beta

The chronic inflammatory immune response triggered by the infection of the tooth root canal system results in the local upregulation of RANKL, resulting in periapical bone loss. While RANKL has a well-characterized role in the control of bone homeostasis/pathology, it can play important roles in the regulation of the immune system, although its possible immunoregulatory role in infectious inflammatory osteolytic conditions remains largely unknown. Here, we used a mouse model of infectious inflammatory periapical lesions subjected to continuous or transitory anti-RANKL inhibition, followed by the analysis of lesion outcome and multiple host response parameters. Anti-RANKL administration resulted in arrest of bone loss but interfered in the natural immunoregulation of the lesions observed in the untreated group. RANKL inhibition resulted in an unremitting proinflammatory response, persistent high proinflammatory and effector CD4 response, decreased regulatory T-cell (Treg) migration, and lower levels of Treg-related cytokines IL-10 and TGFb. Anti-RANKL blockade impaired the immunoregulatory process only in early disease stages, while the late administration of anti-RANKL did not interfere with the stablished immunoregulation. The impaired immunoregulation due to RANKL inhibition is characterized by increased delayed-type hypersensitivity in vivo and T-cell proliferation in vitro to the infecting bacteria, which mimic the effects of Treg inhibition, reinforcing a possible influence of RANKL on Treg-mediated suppressive response. The adoptive transfer of CD4+FOXp3+ Tregs to mice receiving anti-RANKL therapy restored the immunoregulatory capacity, attenuating the inflammatory response in the lesions, reestablishing normal T-cell response in vivo and in vitro, and preventing lesion relapse upon anti-RANKL therapy cessation. Therefore, while RANKL inhibition efficiently limited the periapical bone loss, it promoted an unremitting host inflammatory response by interfering with Treg activity, suggesting that this classic osteoclastogenic mediator plays a role in immunoregulation.

Topics: Adoptive Transfer; Alveolar Bone Loss; Animals; Antibodies, Monoclonal; Cell Proliferation; Cell Survival; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Gene Expression; Immunity, Mucosal; Inflammation; Infliximab; Interleukin-10; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Osteolysis; Periapical Diseases; RANK Ligand; Real-Time Polymerase Chain Reaction; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Increased evidences have shown that unexplained recurrent spontaneous abortion (URSA) is associated with inflammatory responses and breakage of immunological autotolerance. Therefore, the balance between Th17 and Treg cells may elucidate the pathophysiology of URSA.. To investigate the serum concentration of regulatory and inflammatory cytokines associated with Treg and Th17 in both normal and URSA females.. Forty-six women with URSA and 28 non-pregnant control women with at least one successful pregnancy were included. Serum was obtained from both groups and stored at -7º C. The serum concentrations of IL-17, IL-21, IL-22, IL-10, and TGF-β were quantitatively determined by ELISA.. The levels of IL-17, IL-21, and IL-22 in sera were significantly higher (P<0.001, P=0.01 and P<0.001, respectively) and TGF-β serum concentration was significantly lower (P=0.02) in URSA women compared with normal controls.. Our results suggest that enhancement in Th17-associated cytokine levels and reduction in TGF-β may be one of the factors involved in URSA.

Topics: Abortion, Spontaneous; Adult; Biomarkers; Female; Humans; Immune Tolerance; Inflammation; Interleukin-17; Interleukin-22; Interleukins; Pregnancy; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

Animals with impaired transforming growth factor (TGF)-β1 signaling developed spontaneous lethal autoimmune inflammationand autoimmune diseases. Moreover, evidence for modified TGF-β signaling in atopic dermatitis (AD) exists. Therefore, the goal of this study was to determine whether SB-431542, a potent and selective inhibitor of the TGF-β type 1 receptor (TGF-βR1), could attenuate such a severe reaction in mice. In addition, the molecular underpinnings the possible protective effects were also investigated. Repeated epicutaneous application of DNCB was performed on the ear and shaved dorsal skin of miceto induce AD-like symptoms and skin lesions. SB-431542 (1 mg/kg) was given by intra-peritoneal injection three times weekly for 3 weeks to assess the anti-pruritic effects. Serum levels of TGF-β1, TGF-βR1, latency-associated peptide (LAP), tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 were assessed by ELISA. Moreover, the gene expression of TNF-α, IL-1β and IL-6 were determined. Apoptotic pathway was evaluated by measuring the activity of caspase-3 and by staining skin sections with anti-caspase-3 antibodies. We found that SB-431542 alleviated DNCB-induced AD-like symptoms as quantified by skin lesion,dermatitisscore, ear thickness and scratching behavior. In parallel, SB-431542 blocked DNCB-induced elevation in serum levels of TNF-α, TGF-β1, TGF-βR1, LAP, IL-1β, IL-6 and IgE. The collective results indicate that SB-431542 partially suppresses DNCB-induced AD in micevia reduction of TGF-β1 signaling pathway associated with inhibition of inflammation and apoptosis.

Topics: Animals; Antioxidants; Benzamides; Biomarkers; Caspase 3; Dermatitis, Atopic; Dinitrochlorobenzene; Dioxoles; Disease Models, Animal; Enzyme Activation; Fibrosis; Gene Expression Regulation; Hypersensitivity; Inflammation; Inflammation Mediators; Mice, Inbred BALB C; Receptor, Transforming Growth Factor-beta Type I; Skin; Transforming Growth Factor beta

BACKGROUND Fibrosis is the common pathological feature in most kinds of chronic kidney disease (CKD). TGF-β/Smads signaling is the master pathway regulating kidney fibrosis pathogenesis, in which Smad3 acts as the integrator of various pro-fibrosis signals. In this study, we analyzed the role of SIS3, a specific inhibitor of Smad3, in mouse unilateral ureteral obstruction (UUO) kidneys. MATERIAL AND METHODS UUO mice were intraperitoneally injected with 0.2 mg/kg/day or 2 mg/kg/day of SIS3 or control saline for 7 days, followed by analysis of structure injury, fibrosis status, inflammation, apoptosis, and TGF-β/Smads signaling activity. RESULTS Our results indicated that SIS3 treatment dosage-dependently relieved the gross structure injury and tubular necrosis in UUO kidneys. Masson staining, immunohistochemistry, and real-time PCR showed significantly decreased extracellular matrix deposition, fibronectin staining intensity, and RNA levels of collagen I and collagen III in SIS3-treated UUO kidneys. SIS3 treatment also suppressed the activation of myofibroblasts, as evidenced by decreased expression levels of a-SMA and vimentin in UUO kidneys. The TGF-β/Smads signaling activity analysis showed that SIS3 inhibited the phosphorylation of Smad3 but not Smad2 and decreased the protein level of TGF-β1, suggesting specific inhibition of the TGF-β/Smad3 pathway in UUO kidneys. Furthermore, SIS3 treatment also ameliorated the increased pro-inflammatory TNF-α and COX2 in UUO kidneys and circulating IL-1β in UUO mice, and inhibited caspase-3 activity and the number of apoptotic cells. CONCLUSIONS SIS3 ameliorated fibrosis, apoptosis, and inflammation through inhibition of TGF-b/Smad3 signaling in UUO mouse kidneys.

Topics: Animals; Apoptosis; Fibrosis; Inflammation; Isoquinolines; Kidney; Male; Mice, Inbred BALB C; Myofibroblasts; Pyridines; Pyrroles; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta; Ureteral Obstruction

The average age of the human population is rising, leading to an increasing burden of age-related diseases, including increased susceptibility to infection. However, immune function can decrease with age which could impact on processes that require a functional immune system. Aging is also characterized by chronic low-grade inflammation which could further impact immune cell function. While changes to neutrophils in blood during aging have been described, little is known in aging lymphoid organs. This study used female C57BL/6J mice comparing bone marrow (BM), spleen and lymph nodes from young mice aged 2-3 months (equivalent to 18 human years) with healthy elderly mice aged 22-24 months (equivalent to 60-70 human years). Neutrophil proportions increased in BM and secondary lymphoid organs of elderly mice relative to their younger counterparts and presented an atypical phenotype. Interestingly, neutrophils from elderly spleen and lymph nodes were long lived (with decreased apoptosis via Annexin V staining and increased proportion of BrdU

Topics: Adolescent; Aged; Aging; Animals; Apoptosis; B-Lymphocytes; Cell Movement; Disease Susceptibility; Female; Humans; Infections; Inflammation; Lymphoid Tissue; Mice; Mice, Inbred C57BL; Middle Aged; Neutrophils; T-Lymphocytes; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Local Treg responses are involved in Helicobacter pylori-related inflammation and clinical outcomes after infection, and H. pylori-derived HSP60 (HpHSP60) is an important virulence factor associated with gastric carcinogenesis. This study to investigate the role of HpHSP60 in immunosuppression, particularly with regard to whether it could induce the production of Treg cells. For this purpose, human peripheral blood mononuclear cells (PBMCs) were treated with or without HpHSP60 in the presence of an anti-CD3 mAb to determine the effect of HpHSP60 on cell proliferation. In this report, HpHSP60 decreased the expression of CDK4 to significantly arrest the proliferation of mitogen-stimulated T-cells, which correlated with the induction of Treg cells. Moreover, monocytic cells were essential for the induction of HpHSP60-induced Treg cells via the secretion of IL-10 and TGF-β after treatment with HpHSP60. Blockage of HpHSP60 with specific monoclonal antibodies significantly reduced the colonization of H. pylori and the expression of Treg cells in vivo. Overall, our results suggest that HpHSP60 could act on macrophages to trigger the expression of IL-10 and TGF-β, thereby leading to an increase in Treg cells and inhibition of T-cell proliferation.

Topics: Animals; CD3 Complex; Cell Death; Cell Proliferation; Chaperonin 60; Cyclin-Dependent Kinase 4; Cytokines; Female; Gastric Mucosa; Gene Expression Regulation, Bacterial; Helicobacter Infections; Helicobacter pylori; Humans; Immunosuppression Therapy; Inflammation; Interleukin-10; Interleukin-8; Leukocytes, Mononuclear; Mice, Inbred BALB C; Monocytes; T-Lymphocytes, Regulatory; THP-1 Cells; Transforming Growth Factor beta; Virulence Factors

The transient activation of inflammatory networks is required for adipose tissue remodeling including the "browning" of white fat in response to stimuli such as β3-adrenergic receptor activation. In this process, white adipose tissue acquires thermogenic characteristics through the recruitment of so-called beige adipocytes. We investigated the downstream signaling pathways impinging on adipocyte progenitors that promote de novo formation of adipocytes. We showed that the Jak family of kinases controlled TGFβ signaling in the adipose tissue microenvironment through Stat3 and thereby adipogenic commitment, a function that was required for beige adipocyte differentiation of murine and human progenitors. Jak/Stat3 inhibited TGFβ signaling to the transcription factors Srf and Smad3 by repressing local

Topics: Adipocytes, Beige; Adipogenesis; Adipose Tissue; Animals; Cell Differentiation; Cells, Cultured; Female; Gene Expression Profiling; Humans; Inflammation; Janus Kinases; Lipase; Mice, Inbred C57BL; Mice, Knockout; Signal Transduction; STAT3 Transcription Factor; Transforming Growth Factor beta

Hepatic stellate cells (HSC), or Ito cells, store vitamin A when at rest but undergo phenotypic changes in situations of liver injury, which may induce fibrosis, and they may participate in the immune response in the liver. The objective of the present study was to investigate the role of HSC in the livers of dogs with visceral leishmaniasis (VL). Twenty-eight livers from dogs infected with VL that were living in an area endemic for the disease were evaluated, among which 13 were asymptomatic (A) and 15 were symptomatic (S). A control group (C) was formed by five dogs from an area that was not endemic for VL. These organs were subjected to histopathological analysis (Masson's trichrome for fibrosis) and immunohistochemical analysis (Leishmania, smooth-muscle α-actin and TGF-β). In the livers from the symptomatic dogs, a moderate to severe granulomatous inflammatory reaction was observed in the capsule and in the portal, centrilobular and intralobular regions. In the asymptomatic dogs, there was slight to moderate presence of granulomas, and these were even absent in some dogs. The intensity of hepatic fibrosis was predominantly low in the infected dogs (A and S), and fibrosis was absent in the control group. The immunomarking of HSC in the infected groups (A and S) differed significantly (P = 0.0153) from that of the control group. The symptomatic dogs presented the largest number of positive cells. This group also presented a larger number of parasitized macrophages, but did not differ statistically from the asymptomatic group (P > 0.05). The cytokine TGF-β was only detected at low levels, and only in the infected animals, but this did not differ from the control group. Immunomarking for HSC was observed mainly in the nuclei of cells present in the hepatic granulomas of symptomatic dogs and in the sinusoids of the asymptomatic dogs. It was concluded that in the livers of dogs with VL, the HSC are activated and participate in the hepatic response to the parasite. The cytokine TGF-β may be involved in this activation, but in the chronic phase of the infection, this cytokine was detected at lower proportions. It is possible that HSC may also contribute towards chemotaxis of leukocytes for the hepatic compartment, along with other cell types such as Kupffer cells.

Topics: Actins; Animals; Dog Diseases; Dogs; Granuloma; Hepatic Stellate Cells; Inflammation; Leishmania infantum; Leishmaniasis, Visceral; Liver; Liver Cirrhosis; Macrophages; Transforming Growth Factor beta

To evaluate the expression of TNF-α, IL-6, IFN-γ, TGF-β, IL-4, IL-10, RANKL, RANK and OPG on mouse calvarial bone treated with MTA, Geristore. Bone wounds were made on the heads of C57BL/6 mice, breaking the periosteum and the cortical surface of the calvaria. Each repair agent was inserted into sectioned Eppendorf microtubes and placed on the bone wound, and soft tissues were sutured. At 14 and 21 days, animals were sacrificed and the treated region was dissected. The calvaria bone was removed, and RNA was extracted. mRNA expression of the aforementioned cytokines was assessed using real-time PCR. Data were analysed by nonparametric methods, including the Mann-Whitney and Kruskal-Wallis tests (P < 0.05).. Following treatment with Emdogain. The clinical indication of these repair agents depends on the root resorption diagnosis. Whilst MTA and Emdogain

Topics: Aluminum Compounds; Animals; Calcium Compounds; Cytokines; Dental Enamel Proteins; Drug Combinations; Gene Expression Regulation; Glass Ionomer Cements; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-4; Interleukin-6; Mice; Mice, Inbred C57BL; Osteoprotegerin; Oxides; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Resins, Synthetic; RNA, Messenger; Root Resorption; Silicates; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Adipose tissue fibrosis is associated with inflammation and insulin resistance in human obesity. In particular, visceral fat fibrosis is correlated with hyperlipidemia and ectopic fat accumulation. Myocardin-related transcription factor A (MRTFA) is an important coactivator that mediates the transcription of extracellular matrix and other fibrogenic genes. Here, we examine the role of MRTFA in the development of adipose tissue fibrosis and identify a signaling pathway that regulates the fate of vascular progenitors. We demonstrate that obesity induces the formation of Sca1

Topics: Adipocytes; Adipose Tissue; Animals; Cell Differentiation; Chronic Disease; Energy Metabolism; Fatty Liver; Fibrosis; Hypertrophy; Inflammation; Insulin Resistance; Integrin alpha5; Mice, Inbred C57BL; Models, Biological; Myofibroblasts; Obesity; Stem Cells; Trans-Activators; Transforming Growth Factor beta

The effects of diosmin (DS), pentoxifylline (PTX) and their combination on inflammatory response, oxidant/antioxidant balance, cytoglobin and cirrhotic reaction during bile duct ligation (BDL) were investigated and explored.. Fifty adult male Wistar albino rats were randomly allocated to five groups as following, sham: received vehicle only, BDL: subjected to common BDL without treatment, BDL plus DS: received 100 mg/kg/day orally, BDL plus PTX: received 50 mg/kg/day orally, BDL plus DS plus PTX: received DS and PTX in the same manner. The test period lasted 28 days, liver tissues and blood samples were collected to investigate biochemical markers (liver function biomarkers, oxidative stress markers, and antifibrotic markers), mRNA expression of Nrf-2, Keap-1, NF-κB-p65 and p38-MAPK by real-time PCR, protein expression of cytoglobin and NF-κB-p65 by western blot and iNOS and eNOS by immunohistochemistry. Histopathological study was performed to confirm our results.. Chronic BDL induced a significant alteration in liver functions, oxidative stress and fibrotic markers. Furthermore, unfavorable effects on gene and protein expression were observed after BDL. Histopathological findings of this group showed parallel effects. DS, PTX and their combination treatment significantly ameliorated the disturbance that occurred due to BDL. Similar findings were observed in liver histopathology.. DS and PTX could mitigate liver cirrhosis through modulation of Keap-1/Nrf-2/GSH and NF-κB-p65/p38-MAPK signaling pathways. In addition, we demonstrated that the hepatoprotective effect of DS and PTX is mediated by up-regulation of cytoglobin with inhibition of fibrotic reaction.

Topics: Animals; Cytoglobin; Diosmin; Disease Progression; Free Radicals; Gene Expression Profiling; Globins; Inflammation; Kelch-Like ECH-Associated Protein 1; Liver; Liver Cirrhosis; Liver Function Tests; Male; NF-E2-Related Factor 2; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidants; Oxidative Stress; Pentoxifylline; Rats; Rats, Wistar; Signal Transduction; Transforming Growth Factor beta

Coxsackievirus B3 (CVB3) is the primary cause of viral myocarditis. An early and abundant neutrophil accumulation in the myocardium is a hallmark of early CVB3 infection. Yet the relative contribution of neutrophils to host susceptibility to CVB3 myocarditis remains largely unknown. Herein, peripheral neutrophil depletion was implemented in a BALB/c mouse model of acute CVB3 myocarditis using the specific 1A-8 (anti-Ly6G) or a RB6-8C5 (anti-Gr-1) mAb covering a wide range. Anti-Ly6G treatment led to systemic neutropenia throughout the disease, but did not alter virus replication, disease susceptibility and histopathological changes in the heart and pancreas of mice. In contrast, depletion of both neutrophils and monocytes/macrophages by anti-Gr-1 mAb prior to and after infection significantly promoted susceptibility of mice to CVB3 infection which was associated with exacerbated cardiac and pancreatic viral load. However, depletion of Gr1+ cells significantly suppressed acute myocarditis and pancreatic acini destruction at day 7 post infection via reducing Ly6C

Topics: Animals; Antigens, Ly; Coxsackievirus Infections; Cytokines; Disease Models, Animal; Fibrosis; Heart; Inflammation; Leukocytes; Male; Mice; Mice, Inbred BALB C; Myocarditis; Neutropenia; Neutrophils; Pancreas; Receptors, Chemokine; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Viral Load; Virus Replication

Galectin-7 (Gal-7) has been associated with cell proliferation and apoptosis. It is known that Gal-7 antagonises TGFβ-mediated effects in hepatocytes by interacting with Smad3. Previously, we have demonstrated that Gal-7 is related to CD4+ T cells responses; nevertheless, its effect and functional mechanism on CD4+ T cells responses remain unclear. The murine CD4+ T cells were respectively cultured with Gal-7, anti-CD3/CD28 mAbs, or with anti-CD3/CD28 mAbs & Gal-7. The effects of Gal-7 on proliferation and the phenotypic changes in CD4+ T cells were assessed by flow cytometry. The cytokines from CD4+ T cells were analysed by quantitative real-time PCR. Subcellular localisation and expression of Smad3 were determined by immunofluorescence staining and Western blot, respectively. Gal-7 enhanced the proliferation of activated CD4+ T cells in a dose- and β-galactoside-dependent manner. Additionally, Gal-7 treatment did not change the ratio of Th2 cells in activated CD4+ T cells, while it increased the ratio of Th1 cells. Gal-7 also induced activated CD4+ T cells to produce a higher level of IFN-γ and TNF-α and a lower level of IL-10. Moreover, Gal-7 treatment significantly accelerated nuclear export of Smad3 in activated CD4+ T cells. These results revealed a novel role of Gal-7 in promoting proliferation and Th1/2 cells polarization toward Th1 in activated CD4+ T cells by inhibiting the TGFβ/Smad3 pathway.

Topics: Active Transport, Cell Nucleus; Animals; Cell Polarity; Cell Proliferation; Cellular Microenvironment; Galectins; Inflammation; Lymphocyte Activation; Male; Mice, Inbred BALB C; Signal Transduction; Smad3 Protein; Th1 Cells; Th2 Cells; Transforming Growth Factor beta

Wound healing is an orderly complex process involving inflammation, clotting, re-epithelialization, neovascularization and wound closure. In diabetic patients, such process is impaired and delayed, posing negative economic as well as social consequences. Diabetex, (patency# EP 0877617 A1) composed of L-alanine, d-ribose, nicotinic acid and calcium ascorbate, which was initially introduced to treat cancer is thought to have anti- diabetic effects. The present study was designed to investigate the therapeutic merit of diabetex as well as the cellular mechanisms involved in such effects and its safety profile compared to metformin in wounded diabetic rats.. Sixty adult male Sprague-Dawley albino rats were randomly divided into two major groups after induction of full thickness wound; control and treated groups. Liver and kidney function test, as well as cytokines (VEGF, TGF-β, PDGF and MMP2), fasting blood sugar were measured in animal sera. Histopathological studies including hematoxyline and eosin, Masson's trichrome stains were performed on wounded tissue.. Diabetex significantly improved wound healing, collagen formation, induced re-epithelialization and neovascularization. Moreover, cytokines involved in wound healing process were increased by the antidiabetic medication. Noteworthy, the drug exhibited a safe profile on liver and kidney function tests and significantly reduced fasting blood sugar.. The present study offers a novel approach for treating diabetic resistant wounds with a possible more economic, safe strategy.

Topics: Alanine; Animals; Ascorbic Acid; Blood Coagulation; Blood Glucose; Collagen; Diabetes Mellitus, Experimental; Drug Combinations; Inflammation; Male; Matrix Metalloproteinase 2; Neovascularization, Physiologic; Niacin; Platelet-Derived Growth Factor; Rats; Rats, Sprague-Dawley; Ribose; Skin; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Wound Healing

Renal injury is a hallmark adverse reaction to sodium valproate (SVP), and caffeic acid (CAFF) is a phenolic compound that has anti-inflammatory and antioxsidant properties. So, this investigation was assessed to evaluate the nephrotoxic potential of SVP and the defensive impact of CAFF against SVP nephrotoxicity. SVP was given at a dose of 500 mg/kg (i.p.) once daily for 2 weeks, while CAFF was given at a dose of 50 mg/kg (orally), simultaneously with SVP. Concurrent treatment with CAFF reduced urea and creatinine, lipid peroxidation (malondialdehyde), tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), nuclear factor kappa B (NF-κB/p65), and transforming growth factor β (TGF-β) levels. However, with increased glutathione content, CAFF also halted the activated Notch signaling cascade. Furthermore, CAFF suppressed caspase-3 and inducible nitric oxide synthase expressions. To conclude, on the basis of the results obtained, CAFF proved to protect against SVP-induced nephrotoxicity via its antioxidant, anti-inflammatory, and antiapoptotic properties.

Topics: Animals; Anticonvulsants; Biomarkers; Caffeic Acids; Caspase 3; Creatinine; Inflammation; Interferon-gamma; Kidney; Male; Malondialdehyde; NF-kappa B; Nitric Oxide Synthase Type II; Rats, Sprague-Dawley; Receptors, Notch; Signal Transduction; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Urea; Valproic Acid

The present study attempts to elucidate the role of TRPV1 cation channel receptor on primary repair in an incision-wounded mouse cornea in vivo. Previous study revealed that blocking TRPV1 suppressed myofibroblast formation and expression of transforming growth factor β1 (TGFβ1) in cultured keratocytes or ocular fibroblasts. Male C57BL/6 (wild-type; WT) mice and male C57BL/6 Trpv1-null (KO) mice incurred a full-thickness incision injury (1.8 mm in length, limbus to limbus) in the central cornea of one eye with a surgical blade under general and topical anesthesia. The injury was not sutured. On days 0, 5, and 10, the eyes were enucleated, processed for histology, immunohistochemistry, and real-time RT-PCR gene expression analysis to evaluate the effects of the loss of TRPV1 on primary healing. Electron microscopy observation was also performed to know the effect of the loss of TRPV1 on ultrastructure of keratocytes. The results showed that the loss of Trpv1 gene delayed closure of corneal stromal incision with hindered myofibroblast transdifferentiation along with declines in the expression of collagen Ia1 and TGFβ1. Inflammatory cell infiltration was not affected by the loss of TRPV1. Ultrastructurally endoplasmic reticulum of TRPV1-null keratocytes was more extensively dilated as compared with WT keratocytes, suggesting an impairment of protein secretion by TRPV1-gene knockout. These results indicate that injury-related TRPV1 signal is involved in healing of stromal incision injury in a mouse cornea by selectively stimulating TGFβ-induced granulation tissue formation.

Topics: Animals; Cornea; Corneal Injuries; Inflammation; Male; Mice, Inbred C57BL; Mice, Knockout; Myofibroblasts; Transforming Growth Factor beta; TRPV Cation Channels; Wound Healing

Graphene oxide (GO) modulates the functions of antigen-presenting cells including dendritic cells (DCs). Although carbon nanotubes affect expression of the MHC class I-like CD1d molecule, whether GO can influence immune responses of CD1d-dependent invariant natural killer T (iNKT) cells remains unclear. Here, we investigated the impact of GO on inflammatory responses mediated by α-galactosylceramide (α-GalCer), an iNKT cell agonist. We found that in vivo GO treatment substantially inhibited the capacity of α-GalCer to induce the iNKT cell-mediated trans-activation of and cytokine production by innate and innate-like cells, including DCs, macrophages, NK cells, and γδ T cells. Such effects of GO on α-GalCer-induced inflammatory responses closely correlated with iNKT cell polarization towards TGFβ production, which also explains the capacity of GO to expand regulatory T cells. Interestingly, the absence of TLR4, a receptor for GO, failed to downregulate, and instead partially enhanced the anti-inflammatory activity of GO against α-GalCer-elicited responses, implying negative effects of TLR4 signaling on the anti-inflammatory properties of GO. By employing an α-GalCer-induced sepsis model, we further demonstrated that GO treatment significantly protected mice from α-GalCer-induced lethality. Taken together, we provide strong evidence that GO holds promise as an adjuvant to modulate iNKT cell responses for immunotherapy.

Topics: Animals; Antigens, CD1d; Cell Polarity; Dendritic Cells; Disease Models, Animal; Galactosylceramides; Graphite; Humans; Inflammation; Intraepithelial Lymphocytes; Lymphocyte Activation; Mice; Nanotubes, Carbon; Natural Killer T-Cells; Sepsis; Toll-Like Receptor 4; Transforming Growth Factor beta

Scleroderma or systemic sclerosis (SSc) is a clinically heterogeneous rheumatological autoimmune disease affecting the skin, internal organs and blood vessels. There is at present no effective treatment for this condition. Our study investigated the effects of 5-aminolevulinic acid (5-ALA), which is a precursor of haem synthesis, on graft-vs-host disease (GvHD)-induced SSc murine model. Lymphocytes were intravenously injected from donor mice (B10.D2) into recipient BALB/c mice (recombination-activating gene 2 (Rag-2)-null mice) deficient in mature T and B cells to induce sclerodermatous GvHD (scl-GvHD). To investigate the effect of 5-ALA on scl-GvHD, combination of 5-ALA and sodium ferrous citrate (SFC) was orally administered to the recipient mice for 9 weeks. 5-ALA/SFC treatment significantly reduced progressive inflammation and fibrosis in the skin and ears. Furthermore, 5-ALA/SFC suppressed mRNA expression of transforming growth factor-β, type I collagen and inflammatory cytokines. These results indicate that the 5-ALA/SFC combination treatment has a protective effect against tissue fibrosis and inflammation in a murine scl-GvHD-induced skin and ear inflammation and fibrosis. Furthermore, the efficacy of 5-ALA/SFC suggests important implications of HO-1 protective activity in autoimmune diseases, and therefore, 5-ALA/SFC may have promising clinical applications. These findings suggested that the 5-ALA/SFC treatment may be the potential strategies for SSc.

Topics: Aminolevulinic Acid; Animals; Collagen Type I; Cytokines; Disease Models, Animal; Drug Therapy, Combination; Female; Ferrous Compounds; Fibrosis; Gene Expression; Graft vs Host Disease; Heme Oxygenase-1; Inflammation; Membrane Proteins; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; Photosensitizing Agents; RNA, Messenger; Scleroderma, Systemic; Skin; Transforming Growth Factor beta

Elevated levels of mitochondrial reactive oxygen species (ROS) can lead to the development of airway inflammation. In this study, we investigated the role of Aspergillus proteases-which contribute to the pathogenesis of Aspergillus-induced diseases such as allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, and atopic asthma-and their mechanisms of action in airway inflammation using primary human bronchial epithelial cells, and evaluated the inflammatory responses mediated by mitochondrial ROS. We found that Aspergillus proteases regulated the expression of multifunctional inflammatory cytokines such as interleukin (IL)- 1β, - 6, and - 8, and transforming growth factor (TGF)-β, which stimulated cytokine production and chemokines involved in leukocyte migration and activated an inflammatory cascade. Expression of these factors and activator protein (AP)- 1 were decreased by treatment with the mitochondrial ROS scavenger Mito-TEMPO, suggesting that mitochondria are important sources of ROS in the context of inflammatory response by Aspergillus protease. The regulation of mitochondrial ROS influenced the production of proinflammatory mediators by preventing mitochondrial ROS-induced AP-1 activation in airway epithelial cells. In addition, Aspergillus protease-mediated mitochondrial ROS production was associated with downregulation of uncoupling protein (UCP)- 2 expression by TGF-β-SMAD4 signaling, which may play a regulatory role in mitochondrial ROS formation during fungal protease-mediated epithelial inflammation. This improved understanding of the allergenic fungal protease-induced inflammatory mechanism in the bronchial epithelium will help in developing intervention strategies for the regulation of inflammatory response in allergic airway diseases.

Topics: Aspergillus oryzae; Bronchi; Cells, Cultured; Fungal Proteins; Humans; Inflammation; Mitochondria; Peptide Hydrolases; Reactive Oxygen Species; Respiratory Mucosa; Signal Transduction; Smad4 Protein; Transforming Growth Factor beta; Uncoupling Protein 2

There is clear evidence that neuroinflammation plays a crucial role in the pathogenesis of Alzheimer's disease. Consequently, modulating the inflammatory environment in brain has become a powerful and attractive strategy to deal with Alzheimer's disease physiopathology. In spite of the neuroprotective capacity shown by ASS234, a multitarget propargylamine targeted for Alzheimer's disease, its regulation of inflammation in the brain still remains unexplored. Therefore, we aimed to characterize possible anti-inflammatory effects of ASS234, counteracting induced inflammatory effects in RAW 264.7 cells and evaluating seven neuroinflammation related genes expression profiling (IL-6, IL-10, IL1β, NF-κB, TNF-α, TNFR1, and TGF-β), after ASS234 (5 μM) treatment in SH-SY5Y cells. The analysis of the obtained fold changes lead us to conclude that ASS234 may play an important role facing the neuroinflammatory environment in Alzheimer's disease pathology.

Topics: Alzheimer Disease; Animals; Cell Line, Tumor; Cytokines; Gene Expression; Humans; Indoles; Inflammation; Interleukin-10; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Mice; Neurons; NF-kappa B; Piperidines; RAW 264.7 Cells; Receptors, Tumor Necrosis Factor, Type I; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Intestinal macrophages in healthy human mucosa are profoundly down-regulated for inflammatory responses (inflammation anergy) due to stromal TGF-β inactivation of NF-κB. Paradoxically, in cytomegalovirus (CMV) intestinal inflammatory disease, one of the most common manifestations of opportunistic CMV infection, intestinal macrophages mediate severe mucosal inflammation. Here we investigated the mechanism whereby CMV infection promotes macrophage-mediated mucosal inflammation. CMV infected primary intestinal macrophages but did not replicate in the cells or reverse established inflammation anergy. However, CMV infection of precursor blood monocytes, the source of human intestinal macrophages in adults, prevented stromal TGF-β-induced differentiation of monocytes into inflammation anergic macrophages. Mechanistically, CMV up-regulated monocyte expression of the TGF-β antagonist Smad7, blocking the ability of stromal TGF-β to inactivate NF-κB, thereby enabling MyD88 and NF-κB-dependent cytokine production. Smad7 expression also was markedly elevated in mucosal tissue from subjects with CMV colitis and declined after antiviral ganciclovir therapy. Confirming these findings, transfection of Smad7 antisense oligonucleotide into CMV-infected monocytes restored monocyte susceptibility to stromal TGF-β-induced inflammation anergy. Thus, CMV-infected monocytes that recruit to the mucosa, not resident macrophages, are the source of inflammatory macrophages in CMV mucosal disease and implicate Smad7 as a key regulator of, and potential therapeutic target for, CMV mucosal disease.

Topics: Cells, Cultured; Clonal Anergy; Cytomegalovirus; Cytomegalovirus Infections; Humans; Inflammation; Intestinal Mucosa; Macrophages; Monocytes; Myeloid Differentiation Factor 88; NF-kappa B; RNA, Small Interfering; Smad7 Protein; Transforming Growth Factor beta; Young Adult

BACKGROUND Epidermal growth factor receptor (EGFR) expression is associated with hepatic fibrogenesis. Activated hepatic stellate cells (HSCs) release inflammatory cytokines and extracellular matrix (ECM). The aim of this in vitro study was to investigate HSCs, activated by lipopolysaccharide (LPS), and the role of EGFR using the small molecule EGFR inhibitor, AG1478, and using knockdown of the EGFR gene using small interfering RNA (siRNA) cell transfection. MATERIAL AND METHODS HSCs, isolated from male Sprague-Dawley rats, were cultured and treated with and without LPS (100 ng/mL), with and without AG1478 (2.5 μM and 5.0 μM) Cell survival and proliferation were studied using an MTT assay. Western blot was used to measure levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IκBα, cytoplasm and nuclear NFκB and EGFR in the cell lysates before and after small interfering RNA (siRNA) transfection. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to measure the mRNA levels of transforming growth factor (TGF)-β, Col-1, and α-smooth muscle actin (SMA). The Toll-like receptor 4 (TLR4) antagonist TAK-242 and the selective c-Src inhibitor, PP2 in LPS induced-EGFR phosphorylation was evaluated using Western blot. RESULTS Inhibition of EGFR decreased LPS-induced HSC proliferation and inflammatory cytokines. The TLR4 antagonist TAK-242, and the c-Src inhibitor, PP2 reduced EGFR activation of HSCs, indicating a possible role for the TLR4/c-Src signaling cascade in LPS-induced HSC activation. CONCLUSIONS Activation of HSCs by LPS in vitro, including the expression of inflammatory cytokines and mediators of fibrogenesis, were shown to be dependent on the expression of EGFR.

Topics: Animals; Cell Proliferation; Cell Survival; Cytokines; ErbB Receptors; Extracellular Matrix; Gene Knockdown Techniques; Genes, src; Hepatic Stellate Cells; Inflammation; Lipopolysaccharides; Liver; Liver Cirrhosis; Male; NF-kappa B; Primary Cell Culture; Quinazolines; Rats; Rats, Sprague-Dawley; Signal Transduction; Toll-Like Receptor 4; Transforming Growth Factor beta; Tyrphostins

Diabetic cardiomyopathy (DCM) is a kind of disease caused by metabolic disorders and microangiopathy. The main pathophysiological changes of DCM include fibrosis, myocardial cell apoptosis and autonomic neuropathy. Therefore, treatment aimed at these processes may benefit patients with DCM. We designed an experiment with the peroxisome proliferator-activated receptor-gamma (PPARγ) agonist GW 1929 to detect whether the activation of PPARγ could alleviate the degree of DCM. To further detect the mechanism of PPARγ in DCM, we used the PPARγ antagonist GW 9662 and ERK antagonist PD 098059 both in vitro and in vivo and found that PPARγ functioned by inhibiting ERK. We also performed Western blot, PCR, ELISA, immunohistochemistry, TUNEL assay, Sirius red staining and gelatin zymography to investigate inflammation, apoptosis, MMP activity and epithelial-to-mesenchymal transition (EMT). The results showed that the activation of PPARγ inhibited these reactions and inhibiting ERK also simulated this phenomenon. In conclusion, these results demonstrated that PPARγ activation in the diabetic myocardium of mice reduces myocardial fibrosis via regulation of the TGF-β/ERK pathway and EMT.

Topics: Animals; Benzophenones; Diabetic Cardiomyopathies; Epithelial-Mesenchymal Transition; Fibrosis; Inflammation; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Myocardium; Peroxisome Proliferator-Activated Receptors; PPAR gamma; Signal Transduction; Transforming Growth Factor beta; Tyrosine

Pulmonary fibrosis is a multifaceted disease with high mortality and morbidity, and it is commonly nonresponsive to conventional therapy.. We explore the possible discourse of sinapic acid (SA) against the prevention of bleomycin (BLM)-instigated lung fibrosis in rats through modulation of Nrf2/HO-1 and NF-κB signaling pathways.. Lung fibrosis was persuaded in Sprague-Dawley rats by a single intratracheal BLM (6.5 U/kg) injection. Then, these rats were treated with SA (10 and 20 mg/kg, p.o.) for 28 days. The normal control rats provided saline as a substitute of BLM. The lung function and biochemical, histopathological, and molecular alterations were studied in serum, bronchoalveolar lavage fluid (BALF), and the lungs tissues.. SA treatment significantly restored BLM-induced alterations in body weight index and serum biomarkers [lactate dehydrogenase (LDH) and alkaline phosphatase (ALP)]. SA (10 and 20 mg/kg) treatment appeared to show a pneumoprotective effect through upregulation of antioxidant status, downregulation of inflammatory cytokines and MMP-7 expression, and reduction of collagen accumulation (hydroxyproline). Nrf2, HO-1, and TGF-β expression was downregulated in BLM-induced fibrosis model, while the reduced expression levels were significantly and dose-dependently upregulated by SA (10 and 20 mg/kg) treatment. We demonstrated that SA ameliorates BLM-induced lung injuries through inhibition of apoptosis and induction of Nrf2/HO-1-mediated antioxidant enzymes via NF-κB inhibition. The histopathological findings also revealed that SA treatment (10 and 20 mg/kg) significantly ameliorated BLM-induced lung injury.. The present results showed the ability of SA to restore the antioxidant system and to inhibit oxidative stress, proinflammatory cytokines, extracellular matrix, and TGF-β. This is first report demonstrating that SA amoleriates BLM induced lung injuries through inhibition of apoptosis and induction of Nrf2 and HO-1 mediated antioxidant enzyme via NF-κB inhibition. The histopathological finding reveals that SA treatment (10 and 20 mg/kg) significantly ameliorates BLM induced lung injuries.

Topics: Animals; Antioxidants; Apoptosis; Biomarkers; Bleomycin; Bronchoalveolar Lavage Fluid; Coumaric Acids; Disease Models, Animal; Heme Oxygenase-1; Hydroxyproline; Inflammation; Lung; Matrix Metalloproteinase 7; NF-E2-Related Factor 2; NF-kappa B; Organ Size; Oxidative Stress; Pulmonary Fibrosis; Rats, Sprague-Dawley; Transforming Growth Factor beta; Weight Gain

The anaphylatoxin C5a is generated upon activation of the complement system, a crucial arm of innate immunity. C5a mediates proinflammatory actions via the C5a receptor C5aR1 and thereby promotes host defence, but also modulates tissue homeostasis. There is evidence that the C5a/C5aR1 axis is critically involved both in physiological bone turnover and in inflammatory conditions affecting bone, including osteoarthritis, periodontitis, and bone fractures. C5a induces the migration and secretion of proinflammatory cytokines of osteoblasts. However, the underlying mechanisms remain elusive. Therefore, in this study we aimed to determine C5a-mediated downstream signalling in osteoblasts. Using a whole-genome microarray approach, we demonstrate that C5a activates mitogen-activated protein kinases (MAPKs) and regulates the expression of genes involved in pathways related to insulin, transforming growth factor-β and the activator protein-1 transcription factor. Interestingly, using coimmunoprecipitation, we found an interaction between C5aR1 and Toll-like receptor 2 (TLR2) in osteoblasts. The C5aR1- and TLR2-signalling pathways converge on the activation of p38 MAPK and the generation of C-X-C motif chemokine 10, which functions, among others, as an osteoclastogenic factor. In conclusion, C5a-stimulated osteoblasts might modulate osteoclast activity and contribute to immunomodulation in inflammatory bone disorders.

Topics: Anaphylatoxins; Animals; Bone Diseases; Bone Remodeling; Chemokine CXCL10; Complement C5a; Gene Expression Regulation, Developmental; Humans; Immunity, Innate; Inflammation; Mice; Osteoblasts; Osteoclasts; Osteogenesis; p38 Mitogen-Activated Protein Kinases; Receptor, Anaphylatoxin C5a; Signal Transduction; Toll-Like Receptor 2; Transforming Growth Factor beta

A longitudinal case-control animal model.. The aim of this study was to investigate the inflammatory pathways active in the multifidus muscle after spontaneous intervertebral disc degeneration (IDD), and whether these IDD-related muscle changes can be ameliorated by exercise.. A pro-inflammatory response is present in the multifidus muscle after an intervertebral disc lesion and has been proposed to drive the structural alterations present during low back pain. However, it is not known whether spontaneous IDD produces an inflammatory response. Furthermore, exercise/physical activity produces a strong anti-inflammatory response, but its effectiveness in ameliorating inflammation in the multifidus is unknown. We assessed the inflammatory profile of the multifidus and the effectiveness of physical activity as a treatment using an animal model of spontaneous model of IDD.. Wild-type and SPARC null mice that were sedentary or housed with a running wheel were used in this study. Multifidus muscle segments were harvested from L2-L6 from the mice at 9 months of age after they had undergone a magnetic resonance imaging (MRI) scan to determine levels with IDD. The inflammatory profile of the multifidus was examined using quantitative polymerase chain reaction (PCR) assays.. Spontaneous IDD in the SPARC-null mice caused a dysregulation of interleukin (IL)-1β, IL6, transforming growth factor-beta (TGFβ1), and adiponectin expression. More specifically, the proximity and degree of IDD was related to levels of IL-1β expression. Physical activity reduced the pro-inflammatory response to IDD in the multifidus. IL-1β, tumor necrosis factor (TNF), IL-10, adiponectin, and leptin levels were lower in the physically active group.. These results reveal that spontaneous IDD causes dysregulation of the inflammatory pathways active in the multifidus muscle. These alterations were related to the severity of IDD and were prevented by physical activity.. N/A.

Topics: Animals; Disease Models, Animal; Inflammation; Inflammation Mediators; Interleukin-1beta; Intervertebral Disc; Intervertebral Disc Degeneration; Mice, Inbred C57BL; Mice, Knockout; Osteonectin; Paraspinal Muscles; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Low-dose radiotherapy (LD-RT) for benign inflammatory and/or bone destructive diseases has been used long. Therefore, mechanistic investigations on cells being present in joints are mostly made in an inflammatory setting. This raises the question whether similar effects of LD-RT are also seen in healthy tissue and thus might cause possible harmful effects. We performed examinations on the functionality and phenotype of key cells within the joint, namely on fibroblast-like synoviocytes (FLS), osteoclasts and osteoblasts, as well as on immune cells. Low doses of ionizing radiation showed only a minor impact on cytokine release by healthy FLS as well as on molecules involved in cartilage and bone destruction and had no significant impact on cell death and migration properties. The bone resorbing abilities of healthy osteoclasts was slightly reduced following LD-RT and a positive impact on bone formation of healthy osteoblasts was observed after in particular exposure to 0.5 Gray (Gy). Cell death rates of bone-marrow cells were only marginally increased and immune cell composition of the bone marrow showed a slight shift from CD8⁺ to CD4⁺ T cell subsets. Taken together, our results indicate that LD-RT with particularly a single dose of 0.5 Gy has no harmful effects on cells of healthy joints.

Topics: Animals; Apoptosis; Bone Marrow Cells; Cartilage, Articular; Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Fibroblasts; Inflammation; Joints; Mice, Inbred C57BL; Osteoblasts; Osteoclasts; Osteogenesis; Osteoprotegerin; Radiation, Ionizing; Synoviocytes; Transforming Growth Factor beta; Up-Regulation

Previously, we reported the successful regeneration of injured peripheral nerves using human dental pulp stem cells (DPSCs) or differentiated neuronal cells from DPSCs (DF-DPSCs) in a rat model. Here, we attempted to evaluate oxidative stress and supraspinal neuro-inflammation in rat brain after sciatic nerve injury (SNI). We divided our experimental animals into three SNI groups based on time. The expression of a microglial (Iba1) marker and reactive oxygen species (ROS) was lower in DPSCs and higher in DF-DPSCs. In contrast, the expression of an astroglial (GFAP) marker was higher in DPSCs and lower in DF-DPSCs at 2 weeks. However, the expression of ROS, Iba1 and GFAP gradually decreased at 8 and 12 weeks in the SNI DPSCs and DF-DPSCs groups compared to the SNI control. Furthermore, anti-inflammatory cytokine (IL-4 and TGF-β) expression was lower at 2 weeks, while it gradually increased at 8 and 12 weeks after surgery in the SNI DPSCs and DF-DPSCs groups. Similarly, SNI DPSCs had a high expression of pAMPK, SIRT1 and NFkB at the onset of SNI. However, 12 weeks after surgery, pAMPK and SIRT1 expression levels were higher and NFkB was down-regulated in both DPSCs and DF-DPSCs compared to the control group. Finally, we concluded that DPSCs responded early and more efficiently than DF-DPSCs to counterbalance peripheral nerve injury (PNI)-induced oxidative stress and supraspinal neuro-inflammation in rat brain.

Topics: Adenylate Kinase; Animals; Astrocytes; Brain; Dental Pulp; Disease Models, Animal; Female; Inflammation; Inflammation Mediators; Microglia; NF-kappa B; Oxidative Stress; Peripheral Nerve Injuries; Phosphorylation; Rats, Sprague-Dawley; Reactive Oxygen Species; RNA, Messenger; Sciatic Nerve; Sirtuin 1; Stem Cell Transplantation; Stem Cells; Transforming Growth Factor beta

Liver fibrosis is a health concern that leads to organ failure mediated via production of inflammatory cytokines and fibrotic biomarkers. This study aimed to explore the protective effect of tadalafil, a phosphodiesterase-5 inhibitor, against thioacetamide (TAA)-induced liver fibrosis. Fibrosis was induced by administration of TAA (200 mg/kg, i.p.) twice weekly for 6 weeks. Serum transaminases activities, liver inflammatory cytokines, fibrotic biomarkers, and liver histopathology were assessed. TAA induced marked histopathological changes in liver tissues coupled with elevations in serum transaminases activities. Furthermore, hepatic content of nitric oxide and tumor necrosis factor-alpha, interleukin-6, and interleukin-1 beta were elevated, together with a reduction of interleukin-10 in the liver. In addition, TAA increased hepatic contents of transforming growth factor-beta, hydroxyproline, alpha-smooth muscle actin, and gene expression of collagen-1. Pretreatment with tadalafil protected against TAA-induced liver fibrosis, in a dose-dependent manner, as proved by the alleviation of inflammatory and fibrotic biomarkers. The effects of tadalafil were comparable with that of silymarin, a natural antioxidant, and could be assigned to its anti-inflammatory and anti-fibrotic properties.

Topics: Actins; Animals; Anti-Inflammatory Agents; Biomarkers; Collagen Type I; Cytokines; Gene Expression; Hydroxyproline; Inflammation; Interleukin-10; Interleukin-1beta; Interleukin-6; Liver; Liver Cirrhosis; Male; Nitric Oxide; Rats; Rats, Wistar; Tadalafil; Thioacetamide; Transaminases; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The use of inorganic calcium/phosphate supplemented with biopolymers has drawn lots of attention in bone regenerative medicine. While inflammation is required for bone healing, its exacerbation alters tissue regeneration/implants integration. Inspired by bone composition, a friendly automated spray-assisted system was used to build bioactive and osteoinductive calcium phosphate/chitosan/hyaluronic acid substrate (CaP-CHI-HA). Exposing monocytes to CaP-CHI-HA resulted in a secretion of pro-healing VEGF and TGF-β growth factors, TNF-α, MCP-1, IL-6 and IL-8 pro-inflammatory mediators but also IL-10 anti-inflammatory cytokine along with an inflammatory index below 1.5 (versus 2.5 and 7.5 following CaP and LPS stimulation, respectively). Although CD44 hyaluronic acid receptor seems not to be involved in the inflammatory regulation, results suggest a potential role of chemical composition and calcium release from build-up substrates, in affecting the intracellular expression of a calcium-sensing receptor. Herein, our findings indicate a great potential of CaP-CHI-HA in providing required inflammation-healing balance, favorable for bone healing/regeneration.

Topics: Bone and Bones; Bone Regeneration; Bone Substitutes; Calcium Phosphates; Chemokine CCL2; Chitosan; Gene Expression Regulation; Humans; Hyaluronan Receptors; Hyaluronic Acid; Inflammation; Interleukins; Mitochondria; Reactive Oxygen Species; Receptors, Calcium-Sensing; Signal Transduction; THP-1 Cells; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Vinculin

Inflammation helps regulate normal growth and tissue repair. Although bone morphogenetic proteins (BMPs) and inflammation are known contributors to abnormal bone formation, how these pathways interact in ossification remains unclear.. We examined this potential link in patients with fibrodysplasia ossificans progressiva (FOP), a genetic condition of progressive heterotopic ossification caused by activating mutations in the Activin A type I receptor (ACVR1/ALK2). FOP patients show exquisite sensitivity to trauma, suggesting that BMP pathway activation may alter immune responses. We studied primary blood, monocyte, and macrophage samples from control and FOP subjects using multiplex cytokine, gene expression, and protein analyses; examined CD14+ primary monocyte and macrophage responses to TLR ligands; and assayed BMP, TGF-β activated kinase 1 (TAK1), and NF-κB pathways.. FOP subjects at baseline without clinically evident heterotopic ossification showed increased serum IL-3, IL-7, IL-8, and IL-10. CD14+ primary monocytes treated with the TLR4 activator LPS showed increased CCL5, CCR7, and CXCL10; abnormal cytokine/chemokine secretion; and prolonged activation of the NF-κB pathway. FOP macrophages derived from primary monocytes also showed abnormal cytokine/chemokine secretion, increased TGF-β production, and p38MAPK activation. Surprisingly, SMAD phosphorylation was not significantly changed in the FOP monocytes/macrophages.. Abnormal ACVR1 activity causes a proinflammatory state via increased NF-κB and p38MAPK activity. Similar changes may contribute to other types of heterotopic ossification, such as in scleroderma and dermatomyositis; after trauma; or with recombinant BMP-induced bone fusion. Our findings suggest that chronic antiinflammatory treatment may be useful for heterotopic ossification.

Topics: Activin Receptors, Type I; Chemokines; Cytokines; Humans; Inflammation; Macrophages; Monocytes; Myositis Ossificans; NF-kappa B; Ossification, Heterotopic; p38 Mitogen-Activated Protein Kinases; Signal Transduction; Transforming Growth Factor beta

Mesenchymal stromal cells (MSCs) are potent regulators of immune responses largely through paracrine signaling. MSC secreted extracellular vesicles (MSC-EVs) are increasingly recognized as the key paracrine factors responsible for the biological and therapeutic function of MSCs. We report the first comprehensive study demonstrating the immunomodulatory effect of MSC-EVs on dendritic cell (DC) maturation and function. MSC-EVs were isolated from MSC conditioned media using differential ultracentrifugation. Human monocyte-derived DCs were generated in the absence or presence of MSC-EVs (20 ug/ml) then subjected to phenotypic and functional analysis

Topics: Cell Differentiation; Cell Proliferation; Cells, Cultured; Chemokine CCL21; Cytokines; Dendritic Cells; Extracellular Vesicles; Graft vs Host Disease; Humans; Inflammation; Interleukin-12; Interleukin-6; Mesenchymal Stem Cells; MicroRNAs; Receptors, CCR7; Transforming Growth Factor beta

Isoquercetin (IQ), a glucoside derivative of quercetin, has been reported to have beneficial effects in nonalcoholic fatty liver disease (NAFLD). In this study, we investigated the potential improvement of IQ in liver lipid accumulation, inflammation, oxidative condition, and activation in Kupffer cells (KCs) on a high-fat diet (HFD) induced NAFLD models. Male Sprague-Dawley (SD) rats were induced by HFD, lipopolysaccharides/free fatty acids (LPS/FFA) induced co-culture cells model between primary hepatocytes and Kupffer cells was used to test the effects and the underlying mechanism of IQ. Molecular docking was performed to predict the potential target of IQ. Significant effects of IQ were found on reduced lipid accumulation, inflammation, and oxidative stress. In addition, AMP-activated protein kinase (AMPK) pathway was activated by IQ, and is plays an important role in lipid regulation. Meanwhile, IQ reversed the increase of activated KCs which caused by lipid overload, and also suppression of Transforming growth factor beta (TGF-β) signaling by TGF-β Recptor-1 and SMAD2/3 signaling. Finally, TGF-βR1 and TGF-βR2 were both found may involve in the mechanism of IQ. IQ can improve hepatic lipid accumulation and decrease inflammation and oxidative stress by its activating AMPK pathway and suppressing TGF-β signaling to alleviate NAFLD.

Topics: AMP-Activated Protein Kinases; Animals; Biomarkers; Coculture Techniques; Cytokines; Diet, High-Fat; Disease Models, Animal; Down-Regulation; Inflammation; Kupffer Cells; Lipid Metabolism; Liver; Male; Molecular Docking Simulation; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Phosphorylation; Protein Serine-Threonine Kinases; Quercetin; Rats, Sprague-Dawley; Signal Transduction; Transforming Growth Factor beta

Many pathogens initiate infection at mucosal surfaces, and tissue-resident memory T (Trm) cells play an important role in protective immunity, yet the tissue-specific signals that regulate Trm differentiation are poorly defined. During Yersinia infection, CD8

Topics: Adjuvants, Immunologic; Animals; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Antiviral Agents; CD8-Positive T-Lymphocytes; Cell Differentiation; Immunologic Memory; Inflammation; Integrin alpha Chains; Interferons; Interleukin-12; Intestines; Lectins, C-Type; Macrophages; Mice; Mice, Inbred C57BL; Receptors, CCR2; Transforming Growth Factor beta; Yersinia pseudotuberculosis Infections

Inflammation is frequently associated with initiation, progression, and metastasis of colorectal cancer (CRC). Here, we unveil a CRC-specific metastatic programme that is triggered via the transcriptional repressor, GFI1. Using data from a large cohort of clinical samples including inflammatory bowel disease and CRC, and a cellular model of CRC progression mediated by cross-talk between the cancer cell and the inflammatory microenvironment, we identified GFI1 as a gating regulator responsible for a constitutively activated signalling circuit that renders CRC cells competent for metastatic spread. Further analysis of mouse models with metastatic CRC and human clinical specimens reinforced the influence of GFI1 downregulation in promoting CRC metastatic spread. The novel role of GFI1 is uncovered for the first time in a human solid tumour such as CRC. Our results imply that GFI1 is a potential therapeutic target for interfering with inflammation-induced CRC progression and spread.

Topics: Animals; Cell Line, Tumor; Cell Movement; Colorectal Neoplasms; Disease Progression; DNA-Binding Proteins; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Inflammation; Inflammatory Bowel Diseases; Liver Neoplasms; Lymphatic Metastasis; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Transplantation; Proto-Oncogene Proteins c-akt; Receptors, Prostaglandin E, EP2 Subtype; RNA, Small Interfering; Signal Transduction; STAT3 Transcription Factor; Transcription Factors; Transforming Growth Factor beta; Tumor Microenvironment

Chronic kidney disease (CKD) and arterial stiffness are associated with increased cardiovascular morbidity and mortality. Inflammation is proposed to have a role in the development of arterial stiffness, and CKD is recognized as a proinflammatory state. Arterial stiffness is increased in CKD, and cross-sectional data has suggested a link between increased inflammatory markers in CKD and higher measures of arterial stiffness. However, no large scale investigations have examined the impact of inflammation on the progression of arterial stiffness in CKD.. We performed baseline assessments of 5 inflammatory markers in 3,939 participants from the chronic renal insufficiency cohort (CRIC), along with serial measurements of arterial stiffness at 0, 2, and 4 years of follow-up.. A total of 2,933 participants completed each of the follow-up stiffness measures. In cross-sectional analysis at enrollment, significant associations with at least 2 measures of stiffness were observed for fibrinogen, interleukin-6, high-sensitivity C-reactive protein, proteinuria, and composite inflammation score after adjustment for confounders. In longitudinal analyses, there were few meaningful correlations between baseline levels of inflammation and changes in metrics of arterial stiffness over time.. In a large cohort of CKD participants, we observed multiple significant correlations between initial markers of inflammation and metrics of arterial stiffness, but baseline inflammation did not predict changes in arterial stiffness over time. While well-described biologic mechanisms provide the basis for our understanding of the cross-sectional results, continued efforts to design longitudinal studies are necessary to fully elucidate the relationship between chronic inflammation and arterial stiffening.

Topics: Adult; Aged; Blood Pressure; C-Reactive Protein; Cohort Studies; Enzyme-Linked Immunosorbent Assay; Female; Fibrinogen; Follow-Up Studies; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Interleukin-6; Linear Models; Male; Middle Aged; Proteinuria; Pulse Wave Analysis; Renal Insufficiency, Chronic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Stiffness

Topics: Animals; Flow Cytometry; Forkhead Transcription Factors; Gene Expression Regulation; Inflammation; Interleukin-6; Intestinal Diseases; Lacticaseibacillus casei; Male; Mice; Mice, Inbred BALB C; Nuclear Receptor Subfamily 1, Group F, Member 3; Probiotics; Specific Pathogen-Free Organisms; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

Bacillus Calmette-Guerin (BCG) is a potent agent for the prevention of tuberculosis. Current studies have regarded BCG as an immunomodulator. However, there is little information on whether it can be used to inhibit airway inflammation and airway remodeling caused by asthma. Therefore, in this study, we investigate the role of epithelial-mesenchymal transition (EMT) in airway inflammation and airway remodeling as well as the possible therapeutic mechanism of BCG for the treatment of asthma. Wistar rats were sensitized and challenged by ovalbumin for 2 weeks or 8 weeks. BCG was subcutaneously administered daily before every ovalbumin challenge to determine its therapeutic effects. The 2 weeks model group showed extensive eosinophilia, chronic inflammatory responses, bronchial wall thickening, airway epithelium damage, increased levels of transforming growth factor β 1 (TGF-β

Topics: Actins; Airway Remodeling; Animals; Asthma; BCG Vaccine; Bronchi; Bronchoalveolar Lavage Fluid; Cadherins; Disease Models, Animal; Epithelial-Mesenchymal Transition; Fibronectins; Goblet Cells; Humans; Inflammation; Ovalbumin; Rats; Rats, Wistar; Transforming Growth Factor beta; Transforming Growth Factor beta1

Celastrol has been reported to exert therapeutic potential on pro-inflammatory diseases including asthma, Crohn's disease, arthritis and neurodegenerative disorders via inhibiting NF-κB pathway. While the effect of celastrol on intervertebral disc degeneration (IDD), which is also a pro-inflammatory disease, remains unknown. In this study, we evaluated the effect of celastrol on IDD in IL-1β treated human nucleus pulposus cells in vitro as well as in puncture induced rat IDD model in vivo. Our results showed that celastrol reduced the expression of catabolic genes (MMP-3, 9, 13, ADAMTS-4, 5), oxidative stress factors (COX-2, iNOS) and pro-inflammatory factors (IL-6, TNF-a) induced by IL-1β in nucleus pulposus cells, also phosphorylation of IκBα and p65 were attenuated by celastrol, indicating NF-κB pathway was inhibited by celastrol in nucleus pulposus cells. In vivo study showed that celastrol treated rats had stronger T2-weighted signal than vehicle-treated rats at 2 weeks and 6 weeks' time point, suggesting celastrol could attenuate intervertebral disc degeneration in vivo. Together, our study demonstrates that celastrol could reduce IL-1β induced matrix catabolism, oxidative stress and inflammation in human nucleus pulposus cells and attenuates rat intervertebral disc degeneration in vivo, which shows its potential to be a therapeutic drug for IDD.

Topics: ADAMTS5 Protein; Aggrecans; Animals; Cell Death; Cell Nucleus; Cell Survival; Collagen Type II; Cyclooxygenase 2; Cytoprotection; Extracellular Matrix; Gene Expression Regulation; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Intervertebral Disc Degeneration; Magnetic Resonance Imaging; Male; NF-kappa B; Nitric Oxide Synthase Type II; Nucleus Pulposus; Oxidative Stress; Pentacyclic Triterpenes; Protein Transport; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor beta; Triterpenes; Tumor Necrosis Factor-alpha

Activin A belongs to the superfamily of transforming growth factor beta (TGFβ) and is a critical regulatory cytokine in breast cancer and inflammation. However, the role of activin A in migration of breast cancer cells and immune cells was not well characterized. Here, a microfluidic device was used to examine the effect of activin A on the migration of human breast cancer cell line MDA-MB-231 cells and human blood neutrophils as well as their migratory interaction. We found that activin A promoted the basal migration but impaired epidermal growth factor (EGF)-induced migration of breast cancer cells. By contrast, activin A reduced neutrophil chemotaxis and transendothelial migration to N-Formyl-Met-Leu-Phe (fMLP). Finally, activin A promoted neutrophil chemotaxis to the supernatant from breast cancer cell culture. Collectively, our study revealed the different roles of activin A in regulating the migration of breast cancer cells and neutrophils and their migratory interaction. These findings suggested the potential of activin A as a therapeutic target for inflammation and breast cancers.

Topics: Activins; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Humans; Inflammation; Neutrophils; Transforming Growth Factor beta

Despite current standard of care, the average 5-year mortality after an initial diagnosis of heart failure (HF) is about 40%, reflecting an urgent need for new therapeutic approaches. Previous studies demonstrated that the epigenetic reader protein bromodomain-containing protein 4 (BRD4), an emerging therapeutic target in cancer, functions as a critical coactivator of pathologic gene transactivation during cardiomyocyte hypertrophy. However, the therapeutic relevance of these findings to human disease remained unknown. We demonstrate that treatment with the BET bromodomain inhibitor JQ1 has therapeutic effects during severe, preestablished HF from prolonged pressure overload, as well as after a massive anterior myocardial infarction in mice. Furthermore, JQ1 potently blocks agonist-induced hypertrophy in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Integrated transcriptomic analyses across animal models and human iPSC-CMs reveal that BET inhibition preferentially blocks transactivation of a common pathologic gene regulatory program that is robustly enriched for NFκB and TGF-β signaling networks, typified by innate inflammatory and profibrotic myocardial genes. As predicted by these specific transcriptional mechanisms, we found that JQ1 does not suppress physiological cardiac hypertrophy in a mouse swimming model. These findings establish that pharmacologically targeting innate inflammatory and profibrotic myocardial signaling networks at the level of chromatin is effective in animal models and human cardiomyocytes, providing the critical rationale for further development of BET inhibitors and other epigenomic medicines for HF.

Topics: Animals; Azepines; Cardiomegaly; Gene Regulatory Networks; Heart Failure; Humans; Induced Pluripotent Stem Cells; Inflammation; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; NF-kappa B; Proteins; Signal Transduction; Transforming Growth Factor beta; Triazoles

Damage observed in the hippocampus of the adult spontaneously hypertensive rat (SHR) resembles the neuropathology of mineralocorticoid-induced hypertension, supporting a similar endocrine dysfunction in both entities. In the present study, we tested the hypothesis that increased expression of the hippocampal mineralocorticoid receptor (MR) in SHR animals is associated with a prevalent expression of pro-inflammatory over anti-inflammatory factors. Accordingly, in the hippocampus, we measured mRNA expression and immunoreactivity of the MR and glucocorticoid receptor (GR) using a quantitative polymerase chain reaction and histochemistry. We also measured serum-glucocorticoid-activated kinase 1 (Sgk1 mRNA), the number and phenotype of Iba1+ microglia, as well as mRNA expression levels of the pro-inflammatory factors cyclo-oxygenase 2 (Cox2), Nlrp3 inflammasome and tumour necrosis factor α (Tnfα). Expression of anti-inflammatory transforming growth factor (Tgf)β mRNA and the NADPH-diaphorase activity of nitric oxide synthase (NOS) were also determined. The results showed that, in the hippocampus of SHR rats, expression of MR and the number of immunoreactive MR/GR co-expressing cells were increased compared to Wistar-Kyoto control animals. Expression of Sgk1, Cox2, Nlrp3 and the number of ramified glia cells positive for Iba1+ were also increased, whereas Tgfβ mRNA expression and the NADPH-diaphorase activity of NOS were decreased. We propose that, in the SHR hippocampus, increased MR expression causes a bias towards a pro-inflammatory phenotype characteristic for hypertensive encephalopathy.

Topics: Animals; Cyclooxygenase 2; Hippocampus; Immediate-Early Proteins; Inflammation; Male; Microglia; Neurons; Nitric Oxide Synthase; Protein Serine-Threonine Kinases; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Glucocorticoid; Receptors, Mineralocorticoid; Transforming Growth Factor beta

The activation of resident microglial cells, alongside the infiltration of peripheral macrophages, are key neuroinflammatory responses to traumatic brain injury (TBI) that are directly associated with neuronal death. Sexual disparities in response to TBI have been previously reported; however it is unclear whether a sex difference exists in neuroinflammatory progression after TBI. We exposed male and female mice to moderate-to-severe controlled cortical impact injury and studied glial cell activation in the acute and chronic stages of TBI using immunofluorescence and in situ hybridization analysis. We found that the sex response was completely divergent up to 7 days postinjury. TBI caused a rapid and pronounced cortical microglia/macrophage activation in male mice with a prominent activated phenotype that produced both pro- (IL-1β and TNFα) and anti-inflammatory (Arg1 and TGFβ) cytokines with a single-phase, sustained peak from 1 to 7 days. In contrast, TBI caused a less robust microglia/macrophage phenotype in females with biphasic pro-inflammatory response peaks at 4 h and 7 days, and a delayed anti-inflammatory mRNA peak at 30 days. We further report that female mice were protected against acute cell loss after TBI, with male mice demonstrating enhanced astrogliosis, neuronal death, and increased lesion volume through 7 days post-TBI. Collectively, these findings indicate that TBI leads to a more aggressive neuroinflammatory profile in male compared with female mice during the acute and subacute phases postinjury. Understanding how sex affects the course of neuroinflammation following brain injury is a vital step toward developing personalized and effective treatments for TBI.

Topics: Animals; Arginase; Astrocytes; Brain Injuries, Traumatic; Cell Death; Disease Models, Animal; Female; Gliosis; Inflammation; Macrophage Activation; Male; Mice, Inbred C57BL; Microglia; Neuroimmunomodulation; Sex Characteristics; Transforming Growth Factor beta

Obesity is frequently linked to insulin resistance, high insulin levels, chronic inflammation, and alterations in the behaviour of CD4+ T cells. Despite the biomedical importance of this condition, the system-level mechanisms that alter CD4+ T cell differentiation and plasticity are not well understood.. We model how hyperinsulinemia alters the dynamics of the CD4+ T regulatory network, and this, in turn, modulates cell differentiation and plasticity. Different polarizing microenvironments are simulated under basal and high levels of insulin to assess impacts on cell-fate attainment and robustness in response to transient perturbations. In the presence of high levels of insulin Th1 and Th17 become more stable to transient perturbations, and their basin sizes are augmented, Tr1 cells become less stable or disappear, while TGFβ producing cells remain unaltered. Hence, the model provides a dynamic system-level framework and explanation to further understand the documented and apparently paradoxical role of TGFβ in both inflammation and regulation of immune responses, as well as the emergence of the adipose Treg phenotype. Furthermore, our simulations provide new predictions on the impact of the microenvironment in the coexistence of the different cell types, suggesting that in pro-Th1, pro-Th2 and pro-Th17 environments effector and regulatory cells can coexist, but that high levels of insulin severely diminish regulatory cells, especially in a pro-Th17 environment.. This work provides a first step towards a system-level formal and dynamic framework to integrate further experimental data in the study of complex inflammatory diseases.

Topics: Acute Disease; CD4-Positive T-Lymphocytes; Cell Differentiation; Hyperinsulinism; Inflammation; Insulin; Models, Biological; Transforming Growth Factor beta

Nonalcoholic fatty liver disease (NAFLD) is now the most common progressive liver disease in developed countries and is the second leading indication for liver transplantation due to the extensive fibrosis it causes. NAFLD progression is thought to be tied to chronic low-level type 1 inflammation originating in the adipose tissue during obesity; however, the specific immunological mechanisms regulating the progression of NAFLD-associated fibrosis in the liver are unclear. To investigate the immunopathogenesis of NAFLD more completely, we investigated adipose dysfunction, nonalcoholic steatohepatitis (NASH), and fibrosis in mice that develop polarized type 1 or type 2 immune responses. Unexpectedly, obese interleukin-10 (IL-10)/IL-4-deficient mice (type 1-polarized) were highly resistant to NASH. This protection was associated with an increased hepatic interferon-γ (IFN-γ) signature. Conversely, IFN-γ-deficient mice progressed rapidly to NASH with evidence of fibrosis dependent on transforming growth factor-β (TGF-β) and IL-13 signaling. Unlike increasing type 1 inflammation and the marked loss of eosinophils seen in expanding adipose tissue, progression of NASH was associated with increasing eosinophilic type 2 liver inflammation in mice and human patient biopsies. Finally, simultaneous inhibition of TGF-β and IL-13 signaling attenuated the fibrotic machinery more completely than TGF-β alone in NAFLD-associated fibrosis. Thus, although type 2 immunity maintains healthy metabolic signaling in adipose tissues, it exacerbates the progression of NAFLD collaboratively with TGF-β in the liver.

Topics: Adipose Tissue; Animals; Diet, High-Fat; Disease Progression; Eosinophils; Humans; Immunity; Inflammation; Interferon-gamma; Liver Cirrhosis; Male; Metabolic Diseases; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Transforming Growth Factor beta

Pulmonary fibrosis is a progressive lung disease that its pathogenic mechanism currently is incompletely understood. Toll-like receptor (TLR) signaling has recently been identified as a regulator of inflammation and pulmonary fibrosis. In addition, mesenchymal stem cells (MSCs) of different origins offer a great promise in treatment of idiopathic pulmonary fibrosis (IPF). However mechanisms of pathogenic roles of TLR signaling and therapeutic effects of MSCs in the IPF remain elusive. In present study, the involvement of TLR signaling and the therapeutic role of MSCs were interrogated in MyD88-deficient mice using human placental MSCs of fetal origins (hfPMSCs). The results showed an alleviated pulmonary inflammation and fibrosis in myeloid differentiation primary response gene 88 (MyD88)-deficient mice treated with bleomycin (BLM), accompanied with a reduced TGF-β signaling and production of pro-fibrotic cytokines, including TNF-α, IL-1β. An exposure of HLF1 lung fibroblasts, A549 epithelial cells and RAW264.7 macrophages to BLM led an increased expression of key components of MyD88 and TGF-β signaling cascades. Of interest, enforced expression and inhibition of MyD88 protein resulted in an enhanced and a reduced TGF-β signaling in above cells in the presence of BLM, respectively. However, the addition of TGF-β1 showed a marginally inhibitory effect on MyD88 signaling in these cells in the absence of BLM. Importantly, the administration of hfPMSCs could significantly attenuate BLM-induced pulmonary fibrosis in mice, along with a reduced hydroxyproline (HYP) deposition, MyD88 and TGF-β signaling activation, and production of pro-fibrotic cytokines. These results may suggest an importance of MyD88/TGF-β signaling axis in the tissue homeostasis and functional integrity of lung in response to injury, which may offer a novel target for treatment of pulmonary fibrosis.

Topics: A549 Cells; Animals; Bleomycin; Cell Line; Female; Humans; Hydroxyproline; Inflammation; Interleukin-1beta; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88; Placenta; Pregnancy; Pulmonary Fibrosis; Signal Transduction; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Helminth infections have the ability to modulate host's immune response through mechanisms that allow the chronic persistence of the worms in the host. Here, we investigated the mechanisms involved on the suppressive effect of Ascaris suum infection using a murine experimental model of LPS-induced inflammation. We found that infection with A. suum markedly inhibited leucocyte influx induced by LPS into air pouches, suppressed secretion of pro-inflammatory cytokines (IL-1β, TNF-α and IL-6) and induced high levels of IL-10 and TGF-β. Augmented frequency of CD4

Topics: Adoptive Transfer; Animals; Ascariasis; Ascaris suum; CD4 Antigens; Cytokines; Female; Forkhead Transcription Factors; Inflammation; Interleukin-10; Interleukin-2 Receptor alpha Subunit; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; T-Lymphocytes; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Although the widespread use of titanium dioxide nanoparticles (TiO

Topics: 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; Animals; Antioxidants; Biomarkers; Down-Regulation; Glutathione; Glutathione Peroxidase; Inflammation; Kidney; Kidney Diseases; Male; Malondialdehyde; Matrix Metalloproteinase 9; Nanoparticles; Oxidative Stress; Rats; Superoxide Dismutase; Titanium; Transforming Growth Factor beta; Up-Regulation

High aldosterone level may contribute to pathogenesis of hypertension, vessels damage and cardiovascular system deterioration in chronic kidney disease patients. Besides its classical action via mineralocorticoid receptor, aldosterone is also involved in cell growth, inflammation, oxidative stress, endothelial dysfunction and exerts fibroproliferative effects. The aim of the study was to assess whether aldosterone antagonist treatment may influence serum level of inflammatory, fibrosis, thrombosis and mineral-bone metabolism markers in peritoneal dialysis (PD) patients and blood pressure, aortic stiffness, echocardiographic indices after 12 months of treatment.. Twenty-two patients on PD were assigned to spironolactone treatment in dose of 50 mg daily during 12 months. Fifteen PD patients were assigned to control group. Echocardiographic indices, PVW, SBP, DBP (mean values from ABPM) and biochemical parameters such as: aldosterone, osteopontin, IL-6, selectin-P, TGF-β, PTH, MMP-2 were performed at the beginning and after 12 months in spironolactone and control group.. There were no statistically significant differences in echocardiographic indices, PWV, BP (ABPM readings) and biochemical markers: MMP-2, serum aldosterone, TGF-β, IL-6, selectin-P, PTH level after 12 months of spironolactone treatment. There was statistically significant rise in osteopontin level after 12 months of spironolactone treatment. Episodes of life-threatening hyperkalemia were not reported.. Aldosterone antagonists use in PD patients seems to be safe. Longer duration or higher dosage of spironolactone seems to be more effective in improving cardiovascular system status in PD patients. Further studies are required to determine relationship between mineralocorticoid receptor blockade and mineral-bone disturbances in PD patients.

Topics: Adult; Aged; Aged, 80 and over; Aldosterone; Biomarkers; Blood Pressure; Cardiovascular Diseases; Chronic Kidney Disease-Mineral and Bone Disorder; Echocardiography; Female; Fibrosis; Humans; Inflammation; Interleukin-6; Male; Matrix Metalloproteinase 2; Middle Aged; Mineralocorticoid Receptor Antagonists; Osteopontin; P-Selectin; Parathyroid Hormone; Peritoneal Dialysis; Pulse Wave Analysis; Renal Insufficiency, Chronic; Spironolactone; Thrombosis; Transforming Growth Factor beta; Vascular Stiffness

Ginkgo biloba is a plant known from the Mesozoic and has been regarded as one of the first to be used in traditional Chinese medicine (TCM). The plant extract has attracted a great deal of attention in recent years. The Ginkgo biloba leaf contains flavones and diterpenes. In addition, Ginkgo biloba performs certain pharmacologic actions, including antioxidant and anti‑aging activities. The aim of the present study was to examine whether Ginkgo biloba extract prevents acute myocardial infarction (AMI). The results demonstrated that Ginkgo biloba extract significantly inhibited infarct size, increased serum histamine levels and weakened creatine kinase (CK)‑MB activity in AMI mice. Ginkgo biloba extract significantly inhibited serum interleukin (IL)‑6 and IL‑1β levels, and caspase‑3/9 activity. In addition, it suppressed matrix metallopeptidase‑9, transforming growth factor‑β, p38 mitogen‑activated protein kinases (MAPK) and nuclear factor (NF)‑κB protein expression, and promoted B‑cell lymphoma 2 (Bcl‑2) protein expression in AMI mice. The results of in vivo assays demonstrated that Ginkgo biloba extract prevents AMI and suppresses inflammation‑ and apoptosis‑regulating p38 MAPK, NF‑κB and Bcl‑2 signaling pathways.

Topics: Animals; Apoptosis; Caspase 3; Caspase 9; Ginkgo biloba; Inflammation; Matrix Metalloproteinase 9; Mice, Inbred C57BL; Myocardial Infarction; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Plant Extracts; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Transforming Growth Factor beta

Oxidative/antioxidative imbalance and chronic inflammation are the main contributors to the pathogenesis of chronic obstructive pulmonary disease (COPD). This study evaluated the effect of recuperating lung decoction (RLD) on inflammation and oxidative stress in rats with COPD induced by cigarette smoke and lipopolysaccharides (LPS). We used intravenous infusion of LPS combined with cigarette smoke exposure as a COPD rat model. We observed that RLD treatment increased the protein level of GSH and the ratio of GSH/GSSG but decreased 8-OHdG and 4-HNE in the serum. Furthermore, RLD significantly inhibited the expressions of IL-1β, IL-6, TNF-α, and TGF-β induced by cigarette smoke exposure, reduced the number of inflammatory cells in the bronchoalveolar lavage fluid, and alleviated the severity of cigarette smoke-induced emphysema. Mechanistically, RLD treatment prevented disease through downregulation of phosphorylated-ERK and Nrf2 expression, which regulates the production of proinflammatory cytokines. RLD treatment exerted a dramatic therapeutic effect on COPD. This study revealed a mechanism that RLD functions on the regulation of ERK signalling to inhibit inflammation.

Topics: Animals; Antioxidants; Gene Expression Regulation; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Lung; Medicine, Chinese Traditional; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Rats; Smoke; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

D-mannose, a C-2 epimer of glucose, exists naturally in many plants and fruits, and is found in human blood at concentrations less than one-fiftieth of that of glucose. However, although the roles of glucose in T cell metabolism, diabetes and obesity are well characterized, the function of D-mannose in T cell immune responses remains unknown. Here we show that supraphysiological levels of D-mannose safely achievable by drinking-water supplementation suppressed immunopathology in mouse models of autoimmune diabetes and airway inflammation, and increased the proportion of Foxp3

Topics: Adoptive Transfer; Animals; Colitis; Colon; Diabetes Mellitus, Type 1; Dietary Supplements; Disease Models, Animal; Fatty Acids; Flow Cytometry; Forkhead Transcription Factors; Humans; In Vitro Techniques; Inflammation; Integrins; Lipid Metabolism; Lung; Lung Diseases; Mannose; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Ovalbumin; Oxidation-Reduction; Pancreas; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Respiratory Hypersensitivity; Reverse Transcriptase Polymerase Chain Reaction; Spleen; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Up-Regulation

This study aimed to identify host cell recruitment patterns in a mouse model in response to rhBMP-2 releasing hyaluronic acid hydrogels and influence of added nano-hydroxyapatite particles on rhBMP-2 release and pattern of bone formation.. Implanted gels were retrieved after implantation and cells were enzymatically dissociated for flow cytometric analysis. Percentages of macrophages, progenitor endothelial cells and putative mesenchymal stem cells were measured. Implants were evaluated for BMP-2 release by ELISA and by histology to monitor tissue formation.. Hyaluronic acid+BMP-2 gels influenced the inflammatory response in the bone healing microenvironment. Host-derived putative mesenchymal stem cells were major contributors. Addition of hydroxyapatite nanoparticles modified the release pattern of rhBMP-2, resulting in enhanced bone formation.

Topics: Animals; Bone Morphogenetic Protein 2; Delayed-Action Preparations; Durapatite; Endothelial Cells; Humans; Hyaluronic Acid; Hydrogels; Implants, Experimental; Inflammation; Kinetics; Macrophages; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice, Inbred C57BL; Nanoparticles; Osteogenesis; Recombinant Proteins; Subcutaneous Tissue; Transforming Growth Factor beta

The interaction of mesenchymal stromal cells (MSCs) with natural killer (NK) cells is traditionally thought of as a static inhibitory model, whereby resting MSCs inhibit NK cell effector function. Here, we use a dynamic in vitro system of poly(I:C) stimulation to model the interaction of NK cells and tissue-resident MSCs in the context of infection or tissue injury. The experiments suggest a time-dependent system of regulation and feedback, where, at early time points, activated MSCs secrete type I interferon to enhance NK cell effector function, while at later time points TGF-β and IL-6 limit NK cell effector function and terminate inflammatory responses by induction of a regulatory senescent-like NK cell phenotype. Importantly, feedback of these regulatory NK cells to MSCs promotes survival, proliferation, and pro-angiogenic properties. Our data provide additional insight into the interaction of stromal cells and innate immune cells and suggest a model of time-dependent MSC polarization and licensing.

Topics: Apoptosis; Bone Marrow Cells; Cell Communication; Cell Differentiation; Cell Proliferation; Cell Survival; Cellular Senescence; Cytotoxicity, Immunologic; Humans; Inflammation; Interleukin-6; Killer Cells, Natural; Lymphocyte Activation; Mesenchymal Stem Cells; Nasal Mucosa; Phenotype; Poly I-C; Receptors, CXCR4; Regeneration; Time Factors; Transforming Growth Factor beta; Wound Healing

Brain damage due to stroke or traumatic brain injury (TBI), both leading causes of serious long-term disability, often leads to the development of epilepsy. Patients who develop post-injury epilepsy tend to have poor functional outcomes. Emerging evidence highlights a potential role for blood-brain barrier (BBB) dysfunction in the development of post-injury epilepsy. However, common mechanisms underlying the pathological hyperexcitability are largely unknown. Here, we show that comparative transcriptome analyses predict remodeling of extracellular matrix (ECM) as a common response to different types of injuries. ECM-related transcriptional changes were induced by the serum protein albumin via TGFβ signaling in primary astrocytes. In accordance with transcriptional responses, we found persistent degradation of protective ECM structures called perineuronal nets (PNNs) around fast-spiking inhibitory interneurons, in a rat model of TBI as well as in brains of human epileptic patients. Exposure of a naïve brain to albumin was sufficient to induce the transcriptional and translational upregulation of molecules related to ECM remodeling and the persistent breakdown of PNNs around fast-spiking inhibitory interneurons, which was contingent on TGFβ signaling activation. Our findings provide insights on how albumin extravasation that occurs upon BBB dysfunction in various brain injuries can predispose neural circuitry to the development of chronic inhibition deficits.

Topics: Astrocytes; Blood-Brain Barrier; Brain Injuries, Traumatic; Cerebral Cortex; Computational Biology; Extracellular Matrix; Gene Expression; Gene Expression Profiling; Hippocampus; Humans; Inflammation; Interneurons; Losartan; Neurons; Receptor, Transforming Growth Factor-beta Type I; Signal Transduction; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta

Modulation of pro-inflammatory and anti-inflammatory axis and orientation of glial cell function towards neuroinflammation, were hallmark signs of cerebral malaria (CM). CM pathogenesis was concerned with the circulating levels of Interleukin 6 (IL 6) and Transforming growth factor β (TGF β). Definite roles of these two cytokines in brain related pathology remained largely unexplored. To study the effect of these two cytokines, we have examined changes in morphology and in activation profile of the glial cells after TGF β and IL 6 neutralization during CM in cortex and cerebellum of the Plasmodium berghei ANKA (PbA) infected male swiss albino mice. PbA infection caused severe inflammation by inducing changes in morphological features as well as in activation profile of the astrocytes and microglia. Similar inflammatory signs were evident in Anti TGF β treated set. Interestingly in the Anti IL 6 treated set, reduced level of activation of these glial cells corresponds to the reduced level of inflammatory profile. Microglial activation was found to be synchronous with TLR4 engagement. Neuronal death was triggered by neuroinflammatory milieu seen in PbA and PbA+Anti TGF β treated set. In conclusion, it can be said that IL 6 and TGF β perform essential role in CM pathogenesis by modulating the level of glial cell induced neuroinflammation.

Topics: Animals; Apoptosis; Astrocytes; Biomarkers; Brain; CD11b Antigen; Cell Aggregation; DNA-Binding Proteins; Glial Fibrillary Acidic Protein; Inflammation; Inflammation Mediators; Interleukin-6; Malaria, Cerebral; Male; Mice; Nerve Tissue Proteins; Neuroglia; Nuclear Proteins; Plasmodium berghei; Silver Staining; Toll-Like Receptor 4; Transforming Growth Factor beta

Angiotensin-converting enzyme-2 (ACE2) is downregulated in hypertensive nephropathy. The present study investigated the mechanisms whereby loss of ACE2 promoted angiotensin II-induced hypertensive nephropathy in ACE2 gene knockout mice. We found that compared with wild-type animals, mice lacking ACE2 developed much more severe hypertensive nephropathy in response to chronic angiotensin II infusion, including higher levels of blood pressure, urinary protein excretion, serum creatinine, and progressive renal fibrosis and inflammation. Mechanistic studies revealed that worsening kidney injury in ACE2 knockout mice was associated with an increase in Smurf2 (Smad-specific E3 ubiquitin protein ligase 2), a decrease in renal Smad7, and marked activation of TGF-β (transforming growth factor β)/Smad3 and NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) signaling, suggesting that Smurf2-dependent Smad7 ubiquitin degradation may be a key mechanism whereby loss of ACE2 promotes angiotensin II-induced TGF-β/Smad3 and NF-κB-mediated hypertensive nephropathy. This was validated by restoring Smad7 locally in the kidneys of ACE2 knockout mice to block angiotensin II-induced TGF-β/Smad3-mediated renal fibrosis and NF-κB-driven renal inflammation. Moreover, we found that angiotensin II could induce microRNA-21 in the mouse kidney and in cultured mesangial cells via a Smad3-dependent mechanism, which was enhanced by deleting ACE2 but inhibited by overexpressing renal Smad7. In conclusion, loss of ACE2 promotes angiotensin II-induced renal injury by targeting Smad7 for degradation via a Smurf2-dependent mechanism. Overexpression of renal Smad7 protects against hypertensive nephropathy by inactivating angiotensin II-induced TGF-β/Smad3 and NF-κB pathways and by targeting the Smad3-dependent microRNA-21 axis.

Topics: Angiotensin-Converting Enzyme 2; Animals; Blood Pressure; Down-Regulation; Fibrosis; Hypertension; Hypertension, Renal; Inflammation; Kidney; Mice; Mice, Knockout; Nephritis; NF-kappa B; Peptidyl-Dipeptidase A; Signal Transduction; Smad1 Protein; Smad7 Protein; Transforming Growth Factor beta; Ubiquitin

Peripheral T cell tolerance is promoted by the regulatory cytokine TGF-β and Foxp3-expressing Treg cells. However, whether TGF-β and Treg cells are part of the same regulatory module, or exist largely as distinct pathways to repress self-reactive T cells remains incompletely understood. Using a transgenic model of autoimmune diabetes, here we show that ablation of TGF-β receptor II (TβRII) in T cells, but not Foxp3 deficiency, resulted in early-onset diabetes with complete penetrance. The rampant autoimmune disease was associated with enhanced T cell priming and elevated T cell expression of the inflammatory cytokine GM-CSF, concomitant with pancreatic infiltration of inflammatory monocytes that triggered immunopathology. Ablation of the GM-CSF receptor alleviated the monocyte response and inhibited disease development. These findings reveal that TGF-β promotes T cell tolerance primarily via Foxp3-independent mechanisms and prevents autoimmunity in this model by repressing the cross talk between adaptive and innate immune systems.

Topics: Adaptive Immunity; Animals; Autoimmunity; Cytokines; Forkhead Transcription Factors; Granulocyte-Macrophage Colony-Stimulating Factor; Immunity, Innate; Inflammation; Mice; Peripheral Tolerance; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

The present study aimed to investigate the effect of tanshinone IIA on the degradation of articular cartilage in a rat model of osteoarthritis (OA). The OA rat model was established by anterior cruciate ligament transection (ACLT) and medial meniscus resection (MMx). The animals were treated for 28 days with 0.25‑0.5 mg/kg doses of tanshinone IIA following ACLT + MMx. The knee joints of the rats in the ACLT + MMx group exhibited marked alterations in articular cartilage histopathology and higher Mankin scores, compared with those in the normal group. Tanshinone IIA treatment at a dose of 0.5 mg/kg significantly inhibited cartilage degradation and improved Mankin scores in the OA rat model (P<0.002). Tanshinone IIA treatment completely inhibited the ACLT + MMx‑induced accumulation of inflammatory cells and disintegration of synovial lining in the rats. An increase in the dose of tanshinone IIA between 0.25 and 0.5 mg/kg reduced the proportion of apoptotic chrondrocytes from 41 to 2% on day 29. Treatment of the rats in the ACLT + MMx group with 0.5 mg/kg doses of tanshinone IIA markedly inhibited the expression level of matrix metalloproteinase and increased the expression of tissue inhibitor of metalloproteinase in the rat articular cartilage tissues. Tanshinone IIA treatment significantly reduced the levels of inflammatory cytokines, including interleukin‑1β, tumor necrosis factor‑α and nitric oxide in rat serum samples. The protein expression levels of bone morphogenetic protein and transforming growth factor‑β were significantly increased by tanshinone IIA in the ACLT + MMx rats. Therefore, tanshinone IIA inhibited articular cartilage degradation through inhibition of apoptosis and expression levels of inflammatory cytokines, offering potential for use in the treatment of OA.

Topics: Abietanes; Animals; Anterior Cruciate Ligament; Apoptosis; Bone Morphogenetic Proteins; Cartilage, Articular; Chondrocytes; Cytokines; Disease Models, Animal; Inflammation; Interleukin-1beta; Male; Menisci, Tibial; Nitric Oxide; Osteoarthritis; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe inflammatory lung diseases. Methylprednisolone (MP) is a common drug against inflammation in clinic. In this study, we aim to investigate the protective effect of MP on ALI and potential mechanisms.. Respiratory physiologic function was significantly improved by MP treatment. Tissue injury and inflammation were ameliorated in the MP-treated group. After MP treatment, the number of M1 decreased and M2 increased in the lung. In in vitro experiment, MP promoted M2 polarization rather than M1. We then induced M1, M2a and M2c from bone marrow cells. M1 induced more Th17 while M2 induced more CD4. In conclusion, MP ameliorated ALI by promoting M2 polarization. M2, especially M2c, induced Tregs without any influence on Tregs immunosuppression function.

Topics: Acute Lung Injury; Animals; Blood Gas Analysis; Bronchoalveolar Lavage Fluid; Cell Differentiation; Chemokines; Glucocorticoids; Inflammation; Interleukin-10; Lung; Macrophages; Male; Methylprednisolone; Mice, Inbred BALB C; Models, Biological; Organ Size; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Progressive fibrous thickening of the peritoneal membrane is a complication of long-term peritoneal dialysis (PD). TGF-β/Smad pathway activation, inflammation, and neoangiogenesis play important roles in peritoneal membrane (PM) changes induced by PD. Recently, histone deacetilase inhibitors (HDACi) have shown anti-fibrotic and anti-inflammatory effects in different experimental models. These drugs prevent deacetylation of histones causing a loosen chromatin, which in turn induce the expression of some anti-fibrotic genes. In addition, acetylation may increase the activity of proteins involved in tissue fibrosis, such as Smad7. Here, we explored the effect of valproic acid (VPA), an HDACi, on the development of peritoneal fibrosis (PF) in rats.. PF was induced by daily intraperitoneal injections of 0.1% chlorhexidine gluconate (CG) for 15 consecutive days. Male Wistar rats (250-300 g) were divided into 3 groups: CONTROL, control rats receiving only vehicle; PF, peritoneal fibrosis induced in rats; PF+VPA, rats with PF treated with VPA (300 mg/kg/day by gavage). PF was assessed by Masson's trichrome staining. Inflammation and fibrosis-associated factors were assessed by immunohistochemistry, immunofluorescence, multiplex analysis, and qPCR.. Treatment with VPA significantly reduced PM thickness and the expression of myofibroblasts, besides preventing loss of ultrafiltration capacity of the PM. The upregulation of profibrotic factors (TGF-β, fibronectin, and Smad3) in the PF group was significantly ameliorated by VPA. VPA modulated the TGF/Smad pathway, inhibiting phosphorylated Smad3 expression and inducing an increased Smad7 expression in the FP+VPA group. The neoangiogenesis and the expression of proinflammatory cytokines (TNF-α, IL-1β, MCP-1) observed in the PF group was significantly reduced by VPA.. Our results indicate that VPA suppressed experimental PF through modulation of the TGF-β/Smad pathway. Interestingly, VPA treatment induced a higher expression of antifibrotic factors, such as Smad7. These results suggest that VPA may represent a potential strategy for treating long term PD complications.

Topics: Animals; Biological Transport; Biomarkers; Body Weight; Bone Morphogenetic Protein 7; Calcium-Binding Proteins; Capillaries; Cell Count; Cytokines; Fibronectins; Gene Expression Regulation; Inflammation; Inflammation Mediators; Male; Myofibroblasts; Neovascularization, Physiologic; Peritoneal Fibrosis; Peritoneum; Rats, Wistar; RNA, Messenger; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Treatment Outcome; Valproic Acid; Vascular Endothelial Growth Factor A

We aimed at investigating whether the frequency and function of T helper 17 (Th17) and regulatory T cells (Treg) are affected by a restriction of dietary sodium intake in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We enrolled RA and SLE patients not receiving drugs known to increase urinary sodium excretion. Patients underwent a dietary regimen starting with a restricted daily sodium intake followed by a normal-sodium daily intake. The timepoints were identified at baseline (T0), after 3 weeks of low-sodium dietary regimen (T3), after 2 weeks of normal-sodium dietary regimen (T5). On these visits, we measured the 24-hour urinary sodium excretion, the frequency and function of Th17 and Treg cells in the peripheral blood, the serum levels of cytokines. Analysis of urinary sodium excretion confirmed adherence to the dietary regimen. In RA patients, a trend toward a reduction in the frequencies of Th17 cells over the low-sodium dietary regimen followed by an increase at T5 was observed, while Treg cells exhibited the opposite trend. SLE patients showed a progressive reduction in the percentage of Th17 cells that reached a significance at T5 compared to T0 (p = 0.01) and an increase in the percentage of Treg cells following the low-sodium dietary regimen at both T1 and T3 compared to T0 (p = 0.04 and p = 0.02, respectively). No significant apoptosis or proliferation modulation was found. In RA patients, we found a reduction at T5 compared to T0 in serum levels of both TGFβ (p = 0.0016) and IL-9 (p = 0.0007); serum IL-9 levels were also reduced in SLE patients at T5 with respect to T0 (p = 0.03). This is the first study investigating the effects of dietary sodium intake on adaptive immunity. Based on the results, we hypothesize that a restricted sodium dietary intake may dampen the inflammatory response in RA and SLE patients.

Topics: Aged; Apoptosis; Arthritis, Rheumatoid; Cell Proliferation; Cytokines; Diet; Enzyme-Linked Immunosorbent Assay; Female; Humans; Inflammation; Interleukin-9; Leukocytes, Mononuclear; Lupus Erythematosus, Systemic; Male; Middle Aged; Sodium, Dietary; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

Chronic inflammation mediated by persistent microglial activation is associated with the pathogenesis of neurodegenerative diseases. The mechanisms underlying chronic microglial activation are poorly understood. We have previously shown that anti-inflammatory TGF-β signaling is inhibited in LPS-treated microglia. In this study, we assessed whether different disease-related microglial activators could downregulate TGF-β induction of gene expression. We examined the effects of amyloid β (Aβ) (1-42)- or heat-killed Listeria monocytogenes (HKLM) on the TGF-β-regulated gene expression in primary rat microglia. We found that Aβ (1-42) oligomers and HKLM, in addition to LPS, suppressed TGF-β-mediated induction of gene expression in part through reducing expression of TβR1 mRNA encoding the TGF-β receptor 1 in primary microglia. Aβ (1-42) and LPS also prevented induction of TGF-β-induced genes in primary microglia. Additionally, Aβ (1-42) rescued primary microglia from TGF-β-mediated cell death without increasing cell proliferation. Blockage of NFκB signaling, but not the ERK or IRF3 pathways, inhibited Aβ (1-42)- and LPS-mediated reduction of TβR1 mRNA. Finally, LPS and Aβ (1-42) induced transient upregulation of mRNAs encoding SnoN and Bambi, inhibitors of TGF-β signaling. Our data indicate that one mechanism through which activators may prolong microglial stimulation is through direct inhibition of anti-inflammatory signaling. A more detailed understanding of the interaction between inflammatory and anti-inflammatory pathways may reveal potential targets for ameliorating chronic inflammation and hence speed the development of therapeutics to address neurodegenerative diseases.

Topics: Amyloid beta-Peptides; Animals; Cell Line; Cells, Cultured; Extracellular Signal-Regulated MAP Kinases; Female; Inflammation; Interferon Regulatory Factor-3; Lipopolysaccharides; Male; Membrane Proteins; Mice; Microglia; Nerve Tissue Proteins; NF-kappa B; Peptide Fragments; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; RNA, Messenger; Signal Transduction; Transcription Factors; Transforming Growth Factor beta

Besides environmental risk factors, genetic factors play a crucial role in the pathogenesis of primary hypertension. The current study is to unravel whether hypertensive phenotypes vary in mice with different genetic background.. Hypertension was induced in C57BL/6J (B6), DBA/2J (D2), and 25 BXD strains by administrating angiotensin (Ang)II (2.5 mg/kg/day infused by osmotic minipump) for 4 weeks. Systolic blood pressure was monitored before (baseline) and after 4 weeks of AngII treatment by tail cuff. Cardiac and renal fibrosis was evaluated by picrosirius red staining and collagen volume fraction (CVF) was quantitated using imaging analyzing system; cardiac transforming growth factor (TGF)-β gene expression was monitored by RT-PCR, and inflammatory response was detected by immunohistochemical ED-1 staining.. AngII infusion caused hypertension in all strains. However, blood pressure elevation was more evident in the D2 strain than the B6 group, while it was widely variable among BXD strains. Furthermore, chronic AngII treatment lead to development of hypertensive cardiac and renal diseases. Cardiac and renal CVF levels in the D2 strain was significantly higher than the B6 cohort, whereas these varied vastly across BXD strains. Moreover, cardiac TGF-β mRNA levels were markedly diverse among various mouse strains.. Our study unequivocally demonstrates that in response to AngII, BXDs with different genetic background expressed hypertension phenotypes with varied degree in severity. It implicates that genomics contribute to pathogenesis of primary hypertension. Building upon the genotype and hypertensive phenotypes, the BXD cohort can be further exploited experimentally to identify genes that influence blood pressure.

Topics: Angiotensin II; Animals; Blood Pressure; Fibrosis; Heart Diseases; Hypertension; Inflammation; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred Strains; Phenotype; Species Specificity; Transforming Growth Factor beta; Vasoconstrictor Agents

Cryptogenic strokes, those of unknown cause, have been estimated as high as 30% to 40% of strokes. Inflammation has been suggested as a critical etiologic factor. However, there is lack of experimental evidence.. In this study, we investigated inflammation-associated stroke using a mouse model that developed spontaneous stroke because of myeloid deficiency of TGF-β (transforming growth factor-β) signaling.. We report that mice with deletion of. Our studies show that TGF-β signaling in myeloid cells is required for maintenance of vascular health and provide insight into inflammation-mediated cerebrovascular disease and stroke.

Topics: Animals; Cell Line; Immunosuppressive Agents; Inflammation; Metformin; Methotrexate; Mice; Mice, Inbred C57BL; Myeloid Cells; NF-kappa B; Penetrance; Signal Transduction; Stroke; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

As one of the self-protection mechanism, autophagy widely exists in eukaryotic cells. It plays an important role in maintaining cells survival, update, material recycling, and tissue homeostasis. A series of researches discovered that autophagy played dual function in fibrotic diseases. The induction of autophagy can promote the degradation of collagen on one hand, on the other hand, the regulation of autophagy through microRNA, transforming growth factor β, and other factors can promote the occurrence of fibrosis. In wound healing, autophagy may participate in the pathophysiological processes of inflammation, reepithlialization, and wound remodeling. The regulation of cell autophagy may become an effective way and the new target for treatment of wound and pathological scar.

Topics: Autophagy; Biomedical Research; Cicatrix; Collagen; Fibrosis; Humans; Inflammation; Transforming Growth Factor beta; Wound Healing; Wounds and Injuries

Signal transducer and activator of transcription 3 (STAT3) is phosphorylated by various kinases, several of which have been implicated in aberrant fibroblast activation in fibrotic diseases including systemic sclerosis (SSc). Here we show that profibrotic signals converge on STAT3 and that STAT3 may be an important molecular checkpoint for tissue fibrosis. STAT3 signaling is hyperactivated in SSc in a TGFβ-dependent manner. Expression profiling and functional studies in vitro and in vivo demonstrate that STAT3 activation is mediated by the combined action of JAK, SRC, c-ABL, and JNK kinases. STAT3-deficient fibroblasts are less sensitive to the pro-fibrotic effects of TGFβ. Fibroblast-specific knockout of STAT3, or its pharmacological inhibition, ameliorate skin fibrosis in experimental mouse models. STAT3 thus integrates several profibrotic signals and might be a core mediator of fibrosis. Considering that several STAT3 inhibitors are currently tested in clinical trials, STAT3 might be a candidate for molecular targeted therapies of SSc.

Topics: Adolescent; Adult; Aged; Aminosalicylic Acids; Animals; Benzenesulfonates; Biopsy; Bleomycin; Collagen; Enzyme Activation; Female; Fibroblasts; Fibrosis; Humans; Inflammation; Male; Mice; Microscopy, Confocal; Middle Aged; Phosphorylation; Receptors, Transforming Growth Factor beta; Scleroderma, Systemic; Signal Transduction; Skin; STAT3 Transcription Factor; Transforming Growth Factor beta; Young Adult

Chronic inflammation is a hallmark of cystic fibrosis (CF) and associated with increased production of transforming growth factor (TGF) β and interleukin (IL)-8. α-klotho (KL), a transmembrane or soluble protein, functions as a co-receptor for Fibroblast Growth Factor (FGF) 23, a known pro-inflammatory, prognostic marker in chronic kidney disease. KL is downregulated in airways from COPD patients. We hypothesized that both KL and FGF23 signaling modulate TGF β-induced IL-8 secretion in CF bronchial epithelia. Thus, FGF23 and soluble KL levels were measured in plasma from 48 CF patients and in primary CF bronchial epithelial cells (CF-HBEC). CF patients showed increased FGF23 plasma levels, but KL levels were not different. In CF-HBEC, TGF-β increased KL secretion and upregulated FGF receptor (FGFR) 1. Despite increases in KL, TGF-β also increased IL-8 secretion via activation of FGFR1 and Smad 3 signaling. However, KL excess via overexpression or supplementation decreased IL-8 secretion by inhibiting Smad 3 phosphorylation. Here, we identify a novel signaling pathway contributing to IL-8 secretion in the CF bronchial epithelium with KL functioning as an endocrine and local anti-inflammatory mediator that antagonizes pro-inflammatory actions of FGF23 and TGF-β.

Topics: Animals; Cells, Cultured; Cystic Fibrosis; Epithelial Cells; Epithelium; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Humans; Inflammation; Interleukin-8; Klotho Proteins; Male; Mice; Rats; Respiratory Mucosa; Signal Transduction; Transforming Growth Factor beta

Macrophage inhibitory cytokine-1/growth differentiation factor 15 (MIC-1/GDF15) is a divergent transforming growth factor (TGFβ) superfamily cytokine implicated in biological and disease processes including metabolism, cancer, and chronic inflammation, but whose receptor has remained elusive. Four laboratories have recently identified GFRAL, an orphan receptor of the glial-derived neurotrophic factor (GDNF) receptor α family, as the receptor for MIC-1/GDF15, signaling though the coreceptor Ret. These data identify a new systemic to central nervous system (CNS) circuit that regulates metabolism in response to stress and which could be targeted to treat both severe obesity and anorexia/cachexia syndrome.

Topics: Animals; Cachexia; Central Nervous System; Glial Cell Line-Derived Neurotrophic Factor Receptors; Growth Differentiation Factor 15; Humans; Inflammation; Obesity; Orphan Nuclear Receptors; Proto-Oncogene Proteins c-ret; Transforming Growth Factor beta

Periostin is responsible for tissue regeneration, fibrosis, and wound healing via its interaction with integrin. Recently, the role of periostin has been shown to contribute to fibrosis in chronic kidney disease. We investigated the role of periostin and the effect of periostin blockade in renal fibrogenesis.. We investigated the function of periostin in vivo in wild-type and periostin-null mice (Postn-KO) in a unilateral ureteral obstruction (UUO) model. For the in vitro experiments, primary cultured inner medullary collecting duct cells from the wild-type and Postn-KO mice were used.. Periostin expression was strongly induced by UUO in the wild-type mice. UUO induced renal fibrosis and morphological changes in the obstructed kidney of wild-type mice, whereas global knockout of periostin reduced fibrosis induced by UUO and improved kidney structure. Fibrosis- and inflammation-related mRNA were significantly induced in the wild-type mice and were decreased in the Postn-KO mice. Additionally, α-smooth muscle actin expression was increased following the administration of recombinant periostin in vitro. The effect of periostin blockade was examined using 2 methods. The integrin blockade peptide decreased fibrosis-related gene expression in in vitro experiments. Anti-periostin polyclonal antibody attenuated renal fibrosis induced by UUO through changes in transforming growth factor-β signaling and the inflammatory and apoptotic pathways.. Periostin is a marker of renal fibrosis and may augment the progression of fibrogenesis as an extracellular matrix protein. Periostin blockade effectively attenuated renal fibrogenesis. Thus, periostin inhibition may be a therapeutic strategy for the amelioration of renal disease progression.

Topics: Animals; Biomarkers; Cell Adhesion Molecules; Cells, Cultured; Cytokines; Glomerulonephritis, IGA; Humans; Inflammation; Integrins; Kidney; Male; Mice, Inbred C57BL; Mice, Knockout; Nephrosclerosis; Oligopeptides; Transforming Growth Factor beta; Ureteral Obstruction

The aim of this study was to investigate the effect of probiotic strains of Lactobacillus casei IMV B-7280, Bifidobacterium animalis VKL, B. animalis VKB on the pro- and anti-inflammatory cytokines production in Wistar male rats with monosodium glutamate (MSG)-induced obesity. It was established that neonatal administration of MSG to rats leads to increasing levels of the interleukin (IL)-1β and IL-12, and to decreasing ofthe IL-4, IL-10 and tumor growthfactor (TGF)-β levels in the bloodserum. After administration of the B. animalis VKL - B. animalis VKB - L. casei IMV B-7280 composition to obese rats the level of the IL-lP in blood serum wasn't differ from that in the obese rats, that didn't receive of the probiotic bacteria. But there was no statistically signifcant difference comparing with intact rats. The level of the IL-12B p4O in blood serum was decreased under influence of the B. animalis VKL - B. animalis VKB - L. casei IMV B-7280 composition (18.9%, p < 0.05) and B. animalis VKL (10.5%, p < 0.05) compared with obese rats, not receiving probiotic bacteria, but remained higher than in intact animals. After administration to obese rats ofthe B. animalis VKL - B. animalis VKB - L. casei IMV B-7280 composition the levels ofthe IL-4, IL- 10 and TGF-β increased in blood serum comparing with obese rats, not receiving probiotic bacteria. The level of the IL-10 also increased under influence of the B. animalis VKB, and IL-4 - under influence of the L. casei IMVB-7280. Our results suggest that these probiotic bacteria and probiotic composition are able to down-regulation the inflammation in rats with MSG-induced obesity but the strongest anti-inflammatory effects have probiotic composition. The ability of lactobacilli and bifdobacteria to alter the pro- and anti-inflammatory cytokines production, opens perspectives to create new treatments for obesity and metabolic syndrome based on probiotics.

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents; Bifidobacterium; Gene Expression Regulation; Inflammation; Interleukin-10; Interleukin-12; Interleukin-1beta; Interleukin-4; Lacticaseibacillus casei; Obesity; Probiotics; Rats; Rats, Wistar; Sodium Glutamate; Transforming Growth Factor beta

Hypothermic machine perfusion (HMP) has been known as an efficient way to improve kidney graft function, but the underlying mechanisms remain unclear. Here, we adopt a rabbit reperfusion mode to investigate the upstream mechanisms of end-ischemic HMP of kidneys from donors after cardiac death (DCD), with static cold storage (CS) as a control. Eighteen New Zealand healthy male rabbits (12 weeks old, with a weight of 3.0 ± 0.2 kg) were randomly divided into three groups: HMP group, CS group, and Normal group (n = 6). The left kidney of rabbits underwent warm ischemia for 25 min through clamping the left renal pedicle and then reperfusion for 1 h. Then the left kidneys were preserved by CS or HMP (4°C for 4 h) ex vivo respectively, after they were autotransplanted and rabbits were submitted to a right nephrectomy. Twenty-four hours after reperfusion, all left renal specimens were collected. Finally, the expression of Krüppel-like factor 2 (KLF2), transforming growth factor-β (TGF-β) and SMAD4 protein in renal cortical tissue were detected by immunoblotting, and the TGF-β and SMAD4 expressions were further confirmed by immunohistochemistry analysis. We found that expression of KLF2 in HMP group was significantly higher than CS group (P = 0.011), while expression of TGF-β and SMAD4 in HMP group were significantly lower than CS group (P = 0.002, P = 0.01, respectively); Compared with normal group, the expression of TGF-β and SMAD4 in HMP and CS group significantly increased (P<0.05). Compared with CS group, TGF-β and SMAD4 protein were equally down-regulated in glomerular and the tubular epithelial cells in HMP group confirmed by immunohistochemistry. In conclusion, HMP may decrease DCD kidneys inflammation through the pathway of upregulating expression of KLF2 and inhibiting TGF-β signaling after transplantation.

Topics: Animals; Hypothermia, Induced; Inflammation; Kidney; Kidney Transplantation; Kruppel-Like Transcription Factors; Male; Organ Preservation; Rabbits; Reperfusion Injury; Signal Transduction; Transforming Growth Factor beta; Transplants

The sympathetic nervous system (SNS) is known to play a significant role in tumor initiation and metastasis. Hepatocellular carcinoma (HCC) frequently occurs in cirrhotic livers after chronic inflammation, and the SNS is hyperactive in advanced liver cirrhosis. However, it remains unclear whether the SNS promotes hepatocarcinogenesis by modulating chronic liver inflammation. In this study, a retrospective pathological analysis and quantification of sympathetic nerve fiber densities (tyrosine hydroxylase, TH

Topics: Adult; Aged; Animals; Carcinogenesis; Carcinoma, Hepatocellular; Female; Humans; Inflammation; Interleukin-6; Kupffer Cells; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Middle Aged; Nerve Fibers; Prognosis; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Retrospective Studies; Sympathetic Nervous System; Transforming Growth Factor beta

The inhibition of myostatin - a member of the transforming growth factor (TGF-β) family - drives regeneration of functional skeletal muscle tissue. We developed a bioresponsive drug delivery system (DDS) linking release of a myostatin inhibitor (MI) to inflammatory flares of myositis to provide self-regulated MI concentration gradients within tissues of need.. A protease cleavable linker (PCL) - responding to MMP upregulation - is attached to the MI and site-specifically immobilized on microparticle surfaces.. The PCL disintegrated in a matrix metalloproteinase (MMP) 1, 8, and particularly MMP-9 concentration dependent manner, with MMP-9 being an effective surrogate biomarker correlating with the activity of myositis. The bioactivity of particle-surface bound as well as released MI was confirmed by luciferase suppression in stably transfected HEK293 cells responding to myostatin induced SMAD phosphorylation.. We developed a MMP-responsive DDS for MI delivery responding to inflammatory flare of a diseased muscle matching the kinetics of MMP-9 upregulation, with MMP-9 kinetics matching (patho-) physiological myostatin levels. ᅟ: Graphical Abstract Schematic illustration of the matrix metalloproteinase responsive delivery system responding to inflammatory flares of muscle disease. The protease cleavable linker readily disintegrates upon entry into the diseased tissue, therby releasing the mystatin inhibitor.

Topics: Animals; Biomarkers; Cell Line; Drug Delivery Systems; HEK293 Cells; Humans; Inflammation; Matrix Metalloproteinases; Mice; Muscle, Skeletal; Myositis; Myostatin; Pharmaceutical Preparations; Protease Inhibitors; Transforming Growth Factor beta; Up-Regulation

Ghrelin is a peptide with attenuating effect on inflammatory pain. Both anti- and pro-inflammatory mediators have a role in the nociception and development of pain and hyperalgesia. IL-10 and TGF-β are anti-inflammatory cytokines and inhibit the expression of pro-inflammatory cytokines related to peripheral and central inflammatory pain. In this study, the effects of i.p. injection of ghrelin on the early and the late phases of pain, as well as serum levels of IL-10 and TGF-β, as anti-inflammatory cytokines, were investigated in formalin-induced pain in male rats.. Adult male Wistar rats (n=48) were randomly divided into six groups: control, formalin+saline, ghrelin (40, 80, and 160 μg/kg), and morphine. Ghrelin was administered i.p. 30 min before inducing pain by formalin. Pain induced by intraplantar (i.pl.) injection of 50 µl formalin 5%, and pain behavior was studied for 60 min. Serum IL-10 and TGF-β levels were assessed by ELISA method.. The findings of the present study showed that ghrelin with high doses (80 and 160 μg/kg) significantly reduced pain intensity in both the early and the late phases of pain. The serum levels of cytokines, IL-10, and TGF-β1 showed a significant elevation with ghrelin at the dose of 160 μg/kg.. Ghrelin is effective in reducing the intensity of both the early and the late phases of inflammatory pain. It seems that ghrelin exerts its analgesic effects in part by increasing the serum levels of anti-inflammatory cytokines.

Topics: Analgesics; Animals; Disease Models, Animal; Ghrelin; Inflammation; Interleukin-10; Male; Morphine; Nociception; Pain; Rats, Wistar; Transforming Growth Factor beta

To study the efficacy of pirfenidone for prevention of postoperative adhesion formation in an adhesion rat model.. Eighteen female Wistar rats were subjected to right-sided parietal peritoneum and right uterine horn adhesion model. Rats were randomized into three groups: group 1 (control) (closure of midline abdominal incision without any agent administration), group 2 (closure of incision after intraperitoneal administration of pirfenidone), and group 3 (closure of incision and only oral administration of pirfenidone for 14 days). Relaparotomy was performed 14 days after the first surgery. Effect of pirfenidone on adhesion formation was assessed on light microscopy by scoring vascular proliferation, inflammation, fibrosis, and collagen formation in the scarred tissue. Effect of pirfenidone on inflammation was assessed by measurement of transforming growth factor-β and interleukin-17 levels in scarred tissue.. The degree of vascular proliferation (1.32 ± 0.39 versus 2.34 ± 0.46, p < 0.001), inflammation (1.60 ± 0.70 versus 2.60 ± 0.52, p < 0.01), and fibrosis (1.50 ± 0.53 versus 2.40 ± 0.52, p < 0.01) were less prominent in group 2 compared to group 1, respectively. Only vascular proliferation was found to be less prominent in group 3 compared to group 1 (1.60 ± 0.42 versus 2.34 ± 0.46, p < 0.01). Intraperitoneal and oral administration of pirfenidone reduced tissue levels of inflammatory markers (TGF-β and IL-17) in parietal and visceral peritoneum compared to control group. Intraperitoneal administration of pirfenidone compared to oral administration was more effective in reducing tissue levels of inflammatory markers.. Pirfenidone is an effective agent on the prevention of postoperative vascular proliferation, inflammation and fibrosis in scarred tissue particularly with intraperitoneal administration.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Female; Inflammation; Injections, Intraperitoneal; Interleukin-17; Neovascularization, Pathologic; Peritoneum; Postoperative Complications; Pyridones; Rats; Rats, Wistar; Tissue Adhesions; Transforming Growth Factor beta; Treatment Outcome; Uterus

The effects of pomegranate juice (PJ) on the risk factors of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) have been reported previously; however, the effects on NAFLD and its prevention have not yet been clarified. The present study aimed to evaluate the effects of PJ consumption with respect to the prevention of NAFLD/NASH development. Sprague-Dawley rats were fed either a high-fat, high sugar diet (model group); a high-fat, high sugar diet plus PJ (model+PJ); or a chow diet ad libitum for 7 weeks. Serum levels of fasting glucose, triglyceride, cholesterol, liver enzymes, insulin and hepatic tumor necrosis factor-α and tissue growth factor-β gene expression were determined. Hepatic histology was examined by hemotoxylin and eosin staining.. The model+PJ group had significantly lower hepatic steatosis, ballooning, lobular inflammation and portal inflammation (P < 0.001); lower hepatic pro-inflammatory and pro-fibrotic gene expression (P < 0.001); and lower plasma levels of alanine aminotransferase (P = 0.026), aspartate aminotransferase (P = 0.041), insulin (P < 0.001), triglycerides (P = 0.041) and glucose (P = 0.009) compared to the model group; however, weight gain, food intake and plasma high-density lipoprotein levels were not significantly different between these two groups.. The data obtained in the present study indicate that the regular consumption of PJ can prevent NAFLD even in the presence of the other risk factors such as obesity, hypercholesterolemia, and high energy, fat and sugar intakes. © 2016 Society of Chemical Industry.

Topics: Animals; Blood Glucose; Cholesterol; Diet, High-Fat; Dietary Carbohydrates; Fruit and Vegetable Juices; Inflammation; Insulin; Liver; Lythraceae; Male; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Rats, Sprague-Dawley; Transforming Growth Factor beta; Triglycerides

Abdominal aortic aneurysm (AAA) is a frequent, potentially life-threatening, disease that can only be treated by surgical means such as open surgery or endovascular repair. No alternative treatment is currently available, and despite expanding knowledge about the pathomechanism, clinical trials on medical aneurysm abrogation have led to inconclusive results. The heterogeneity of human AAA based on histologic examination is thereby generally neglected. In this study we aimed to further elucidate the role of these differences in aneurysm disease.. Tissue samples from AAA and popliteal artery aneurysm patients were examined by histomorphologic analysis, immunohistochemistry, Western blot, and polymerase chain reaction. The results were correlated with clinical data such as aneurysm diameter and laboratory results.. The morphology of human AAA vessel wall probes varies tremendously based on the grade of inflammation. This correlates with increasing intima/media thickness and upregulation of the vascular endothelial growth factor cascade but not with any clinical parameter or the aneurysm diameter. The phenotypic switch of vascular smooth muscle cells occurred regardless of the inflammatory state and expressional changes of the transcription factors Kruppel-like factor-4 and transforming growth factor-β lead to differential protein localization in aneurysmal compared with control arteries. These changes were in similar manner also observed in samples from popliteal artery aneurysms, which, however, showed a more homogenous phenotype.. Heterogeneity of AAA vessel walls based on inflammatory morphology does not correlate with AAA diameter yet harbors specific implications for basic research and possible aneurysm detection.

Topics: Aneurysm; Angiogenic Proteins; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Aortography; Biomarkers; Cell Dedifferentiation; Computed Tomography Angiography; Dilatation, Pathologic; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Inflammation; Inflammation Mediators; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Popliteal Artery; Transforming Growth Factor beta; Vascular Remodeling

High glucose stimulates peritoneal inflammation and extracellular matrix accumulation in human peritoneal mesothelial cells (HPMCs). However, the roles of Toll-like receptor 4 (TLR4) and TLR2 in high-glucose-induced inflammation and fibrosis in peritoneal dialysis (PD) remain unclear. This study aimed to evaluate the effect of high glucose on TLR2 and TLR4 expression in HPMCs and to assess their impact on peritoneal inflammatory and fibrosis markers.. Using cultured HPMCs, TLRs expression by high-glucose (50 mM) stimulation was assessed by quantitative real-time PCR. The association of reactive oxygen species (ROS) in high-glucose-induced TLR2 and TLR4 expression was measured by 2',7'-dichlorodihydrofluorescein diacetate staining with or without ROS inhibitor. In addition, the role of TLR2 and TLR4 on high-glucose-induced inflammatory and fibrosis markers including chemoattractant protein-1 (MCP-1), NF-κB, alpha-smooth muscle actin (α-SMA), transforming growth factor-β (TGF-ß), and fibronectin was evaluated after inhibition of TLR2 and TLR4 by small-interfering RNA (siRNA) or anti-TLR4/TLR2 antibodies, respectively.. High glucose induced TLR1, TLR2, and TLR4 mRNAs expressions. High-glucose-induced TLR4 and TLR2 mRNAs were associated partly with the generation of ROS. Inhibition of TLR4 attenuated the high-glucose-induced expression of MCP-1 mRNA and protein, MyD88 mRNA, nuclear NF-κB p65 protein, TGF-β, fibronectin, and α-SMA mRNA and protein. However, inhibition of TLR2 did not change the expression of MCP-1 mRNA and protein.. High glucose induces inflammatory and fibrosis markers in HPMCs partly through the TLR4/MyD88/NF-κB signaling pathway rather than TLR2. Therefore, TLR4 might be a therapeutic target for ameliorating peritoneal inflammation and fibrosis in PD.

Topics: Actins; Cells, Cultured; Chemokine CCL2; Epithelial Cells; Fibronectins; Fibrosis; Gene Expression; Gene Knockdown Techniques; Glucose; Humans; Inflammation; Myeloid Differentiation Factor 88; Peritoneum; Reactive Oxygen Species; RNA, Small Interfering; Signal Transduction; Toll-Like Receptor 1; Toll-Like Receptor 2; Toll-Like Receptor 4; Transcription Factor RelA; Transforming Growth Factor beta

Activins are members of the transforming growth factor-beta (TGF-β) superfamily of cytokines. They play critical roles in the onset of acute and chronic inflammatory responses. The aim of this study was to investigate how activin inhibition affects acute kidney injury and inflammation after transplantation. The study was carried out in kidney transplantation and renal ischemia-reperfusion models in the rat. Soluble activin type 2 receptor (sActRIIB-Fc) was used to inhibit activin signaling. Transplantation groups were as follows: (i) cyclosporine A (CsA) (ii) CsA + sActRIIB-Fc, (iii) CsA+ inactive protein control Fc-G1. IRI groups were as follows: (i) no treatment, (ii) sActRIIB-Fc. Serum activin B concentration was significantly elevated after transplantation and IRI, whereas activin A was produced locally in renal allografts. Activin inhibition efficiently limited neutrophil, macrophage, and dendritic cell infiltration to the allografts measured 72 h after transplantation. In addition, sActRIIB-Fc treatment modulated serum cytokine response after transplantation and reduced the early accumulation of fibroblasts in the graft interstitium. In conclusion activin inhibition reduces the innate immune response early after renal transplantation in the rat. It also limits the accumulation of fibroblasts in the graft suggesting that activins may be involved in the fibrogenic signaling already early after kidney transplantation.

Topics: Activins; Allografts; Animals; Cytokines; Enzyme-Linked Immunosorbent Assay; Fibroblasts; Humans; Immunity, Innate; Inflammation; Kidney; Kidney Transplantation; Male; Pilot Projects; Rats; Rats, Wistar; Renal Insufficiency; Reperfusion Injury; Signal Transduction; Time Factors; Transforming Growth Factor beta; Transplantation, Homologous

The bile acid conjugate tauroursodeoxycholic acid (TUDCA) is a neuroprotective agent in various animal models of neuropathologies. We have previously shown the anti-inflammatory properties of TUDCA in an animal model of acute neuroinflammation. Here, we present a new anti-inflammatory mechanism of TUDCA through the regulation of transforming growth factor β (TGFβ) pathway. The bacterial lipopolysaccharide (LPS) was injected intravenously (iv) on TGFβ reporter mice (Smad-binding element (SBE)/Tk-Luc) to study in their brains the real-time activation profile of the TGFβ pathway in a non-invasive way. The activation of the TGFβ pathway in the brain of SBE/Tk-Luc mice increased 24 h after LPS injection, compared to control animals. This activation peak increased further in mice treated with both LPS and TUDCA than in mice treated with LPS only. The enhanced TGFβ activation in mice treated with LPS and TUDCA correlated with both an increase in TGFβ3 transcript in mouse brain and an increase in TGFβ3 immunoreactivity in microglia/macrophages, endothelial cells, and neurons. Inhibition of the TGFβ receptor with SB431542 drug reverted the effect of TUDCA on microglia/macrophages activation and on TGFβ3 immunoreactivity. Under inflammatory conditions, treatment with TUDCA enhanced further the activation of TGFβ pathway in mouse brain and increased the expression of TGFβ3. Therefore, the induction of TGFβ3 by TUDCA might act as a positive feedback, increasing the initial activation of the TGFβ pathway by the inflammatory stimulus. Our findings provide proof-of-concept that TGFβ contributes to the anti-inflammatory effect of TUDCA under neuroinflammatory conditions.

Topics: Animals; Anti-Inflammatory Agents; Brain; Disease Models, Animal; Inflammation; Luminescent Measurements; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Taurochenodeoxycholic Acid; Transforming Growth Factor beta

Systemic sclerosis (SSc) is a multisystem inflammatory and vascular disease resulting in extensive tissue fibrosis. Glycyrrhizin, clinically used for chronic hepatic diseases and itching dermatitis, modulates the pathological processes of inflammation, vasculopathy, and fibrosis in human diseases and their animal models. Therefore, we investigated a potential impact of glycyrrhizin on the key pathological manifestations of SSc, including inflammation, vasculopathy, and tissue fibrosis, with bleomycin-treated mice mimicking the fibrotic and inflammatory components of SSc and endothelial cell-specific Fli1-knockout mice recapitulating SSc vasculopathy. Glycyrrhizin significantly ameliorated dermal fibrosis in bleomycin-treated mice, which was partly attributable to blockade of transforming growth factor-β signaling in dermal fibroblasts through the down-regulation of thrombospondin 1, a latent transforming growth factor-β receptor, and transcription factors Smad3 and Ets1. Furthermore, bleomycin-dependent induction of T helper type 2-skewed immune polarization, M2 macrophage infiltration, and endothelial-to-mesenchymal transition were greatly suppressed in mice administered glycyrrhizin. Glycyrrhizin also improved vascular permeability of endothelial cell-specific Fli1-knockout mice by increasing the expression of molecules regulating vascular integrity. These results indicate that glycyrrhizin ameliorates bleomycin-induced dermal fibrosis through the inhibition of fibroblast activation, T helper type 2-skewed immune polarization, M2 macrophage infiltration, and endothelial-to-mesenchymal transition and improves endothelial Fli1 deficiency-dependent vascular disintegrity, implying its potential as a disease-modifying drug for SSc.

Topics: Animals; Bleomycin; Disease Models, Animal; Fibroblasts; Fibrosis; Glycyrrhizic Acid; Humans; Inflammation; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Scleroderma, Systemic; Skin; Th2 Cells; Transforming Growth Factor beta; Vascular Diseases

Optimization of the differentiation medium through using autologous factors such as PRP is of great consideration, but due to the complex, variable and undefined composition of PRP on one hand and lack of control over the absolute regulatory mechanisms in in vitro conditions or disrupted and different mechanisms in diseased tissue microenvironments in in vivo conditions on the other hand, it is complicated and rather unpredictable to get the desired effects of PRP making it inevitable to monitor the possible pathologic or undesired differentiation pathways and therapeutic effects of PRP. Therefore, in this study the probable potential of PRP on inducing calcification, inflammation and angiogenesis in chondrogenically-differentiated cells was investigated.. The expressions of chondrogenic, inflammatory, osteogenic and angiogenic markers from TGFβ or PRP-treated cells during chondrogenic differentiation of human adipose-derived stem cells (ADSCs) was evaluated. Expressions of Collagen II (Col II), Aggrecan, Sox9 and Runx2 were quantified using q-RT PCR. Expression of Col II and X was investigated by immunocytochemistry as well. Glycosaminoglycans (GAGs) production was also determined by GAG assay. Possible angiogenic/inflammatory potential was determined by quantitatively measuring the secreted VEGF, TNFα and phosphorylated VEGFR2 via ELISA. In addition, the calcification of the construct was monitored by measuring ALP activity and calcium deposition.. Our data showed that PRP positively induced chondrogenesis; meanwhile the secretion of angiogenic and inflammatory markers was decreased. VEGFR2 phosphorylation and ALP activity had a decreasing trend, but tissue mineralization was enhanced upon treating with PRP.. Although reduction in inflammatory/angiogenic potential of the chondrogenically differentiated constructs highlights the superior effectiveness of PRP in comparison to TGFβ for chondrogenic differentiation, yet further improvement of the PRP-based chondrogenic differentiation media is required to inhibit the production of angiogenic/inflammatory markers, calcification and the release of synthesized GAG out of the construct.

Topics: Adipocytes; Adipose Tissue; Biomarkers; Calcification, Physiologic; Cell Differentiation; Cell Proliferation; Chondrocytes; Chondrogenesis; Humans; Inflammation; Mesenchymal Stem Cells; Neovascularization, Pathologic; Osteogenesis; Platelet-Rich Plasma; Transforming Growth Factor beta

Sepsis is a systemic inflammatory condition resulting from bacterial infections. It is associated with high mortality rates, and its therapeutic options are limited. Transforming growth factor β induced protein (TGFBIp) is an extracellular matrix protein that functions as a mediator of experimental sepsis. C-27-carboxylated pentacyclic triterpenoids are specifically found in species of the genus Astilbe, and show several biological effects. Given the anti-inflammatory effects of pentacyclic triterpenoids, we investigated the effects of 3β-trans-p-coumaroyloxy-olean-12-en-27-oic acid (1) and 6β-hydroxy-3-oxoolean-12-en-27-oic acid (2) on TGFBIp-mediated vascular inflammatory responses. The anti-inflammatory activities of compounds 1 and 2 were determined by measuring the permeability, leukocyte adhesion and migration, and activation of pro-inflammatory proteins in TGFBIp-activated human umbilical vein endothelial cells (HUVECs) and mice. We found that compounds 1 and 2 inhibited lipopolysaccharide (LPS)-induced TGFBIp secretion, TGFBIp-induced barrier disruption, expression of cell adhesion molecules (CAMs), and the adhesion/transendothelial migration of the neutrophils to the human endothelial cells. Compounds 1 and 2 also suppressed TGFBIp-induced hyperpermeability and leukocyte migration in vivo. These results suggested that C-27-carboxylated pentacyclic triterpenoids 1 and 2 have anti-inflammatory functions by inhibiting hyperpermeability, CAM expression, and leukocyte adhesion/migration. Therefore, these compounds can be considered as a potential therapy for vascular inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Cecum; Cell Adhesion; Cell Adhesion Molecules; Cell Movement; Extracellular Matrix Proteins; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Interleukin-6; Ligation; Lipopolysaccharides; Lung; Male; Mice, Inbred C57BL; Neutrophils; NF-kappa B; Pentacyclic Triterpenes; Permeability; Protective Agents; Punctures; Saxifragaceae; Sepsis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Pre-eclampsia (PE), a hypertensive disorder of pregnancy, is detrimental to both mother and foetus. There is currently no effective treatment, but we have shown that Sildenafil Citrate (SC) improve various foetal outcomes in N

Topics: Animals; Biomarkers; Blood Pressure; Disease Models, Animal; Female; Gene Expression Regulation; Inflammation; Interferon-gamma; Neovascularization, Physiologic; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sildenafil Citrate; Time Factors; Transforming Growth Factor beta; Uterus; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

The signaling cross talk between the tracheal mesenchyme and epithelium has not been researched extensively, leaving a substantial gap of knowledge in the mechanisms dictating embryonic development of the proximal airways by the adjacent mesenchyme. Recently, we reported that embryos lacking mesenchymal expression of Sox9 did not develop tracheal cartilage rings and showed aberrant differentiation of the tracheal epithelium. Here, we propose that tracheal cartilage provides local inductive signals responsible for the proper differentiation, metabolism, and inflammatory status regulation of the tracheal epithelium. The tracheal epithelium of mesenchyme-specific Sox9

Topics: Animals; Biomarkers; Cartilage; Cell Differentiation; Cell Shape; Chondrocytes; Culture Media, Conditioned; Embryo, Mammalian; Epithelial Cells; Epithelium; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Glycogen; Inflammation; Interferon-gamma; Male; Mesoderm; Mice, Knockout; Models, Biological; Mutation; Oxidation-Reduction; Signal Transduction; SOX9 Transcription Factor; Trachea; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Short-chain fatty acids (SCFAs) with the anti-inflammatory capacity are produced by intestinal bacteria; however, their effect on the acute systematical inflammation remains unclear. This study aimed to investigate the effects of SCFAs, acetate, propionate and butyrate, on septic shock and the underlying mechanism. The LPS-induced septic model was used to evaluate the function of SCFAs by survival rate observation. Only butyrate, but not acetate or propionate, significantly decrease the mortality of septic mice. At 2 h and 6 h of LPS administration, the levels of TNF-α, IL-6 and IL-1β in plasma were measured by ELISA to estimate the effects of butyrate pretreatment on excessive inflammation. And the anti-inflammatory mediators including TGF-β, IL-10 and LXT4 in plasma were detected for further mechanism study in septic mice. Moreover, the murine macrophage-like RAW 264.7 cells were stimulated by LPS to further confirm the finding in vivo. Pretreatment with butyrate led to significant attenuation of the LPS-induced elevation of TNF-α, IL-6 and IL-1β levels. However, when detecting the anti-inflammatory factors, a significant increase in IL-10, but not TGF-β or LXT4, was shown in butyrate-pretreated group. Pretreatment of RAW 264.7 cells with butyrate led to downregulation of LPS-induced pro-inflammatory mediators, IL-6 and IL-1β, but did not affect the level of TNF-α, and increased IL-10 (P < 0.01). In conclusion, SCFA butyrate significantly attenuated the inflammation against sepsis through upregulation of anti-inflammatory IL-10.

Topics: Acetates; Animals; Anti-Inflammatory Agents; Butyrates; Cell Line; Enzyme-Linked Immunosorbent Assay; Inflammation; Interleukin-10; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; Propionates; RAW 264.7 Cells; Shock, Septic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Interleukin 23 (IL-23) is an inflammatory cytokine which plays a vital role in autoimmune diseases as well as in tumorigenesis. However, the role of IL-23 in tumor procession is still controversial and the underlying mechanism remains unclear. Here we established a stable cell line overexpressing IL-23 to prove that IL-23 promoted tumor growth and pulmonary metastasis through induction of tumor-related inflammation and absence of immune surveillance. IL-23 promotes tumor-associate inflammatory response such as infiltration of M2 macrophages, neutrophils and their elevated secretions of immunosuppressive cytokines transforming growth factor-β (TGF-β), IL-10 and vascular endothelial growth factor (VEGF) into tumor tissues, meanwhile the increase of the matrix metalloprotease MMP9. In addition, IL-23 increases the expression of the endothelial marker CD31 and proliferative marker Ki67 in tumors. Moreover, IL23 induces immunosuppression though reducing the infiltration of CD4

Topics: Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Proliferation; Disease Progression; Female; Inflammation; Interleukin-10; Interleukin-23; Ki-67 Antigen; Macrophages; Mammary Neoplasms, Animal; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neutrophils; Platelet Endothelial Cell Adhesion Molecule-1; Transforming Growth Factor beta; Tumor Microenvironment; Vascular Endothelial Growth Factor A

We developed a spinal nerve root wrapping rodent model to evaluate the relationship between recombinant human bone morphogenetic protein 2 (rhBMP-2) dosage and the degree of inflammation.. To investigate the direct effects of recombinant human bone morphogenetic protein 2 (rhBMP-2) dosage and the degree of inflammation in rodent spinal nerve roots.. rhBMP-2 is commonly used in clinical practice to augment spinal fusion. However, complications such as postoperative leg pain, and a higher rate of postoperative neurologic deficits have been reported. These may be attributable to the exposure of adjacent nerve roots to high doses of rhBMP-2.. Eighteen rats were randomized into three groups as follows: Group 1: absorbable collagen sponge (ACS) + 10 μg rhBMP-2, Group 2: ACS + 1 μg rhBMP-2, and Group 3 ACS with 20 μL saline. The ACS containing rhBMP-2 or saline were then wrapped around the L5 nerve root and secured loosely with nonabsorbable sutures. At 1-week postoperation, the rats were sacrificed, and the L5 nerve root and dorsal root ganglion harvested for reverse transcription polymerase chain reaction (RT-PCR), histology and immunohistochemical staining.. In our study, 10 μg rhBMP-2 induced a 10-fold increase in seroma compared with 1 μg group. Using RT-PCR, macrophage markers MIP3-α, and CD-68 were upregulated by 8- and 2-fold respectively in comparison with the saline group. Haematoxylin and eosin (H&E) images demonstrated disruption of nerve structures in the high dose 10 μg rhBMP-2, but not at 1 μg rhBMP-2 and with saline.. High doses of rhBMP-2 induced neuroinflammation in a dose dependent manner, resulting in higher seroma volume, macrophage marker gene expressions, and higher proportions of immunohistochemically stained TNF-alpha and more macrophage infiltration.. 2.

Topics: Animals; Bone Morphogenetic Protein 2; Disease Models, Animal; Inflammation; Lumbar Vertebrae; Rats, Sprague-Dawley; Recombinant Proteins; Spinal Fusion; Spinal Nerves; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The objective of this work is to study the protective effects of Quercetin against sodium nitrite-induced hypoxia on liver, lung, kidney and cardiac tissues, also to explore novel mechanism of this compound. Male albino rats were injected with sodium nitrite (75 mg/kg). Quercetin (200 mg kg

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Male; Organ Specificity; Proto-Oncogene Proteins c-akt; Quercetin; Rats; Rats, Wistar; Smad2 Protein; Sodium Nitrite; Transforming Growth Factor beta

The synthesized short peptide-polymers would provide key functions for tissue regeneration and repair, through enriching bioactive molecules on polymers or releasing these molecules pre-conjugated on the materials. We have developed a degradable polyurethane (PU) bearing HSNGLPL peptide, which has affinity binding ability to transforming growth factor-betas (TGF-β). For deeply understanding spatial release of TGF-β from the PU polymers and its localized bioactivity, quartz crystal microbalance (QCM) and Elisa test were used to verify TGF-β binding capacities in vitro and in vivo. The PU polymers, with or without pre-conjugating of TGF-β, were implanted into gastronomies muscle (GN) of C57BL/6 mice, for addressing TGF-β release from the polymers and its bio-regulating function in vivo. QCM result shows that PU bearing HSNGLPL peptide has affinity binding ability to TGF-β in vitro. Intramuscular implanting experiment further supports the enrichment efficiency of TGF-β on PU polymers in vivo. The detecting data involving intramuscular inflammatory infiltration triggered by the implants, myofiber regeneration, muscular fibrosis degree, and activation of endoplasmic reticulum stress (ER stress), evidence TGF-β can be released from PU polymers, and exerts regulating effects on the material-induced inflammation. Thus, our present results suggest it is feasible to improve biocompatibility of PU polymers in vivo, by pre-bearing bioactive molecules on materials before the implanting. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1156-1165, 2017.

Topics: Animals; Delayed-Action Preparations; Endoplasmic Reticulum Stress; Implants, Experimental; Inflammation; Mice; Muscle, Skeletal; Peptides; Polyurethanes; Transforming Growth Factor beta

We hypothesize that periodically early, local suppression of cysteinyl leukotrienes (CysLTs), which are potent inflammatory mediators, can reduce the fibrotic capsular contracture around silicone implants. We tested this hypothesis with the silicone implants enabled with the sustained release of montelukast, a CysLT receptor antagonist, for 3 and 15days. In this work, we inserted each of the distinct implants into the pocket of the subpanniculus carnosus plane of living rats and performed histological and immunofluorescent (IF) analyses of the tissues biopsied at predetermined periods for 12weeks after implant insertion. The implants with montelukast exhibited significantly reduced polymorphonuclear leukocytes (i.e., PMNs), implying a concurrent reduction of CysLT. This effect was more prominent after long-term local montelukast exposure. Thus, fewer fibroblasts were recruited, thereby reducing transforming growth factor (TGF)-β and myofibroblasts in the tissue around the implant. Therefore, the fibrotic capsule formation, which was assessed using the capsule thickness and collagen density, decreased along with the myofibroblasts. Additionally, the tissue biopsied at the experimental end point exhibited significantly decreased mechanical stiffness.. Capsular contracture is troublesome, making the tissues hardened around the silicone implant. This causes serious pain and discomfort to the patients, often leading to secondary surgery for implant replacement. To resolve this, we suggest a strategy of long-term, local suppression of cysteinyl leukotriene, an important mediator present during inflammation. For this, we propose a silicone implant abled to release a drug, montelukast, in a sustained manner. We tested our drug-release implant in living animals, which exhibited a significant decrease in capsule formation compared with the intact silicone implant. Therefore, we conclude that the sustained release of montelukast at the local insertion site represents a promising way to reduce capsular contracture around silicone implants.

Topics: Adipose Tissue; Animals; Collagen; Cysteine; Female; Fibroblasts; Implants, Experimental; Inflammation; Lactic Acid; Leukotrienes; Macrophages; Microscopy, Electron, Scanning; Myofibroblasts; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Rats, Sprague-Dawley; Silicones; Transforming Growth Factor beta

Inflammation plays a considerable role in the progression of Duchenne Muscular Dystrophy (DMD), a severe muscle disease caused by a mutation in the dystrophin gene. We previously showed that genetic ablation of Protein Kinase C θ (PKCθ) in mdx, the mouse model of DMD, improves muscle healing and regeneration, preventing massive inflammation. To establish whether pharmacological targeting of PKCθ in DMD can be proposed as a therapeutic option, in this study we treated young mdx mice with the PKCθ inhibitor Compound 20 (C20). We show that C20 treatment led to a significant reduction in muscle damage associated with reduced immune cells infiltration, reduced inflammatory pathways activation, and maintained muscle regeneration. Importantly, C20 treatment is efficient in recovering muscle performance in mdx mice, by preserving muscle integrity. Together, these results provide proof of principle that pharmacological inhibition of PKCθ in DMD can be considered an attractive strategy to modulate immune response and prevent the progression of the disease.. Duchenne muscular dystrophy (DMD) is a severe muscle disease affecting 1:3500 male births. DMD is caused by a mutation in dystrophin gene, coding for a protein required for skeletal and cardiac muscle integrity. Lack of a functional dystrophin is primarily responsible for the muscle eccentric contraction-induced muscle damage, observed in dystrophic muscle. However, inflammation plays a considerable role in the progression of DMD. Glucocorticoids, which have anti-inflammatory properties, are being used to treat DMD with some success; however, long term treatment with these drugs induces muscle atrophy and wasting, outweighing their benefit. The identification of specific targets for anti-inflammatory therapies is one of the ongoing therapeutic options. Although blunting inflammation would not be a "cure" for the disease, the emerging clue is that multiple strategies, addressing different aspects of the pathology, which may eventually converge, may be successful. In this context, we previously showed that genetic ablation of Protein Kinase C θ (PKCθ), an enzyme known to be involved in immune response, in mdx, the mouse model of DMD, improves muscle healing and regeneration, preventing massive inflammation. To establish whether pharmacological targeting of PKCθ in DMD can be proposed as a therapeutic option, in this study we treated young mdx mice with the PKCθ inhibitor Compound 20 (C20). We show that C20 treatment led to a significant reduction in muscle damage associated with reduced immune cells infiltration, reduced inflammatory pathways activation, and maintained muscle regeneration. Importantly, C20 treatment is efficient in recovering muscle performance in mdx mice, by preserving muscle integrity. Together, these results provide proof of principle that pharmacological inhibition of PKCθ in DMD can be considered an attractive strategy to modulate immune response and prevent the progression of the disease.

Topics: Animals; Blotting, Western; Dipeptides; Disease Models, Animal; Gene Expression; Humans; Inflammation; Isoenzymes; Male; Mice, Inbred C57BL; Mice, Inbred mdx; Mice, Knockout; Microscopy, Fluorescence; Motor Activity; Muscle, Skeletal; Muscular Dystrophy, Animal; Muscular Dystrophy, Duchenne; Myocardium; Protein Kinase C; Protein Kinase C-theta; Regeneration; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta

Angiogenesis is involved in the inflammation and proliferation stages of wound healing, to bring inflammatory cells to the wound and provide a microvascular network to maintain new tissue formation. An excess of inflammation, however, leads to prolonged wound healing and scar formation, often resulting in unfavourable outcomes such as amputation. CC-chemokines play key roles in the promotion of inflammation and inflammatory-driven angiogenesis. Therefore, inhibition of the CC-chemokine class may improve wound healing. We aimed to determine if the broad-spectrum CC-chemokine inhibitor "35K" could accelerate wound healing in vivo in mice. In a murine wound healing model, 35K protein or phosphate buffered saline (PBS, control) were added topically daily to wounds. Cohorts of mice were assessed in the early stages (four days post-wounding) and in the later stages of wound repair (10 and 21 days post-wounding). Topical application of the 35K protein inhibited CC-chemokine expression (CCL5, CCL2) in wounds and caused enhanced blood flow recovery and wound closure in early-mid stage wounds. In addition, 35K promoted neovascularisation in the early stages of wound repair. Furthermore, 35K treated wounds had significantly lower expression of the p65 subunit of NF-κB, a key inflammatory transcription factor, and augmented wound expression of the pro-angiogenic and pro-repair cytokine TGF-β. These findings show that broad-spectrum CC-chemokine inhibition may be beneficial for the promotion of wound healing.

Topics: Administration, Topical; Animals; Biomarkers; Chemokines; Collagen; Inflammation; Macrophages; Mice, Inbred C57BL; Neovascularization, Physiologic; Perfusion; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Wound Healing

Although master transcription factors (TFs) are key to the development of specific T cell subsets, whether additional transcriptional regulators are induced by the same stimuli that dominantly repress the development of other, non-specific T cell lineages has not been fully elucidated. Through the use of regulatory T cells (T

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Differentiation; Cells, Cultured; Forkhead Transcription Factors; GATA3 Transcription Factor; Gene Expression Regulation; Inflammation; Intestinal Mucosa; Mice; Mice, Inbred C57BL; Mice, Knockout; Pneumonia; T-Lymphocytes, Regulatory; Th2 Cells; Transcription Factors; Transcription, Genetic; Transforming Growth Factor beta

Anti-inflammatory therapy is a logical approach to slowing the inevitable lung function deterioration in cystic fibrosis (CF) patients. This study's aim was to evaluate inflammatory markers and disease progression in paediatric CF patients chronically treated with azithromycin or low-dose prednisolone.. The study included 204 patients with CF and 100 healthy controls; 102 CF patients were treated with basic therapy only (without anti-inflammatory treatment; WAT), and 102 individuals received basic therapy along with azithromycin (n = 59) or low-dose prednisolone (n = 43). The median duration of therapy was 24 months (range 12-82) with azithromycin and 31 months (range 12-180) with prednisolone. A cross-sectional analysis of plasma and sputum biomarkers was performed.. Compared with the healthy controls, the WAT group showed elevated IFN-γ, IL-10 (total), and TGFβ1 concentrations, and decreased TNFα (total) and adrenocorticotropic hormone (ACTH) levels (all p < 0.05). Plasma TNFα (total) concentrations in azithromycin/prednisolone patients were significantly higher than those in WAT patients and similar to those of healthy children. In contrast, IL-10 (total) levels were significantly decreased in azithromycin/prednisolone-treated patients compared with WAT patients. Children from the azithromycin group demonstrated ACTH levels similar to those of healthy controls. Azithromycin-treated patients showed a significantly reduced rate of CF-related liver disease and a significantly increased incidence of glucose metabolism disturbances.. Steady-state anti-inflammatory treatments may have a sustained immunomodulatory action at systemic and local levels in CF patients. Further investigations are needed to assess the effects of supportive azithromycin therapy on the hypothalamic-pituitary-adrenal axis and the incidence of non-pulmonary CF complications.

Topics: Adolescent; Adrenocorticotropic Hormone; Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Biomarkers; Child; Cross-Sectional Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Progression; Female; Genotype; Humans; Inflammation; Interferon-gamma; Interleukin-10; Leukocyte Elastase; Male; Prednisolone; Transforming Growth Factor alpha; Transforming Growth Factor beta

Keloid disease (KD) is a fibroproliferative cutaneous tumour characterised by heterogeneity, excess collagen deposition and aggressive local invasion. Lack of a validated animal model and resistance to a multitude of current therapies has resulted in unsatisfactory clinical outcomes of KD management. In order to address KD from a new perspective, we applied for the first time a site-specific in situ microdissection and gene expression profiling approach, through combined laser capture microdissection and transcriptomic array. The aim here was to analyse the utility of this approach compared with established methods of investigation, including whole tissue biopsy and monolayer cell culture techniques. This study was designed to approach KD from a hypothesis-free and compartment-specific angle, using state-of-the-art microdissection and gene expression profiling technology. We sought to characterise expression differences between specific keloid lesional sites and elucidate potential contributions of significantly dysregulated genes to mechanisms underlying keloid pathobiology, thus informing future explorative research into KD. Here, we highlight the advantages of our in situ microdissection strategy in generating expression data with improved sensitivity and accuracy over traditional methods. This methodological approach supports an active role for the epidermis in the pathogenesis of KD through identification of genes and upstream regulators implicated in epithelial-mesenchymal transition, inflammation and immune modulation. We describe dermal expression patterns crucial to collagen deposition that are associated with TGFβ-mediated signalling, which have not previously been examined in KD. Additionally, this study supports the previously proposed presence of a cancer-like stem cell population in KD and explores the possible contribution of gene dysregulation to the resistance of KD to conventional therapy. Through this innovative in situ microdissection gene profiling approach, we provide better-defined gene signatures of distinct KD regions, thereby addressing KD heterogeneity, facilitating differential diagnosis with other cutaneous fibroses via transcriptional fingerprinting, and highlighting key areas for future KD research.

Topics: Biopsy; Collagen; Epidermis; Epithelial-Mesenchymal Transition; Fibroblasts; Gene Expression Profiling; Gene Expression Regulation; Humans; Inflammation; Keloid; Keratinocytes; Laser Capture Microdissection; Microarray Analysis; Neoplastic Stem Cells; Organ Specificity; Primary Cell Culture; Signal Transduction; Transcriptome; Transforming Growth Factor beta

Epithelial-mesenchymal transition (EMT) has been recognized to accelerate peritoneal membrane dysfunction. 1,25(OH)2D3/vitamin D receptor (VDR) is important for preventing various types of EMT in vivo. However, its function on EMT and inflammation of human peritoneal mesothelial cells (HPMCs) remains to be elucidated. Therefore, the present study investigated the effects of 1,25(OH)2D3/VDR on high glucose (HG)‑induced EMT and inflammation in HPMCs and the underlying molecular mechanism. It was determined that HG reduced VDR expression, increased inflammatory cytokine expression, including transforming growth factor β (TGFβ) and interleukin‑6 (IL‑6) and phosphorylated‑SMAD family member 3 (p‑Smad3) expression. EMT was promoted as the expression level of the epithelial marker E‑cadherin was reduced, whereas expression levels of the mesenchymal markers α‑SMA and FN were increased. 1,25(OH)2D3 pretreatment inhibited the expression of inflammatory cytokines in HPMCs and attenuated HG‑induced EMT, possibly through inhibition of the TGFβ/Smad pathway by binding to its receptor VDR.

Topics: Calcitriol; Cell Line; Cytokines; Epithelial Cells; Epithelial-Mesenchymal Transition; Glucose; Humans; Inflammation; Peritoneum; Receptors, Calcitriol; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

Hepatic fibrosis, a progressive chronic disease mainly caused by hepatitis viral infections, alcohol abuse or metabolic syndrome leading to liver dysfunction and is the growing cause of mortality worldwide. Tyrosine kinase inhibitor BIBF1120 (Nintedanib) has been evaluated in clinical trials for idiopathic pulmonary fibrosis and advanced Hepatocellular carcinoma, but has not been explored for liver fibrosis yet. In this study, we aimed to investigate the therapeutic effects and mechanism of BIBF1120 in liver fibrogenesis. The effects of BIBF1120 were evaluated in TGFβ-activated mouse 3T3 fibroblasts, LX2 cells, primary human hepatic stellate cells (HSCs) and CCl

Topics: 3T3 Cells; Animals; Carbon Tetrachloride; Disease Models, Animal; Humans; Indoles; Inflammation; Liver Cirrhosis; Mice; Neovascularization, Pathologic; Protein-Tyrosine Kinases; Signal Transduction; Transforming Growth Factor beta

The vertebrate-conserved RNA-binding protein DND1 is required for the survival of primordial germ cells (PGCs), as well as the suppression of germ cell tumours in mice. Here we show that in mice DND1 binds a UU(A/U) trinucleotide motif predominantly in the 3' untranslated regions of mRNA, and destabilizes target mRNAs through direct recruitment of the CCR4-NOT deadenylase complex. Transcriptomic analysis reveals that the extent of suppression is dependent on the number of DND1-binding sites. This DND1-dependent mRNA destabilization is required for the survival of mouse PGCs and spermatogonial stem cells by suppressing apoptosis. The spectrum of target RNAs includes positive regulators of apoptosis and inflammation, and modulators of signalling pathways that regulate stem-cell pluripotency, including the TGFβ superfamily, all of which are aberrantly elevated in DND1-deficient PGCs. We propose that the induction of the post-transcriptional suppressor DND1 synergizes with concurrent transcriptional changes to ensure precise developmental transitions during cellular differentiation and maintenance of the germ line.

Topics: 3' Untranslated Regions; Animals; Apoptosis; Base Sequence; Binding Sites; Cell Differentiation; Gene Expression Profiling; Gene Silencing; Humans; Inflammation; Male; Mice; Multiprotein Complexes; Neoplasm Proteins; Nucleotide Motifs; Pluripotent Stem Cells; Protein Binding; Ribonucleases; RNA Stability; RNA, Messenger; Signal Transduction; Spermatogonia; Stem Cells; Transcription Factors; Transcription, Genetic; Transforming Growth Factor beta

To evaluate the efficacy and safety of suramin, genistein and collagen matrix for the prevention of inflammation, the reduction of fibrosis and the delay in adjustment after strabismus surgery on a rabbit model.. By using an adjustable suture technique, a recession of the superior rectus muscle (SRM) was made in 36 eyes of 18 rabbits. Three study groups were created using genistein, suramin and collagen matrix (n = 6 per group). Two control groups utilized dimethyl sulphoxide (DMSO) (n = 6) and balanced salt solution (n = 12). The adjustments and measurements were made on days 2, 7, 14. After enucleation was done on day 21, the degree of inflammation was evaluated quantitatively in histopathological sections and immunohistochemical investigations were performed for tissue expression of cytoplasmic vascular endothelial growth factor (VEGF), MAC 387, TGF-β and bFGF.. The adhesions between conjunctiva and SRM were significantly less in the collagen matrix and suramin groups (p = 0.002) and adhesions between the sclera and SRM were considerably reduced in the genistein and DMSO groups (p = 0.006) on day 7. Force exerted for adjustment was significantly less in the collagen matrix and suramin groups on day 14 (p = 0.006). Expression of b-FGF was significantly lower in the conjunctival epithelium in the suramin and genistein groups (p = 0.0001 for both). TGF-β was significantly lower (p = 0.001) in the suramin group and VEGF expression was totally absent. MAC 387 expression was lower in the genistein and suramin groups (p = 0.0001).. Suramin, genistein and collagen matrix successfully reduce adhesions, and facilitate adjustment following recession surgery. Both suramin and genistein effectively suppress growth factor expression, while collagen matrix offers the longest time interval for adjustability after strabismus surgery.

Topics: Animals; Antineoplastic Agents; Biomarkers; Collagen; Conjunctiva; Endoglin; Epithelium; Female; Fibrosis; Genistein; Inflammation; Male; Oculomotor Muscles; Ophthalmologic Surgical Procedures; Rabbits; Strabismus; Suramin; Suture Techniques; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

CD248 (endosialin) is a stromal cell marker expressed on fibroblasts and pericytes. During liver injury, myofibroblasts are the main source of fibrotic matrix.. To determine the role of CD248 in the development of liver fibrosis in the rodent and human setting.. CD248 expression was studied by immunostaining and quantitative PCR in both normal and diseased human and murine liver tissue and isolated hepatic stellate cells (HSCs). Hepatic fibrosis was induced in CD248(-/-) and wild-type controls with carbon tetrachloride (CCl4) treatment.. Expression of CD248 was seen in normal liver of humans and mice but was significantly increased in liver injury using both immunostaining and gene expression assays. CD248 was co-expressed with a range of fibroblast/HSC markers including desmin, vimentin and α-smooth muscle actin (α-SMA) in murine and human liver sections. CD248 expression was restricted to isolated primary murine and human HSC. Collagen deposition and α-SMA expression, but not inflammation and neoangiogenesis, was reduced in CD248(-/-) mice compared with wild-type mice after CCl4 treatment. Isolated HSC from wild-type and CD248(-/-) mice expressed platelet-derived growth factor receptor α (PDGFR-α) and PDGFR-β at similar levels. As expected, PDGF-BB stimulation induced proliferation of wild-type HSC, whereas CD248(-/-) HSC did not demonstrate a proliferative response to PDGF-BB. Abrogated PDGF signalling in CD248(-/-) HSC was confirmed by significantly reduced c-fos expression in CD248(-/-) HSC compared with wild-type HSC.. Our data show that deletion of CD248 reduces susceptibility to liver fibrosis via an effect on PDGF signalling, making it an attractive clinical target for the treatment of liver injury.

Topics: Actins; Angiogenesis Inducing Agents; Animals; Antigens, CD; Antigens, Neoplasm; Becaplermin; Carbon Tetrachloride; Cell Proliferation; Cells, Cultured; Chemical and Drug Induced Liver Injury; Chronic Disease; Collagen; Desmin; Fibrosis; Gene Expression; Hepatic Stellate Cells; Humans; Inflammation; Liver; Liver Cirrhosis; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Pathologic; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-sis; Receptor, Platelet-Derived Growth Factor alpha; Receptor, Platelet-Derived Growth Factor beta; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta; Vimentin

AKI with incomplete epithelial repair is a major contributor to CKD characterized by tubulointerstitial fibrosis. Injury-induced epithelial secretion of profibrotic factors is hypothesized to underlie this link, but the identity of these factors and whether epithelial injury is required remain undefined. We previously showed that activation of the canonical Wnt signaling pathway in interstitial pericytes cell autonomously drives myofibroblast activation in vivo. Here, we show that inhibition of canonical Wnt signaling also substantially prevented TGFβ-dependent myofibroblast activation in vitro. To investigate whether Wnt ligand derived from proximal tubule is sufficient for renal fibrogenesis, we generated a novel mouse strain with inducible proximal tubule Wnt1 secretion. Adult mice were treated with vehicle or tamoxifen and euthanized at 12 or 24 weeks postinjection. Compared with vehicle-treated controls, kidneys with tamoxifen-induced Wnt1 expression from proximal tubules displayed interstitial myofibroblast activation and proliferation and increased matrix protein production. PDGF receptor β-positive myofibroblasts isolated from these kidneys exhibited increased canonical Wnt target gene expression compared with controls. Notably, fibrotic kidneys had no evidence of inflammatory cytokine expression, leukocyte infiltration, or epithelial injury, despite the close histologic correlation of each with CKD. These results provide the first example of noninflammatory renal fibrosis. The fact that epithelial-derived Wnt ligand is sufficient to drive interstitial fibrosis provides strong support for the maladaptive repair hypothesis in the AKI to CKD transition.

Topics: Actins; Animals; Antineoplastic Agents, Hormonal; Cell Proliferation; Disease Models, Animal; Fibronectins; Fibrosis; Gene Expression; Inflammation; Kidney Tubules, Proximal; Ligands; Mice; Myofibroblasts; Paracrine Communication; Receptor, Platelet-Derived Growth Factor beta; Tamoxifen; Transforming Growth Factor beta; Wnt Signaling Pathway; Wnt1 Protein

Hyperglycemia induces all isoforms of transforming growth factor β (TGFβ), which in turn play key roles in inflammation and fibrosis that characterize diabetic nephropathy. Sphingosine 1-phosphate (S1P) is a signaling sphingolipid, derived from sphingosine by the action of sphingosine kinase (SK). S1P mediates many biological processes, which mimic TGFβ signaling. To determine the role of SK1 and S1P in inducing fibrosis and inflammation, and the interaction with TGFβ-1, 2 and 3 signalling in diabetic nephropathy, human proximal tubular cells (HK2 cells) were exposed to normal (5 mmol/L) or high (30 mmol/L) glucose or TGFβ-1, -2, -3 ± an SK inhibitor (SKI-II) or SK1 siRNA. Control and diabetic wild type (WT) and SK1(-/-) mice were studied. Fibrotic and inflammatory markers, and relevant downstream signalling pathways were assessed. SK1 mRNA and protein expression was increased in HK2 cells exposed to high glucose or TGFβ1,-2,-3. All TGFβ isoforms induced fibronectin, collagen IV and macrophage chemoattractant protein 1 (MCP1), which were reversed by both SKI-II and SK1 siRNA. Exposure to S1P increased phospho-p44/42 expression, AP-1 binding and NFkB phosphorylation. WT diabetic mice exhibited increased renal cortical S1P, fibronectin, collagen IV and MCP1 mRNA and protein expression compared to SK1(-/-) diabetic mice. In summary, this study demonstrates that inhibiting the formation of S1P reduces tubulointerstitial renal inflammation and fibrosis in diabetic nephropathy.

Topics: Animals; Biomarkers; Cell Line; Diabetic Nephropathies; Dose-Response Relationship, Drug; Enzyme Inhibitors; Extracellular Matrix; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Gene Expression Regulation, Enzymologic; Gene Silencing; Glucose; Humans; Inflammation; Kidney Cortex; Kidney Tubules; Lysophospholipids; Male; Mice; NF-kappa B; Phosphoproteins; Phosphotransferases (Alcohol Group Acceptor); Sphingosine; Transcription Factor AP-1; Transforming Growth Factor beta

Recombinant human bone morphogenetic protein type 2 (rhBMP-2) has been used to promote bone regeneration. In contrast, some reports have suggested rhBMP-2 does not provide advantages over autogenous bone grafting owing to the undesirable postoperative symptoms of this growth factor. Because the undesirable symptoms of rhBMP-2 are usually promoted by inflammation, this study evaluated the in vivo effect of human adipose-derived stem cells (ASCs) incorporated into polylactic co-glycolic acid (PLGA) scaffolds in decreasing the inflammatory response induced by a low dose of rhBMP-2.. PLGA scaffolds were characterized and loaded with rhBMP-2 1, 2.5, or 5 μg per scaffold (n = 6) and the in vitro released protein amounts were quantified at 7 hours and 1, 7, and 21 days after loading (n = 3). The muscle tissue of 6 beagles received the following treatments: PLGA, PLGA plus rhBMP-2 (2.5 μg), and PLGA plus rhBMP-2 plus ASCs (1 × 10(6) ASCs). The samples were evaluated 45 days after surgery. Statistical analyses were performed and the P value was set at .05.. PLGA plus rhBMP-2 plus ASCs yielded the smallest number of inflammatory foci (P < .001) and giant cells (P < .001) and the largest number of angiogenesis sites (P < .001).. Human ASCs administered in vivo into PLGA scaffolds with a low dose of rhBMP-2 decrease tissue inflammation and increase angiogenesis in muscular sites.

Topics: Absorbable Implants; Adipose Tissue; Animals; Biocompatible Materials; Bone Morphogenetic Protein 2; Cell Culture Techniques; Cell Survival; Dogs; Giant Cells; Humans; Inflammation; Lactic Acid; Mesenchymal Stem Cells; Muscle, Skeletal; Neovascularization, Physiologic; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Recombinant Proteins; Time Factors; Tissue Scaffolds; Transforming Growth Factor beta; Young Adult

Atherosclerosis is an autoimmune inflammatory disease involving both innate and adaptive immune mechanisms. Immune tolerance induction may have therapeutic potential for the suppression of atherosclerosis. Current interest is directed towards mucosal tolerance induction, especially nasal tolerance. Previous studies have shown that heat shock protein 60 (HSP60) is recognized as an important autoantigen in atherosclerosis, and nasal or oral HSP60 can induce tolerance and ameliorate atherosclerosis by inducing several subsets of regulatory T cells (Tregs ) such as latency-associated peptide (LAP)(+) and forkhead box transcription factor 3 (FoxP3)(+) Tregs. However, little is known regarding the detailed mechanisms of nasal tolerance. Here, we again investigated the impact of nasal HSP60 on atherosclerosis and the mechanisms underlying the anti-atherosclerosis responses. We found that nasal HSP60 caused a significant 33·6% reduction in plaque size at the aortic root in the early stages of atherosclerosis (P < 0·001). Notably, a significant increase in activated CD4(+) CD25(+) glycoprotein A repetitions predominant (GARP)(+) Tregs, type 1 Tregs (Tr1 cells), and CD4(+) CD25(+) FoxP3(+) Tregs, as well as a marked decrease in the numbers of type 1 and 17 T helper cells was detected in the spleens and cervical lymph nodes of HSP60-treated mice. Moreover, nasal HSP60 increases the production of transforming growth factor (TGF)-β and interleukin (IL)-10 and decreases the secretion of IFN-γ and IL-17. Interestingly, the atheroprotective role of nasal HSP60 treatment was abrogated partly by the neutralization of IL-10. Our findings show that nasal administration of HSP60 can attenuate atherosclerotic formation by inducing GARP(+) Tregs, Tr1 cells and FoxP3(+) Tregs, and that these Tregs maintain immune homeostasis by secreting IL-10 and TGF-β.

Topics: Administration, Intranasal; Animals; Atherosclerosis; Chaperonin 60; Forkhead Transcription Factors; Immune Tolerance; Immunization; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-17; Interleukin-2 Receptor alpha Subunit; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Transforming growth factor (TGF-β) is a well-known component of a regulatory cytokines superfamily that has pleiotropic functions in a broad range of cell types and is involved, in vertebrates, in numerous physiological and pathological processes. In the current study, we report on Ciona intestinalis molecular characterisation and expression of a transforming growth factor β homologue (CiTGF-β). The gene organisation, phylogenetic tree and modelling supported the close relationship with the mammalian TGF suggesting that the C. intestinalis TGF-β gene shares a common ancestor in the chordate lineages. Functionally, real-time PCR analysis showed that CiTGF-β was transcriptionally upregulated in the inflammatory process induced by LPS inoculation, suggesting that is involved in the first phase and significant in the secondary phase of the inflammatory response in which cell differentiation occurs. In situ hybridisation assays revealed that the genes transcription was upregulated in the pharynx, the main organ of the ascidian immune system, and expressed by cluster of hemocytes inside the pharynx vessels. These data supported the view that CiTGF-β is a potential molecule in immune defence systems against bacterial infection.

Topics: Amino Acid Sequence; Animals; Ciona intestinalis; Cloning, Molecular; Hemocytes; Immunity, Innate; Inflammation; Lipopolysaccharides; Mammals; Molecular Sequence Data; Pharynx; Phylogeny; Transforming Growth Factor beta; Up-Regulation

Nontypeable Haemophilus influenzae (NTHi) is associated with chronic otitis media (COM). In this study, we generated a murine model of COM by using eustachian tube (ET) obstruction and NTHi (10(7) CFU) inoculation into the tympanic bulla, and we investigated the relationship between regulatory T cells (Treg) and chronic inflammation in the middle ear. Middle ear effusions (MEEs) and middle ear mucosae (MEM) were collected at days 3 and 14 and at 1 and 2 months after inoculation. Untreated mice served as controls. MEEs were used for bacterial counts and to measure the concentrations of cytokines. MEM were collected for histological evaluation and flow cytometric analysis. Inflammation of the MEM was prolonged throughout this study, and the incidence of NTHi culture-positive MEE was 38% at 2 months after inoculation. The levels of interleukin-1β (IL-β), tumor necrosis factor alpha, IL-10, and transforming growth factor β were increased in the middle ear for up to 2 months after inoculation. CD4(+) CD25(+) FoxP3(+) Treg accumulated in the middle ear, and the percentage of Treg in the MEM increased for up to 2 months after inoculation. Treg depletion induced a 99.9% reduction of bacterial counts in MEEs and also significantly reduced the ratio of NTHi culture-positive MEE. The levels of these cytokines were also reduced in MEEs. In summary, we developed a murine model of COM, and our findings indicate that Treg confer infectious tolerance to NTHi in the middle ear.

Topics: Animals; Chronic Disease; Disease Models, Animal; Ear, Middle; Eustachian Tube; Haemophilus Infections; Haemophilus influenzae; Inflammation; Interleukin-10; Interleukin-1beta; Lymphocyte Count; Mice; Mice, Inbred BALB C; Mucous Membrane; Otitis Media with Effusion; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Nuclear Factor (NF)-κB is positioned to provide the interface between COPD and carcinogenesis through regulation of chronic inflammation in the lungs. Using a tetracycline-inducible transgenic mouse model that conditionally expresses activated IκB kinase β (IKKβ) in airway epithelium (IKTA), we found that sustained NF-κB signaling results in chronic inflammation and emphysema by 4 months. By 11 months of transgene activation, IKTA mice develop lung adenomas. Investigation of lung inflammation in IKTA mice revealed a substantial increase in M2-polarized macrophages and CD4+/CD25+/FoxP3+ regulatory T lymphocytes (Tregs). Depletion of alveolar macrophages in IKTA mice reduced Tregs, increased lung CD8+ lymphocytes, and reduced tumor numbers following treatment with the carcinogen urethane. Alveolar macrophages from IKTA mice supported increased generation of inducible Foxp3+ Tregs ex vivo through expression of TGFβ and IL-10. Targeting of TGFβ and IL-10 reduced the ability of alveolar macrophages from IKTA mice to induce Foxp3 expression on T cells. These studies indicate that sustained activation of NF-κB pathway links COPD and lung cancer through generation and maintenance of a pro-tumorigenic inflammatory environment consisting of alternatively activated macrophages and regulatory T cells.

Topics: Animals; Blotting, Western; CD8-Positive T-Lymphocytes; Cells, Cultured; Epithelium; Female; Flow Cytometry; Humans; I-kappa B Kinase; Immunosuppressive Agents; Inflammation; Interleukin-10; Lung; Lung Neoplasms; Macrophages, Alveolar; Male; Mice; Mice, Transgenic; NF-kappa B; Pulmonary Disease, Chronic Obstructive; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Previous studies suggest that inflammation may play a role in the pathophysiology of post-thrombotic syndrome (PTS). The aims of the present study were to evaluate markers of inflammation as possible predictors for PTS after pregnancy-related deep vein thrombosis (DVT). We included 182 women with a pregnancy-related DVT during 1990-2003 and 314 controls. All women answered a questionnaire and donated a blood sample in 2006. PTS was diagnosed when a self-reported Villalta score was above 4. The following predictors of PTS were included: high sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, IL-8, IL-10, monocyte chemotactic protein (MCP)-1, transforming growth factor (TGF)-β1, platelet derived growth factor (PDGF)-BB, and the two adhesion molecules intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1. High values were defined as above median value among controls. We found that 41% of cases were diagnosed with PTS 3-16years after index pregnancy. In univariate analyses, high values of hsCRP, IL-6, and IL-10 were significantly associated with PTS with ORs 2.3 (95% CI; 1.2-4.2, p=0.008), 1.9 (1.0-3.5, p=0.04), and 10.8 (1.3-89.8, p=0.01), respectively. Only hsCRP, which has previously been found to be independently associated with PTS, was independently associated with PTS in a multivariate logistic regression model, when adjusting for proximal DVT occurring postpartum, age above 33years, and smoking (adjusted OR 2.4; 95% CI 1.2-4.8, p=0.01). We conclude that hsCRP was associated with PTS 3-16years after pregnancy-related DVT.

Topics: Adult; Biomarkers; C-Reactive Protein; Chemokine CCL2; Cross-Sectional Studies; Female; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukins; Postthrombotic Syndrome; Pregnancy; Pregnancy Complications, Cardiovascular; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1; Venous Thrombosis

Titanium dioxide nanoparticles (TiO2 NPs) have been demonstrated to damage the kidneys. However, whether chronic nephritis leads to renal fibration or the fibrosis is associated with the activation of TGF-β/Smads/p38MAPK pathway caused by TiO2 NPs exposure is not well understood. Forty male mice were separately exposed to 0, 2.5, 5, or 10 mg/kg body weight TiO2 NPs for 6 months. Renal biochemical functions and levels of TGF-β/Smads/p38MAPK pathway-related markers and extracellular matrix (ECM) expression in the kidneys were investigated. The findings showed that subchronic TiO2 NPs exposure increased levels of urinary creatisix (Cr), N-acetyl-glucosaminidase, and vanin-1, resulted in severe renal inflammation and fibration. Furthermore, TiO2 NP exposure upregulated expression of transforming growth factor-β1 (TGF-β1, 0.07- to 2.72-fold), Smad2 (0.42- to 1.63-fold), Smad3 (0.02- to 1.94-fold), ECM (0.15- to 2.75-fold), α-smooth muscle actin (0.14- to 3.06-fold), p38 mitogen-activated protein kinase (p38MAPK, 0.11- to 3.78-fold), and nuclear factor-κB (0.4- to 2.27-fold), and downregulated Smad7 (0.05- to 0.61-fold) expression in mouse kidney. Subchronic TiO2 NPs exposure induced changes of renal characteristics towards inflammation and fibration may be mediated via TGF-β/Smads/p38MAPK pathway, and the uses of TiO2 NPs should be carried out cautiously, especially in humans. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1452-1461, 2016.

Topics: Animals; Biomarkers; Drinking Behavior; Feeding Behavior; Fibrosis; Gene Expression Regulation; Inflammation; Kidney; Male; Mice, Inbred ICR; Nanoparticles; p38 Mitogen-Activated Protein Kinases; Particle Size; RNA, Messenger; Signal Transduction; Smad Proteins; Titanium; Transforming Growth Factor beta

Necrotizing enterocolitis (NEC) is an inflammatory bowel necrosis of premature infants. Based on our recent findings of increased Smad7 expression in surgically resected bowel affected by NEC, we hypothesized that NEC macrophages undergo inflammatory activation because increased Smad7 expression renders these cells resistant to normal, gut-specific, transforming growth factor (TGF)-β-mediated suppression of inflammatory pathways.. We used surgically resected human NEC tissue, murine models of NEC-like injury, bone marrow-derived and intestinal macrophages, and RAW264.7 cells. Smad7 and IκB kinase-beta (IKK-β) were measured by quantitative PCR, western blots, and immunohistochemistry. Promoter activation was confirmed in luciferase reporter and chromatin immunoprecipitation assays.. NEC macrophages showed increased Smad7 expression, particularly in areas with severe tissue damage and high bacterial load. Lipopolysaccharide-induced Smad7 expression suppressed TGF-β signaling and augmented nuclear factor-kappa B (NF-κB) activation and cytokine production in macrophages. Smad7-mediated NF-κB activation was likely mediated via increased expression of IKK-β, which, further increased Smad7 expression in a feed-forward loop. We show that Smad7 induced IKK-β expression through direct binding to the IKK-β promoter and its transcriptional activation.. Smad7 expression in NEC macrophages interrupts TGF-β signaling and promotes NF-κB-mediated inflammatory signaling in these cells through increased expression of IKK-β.

Topics: Animals; Enterocolitis, Necrotizing; Humans; I-kappa B Kinase; Inflammation; Intestinal Mucosa; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred C57BL; NF-kappa B; RAW 264.7 Cells; Signal Transduction; Smad7 Protein; Transforming Growth Factor beta

Multifocal inflammatory lesions featuring destruction of lipid-rich myelin are pathologic hallmarks of multiple sclerosis. Lesion activity is assessed by the extent and composition of myelin uptake by myeloid cells present in such lesions. In the inflamed CNS, myeloid cells are comprised of brain-resident microglia, an endogenous cell population, and monocyte-derived macrophages, which infiltrate from the systemic compartment. Using microglia isolated from the adult human brain, we demonstrate that myelin phagocytosis is dependent on the polarization state of the cells. Myelin ingestion is significantly enhanced in cells exposed to TGF-β compared with resting basal conditions and markedly reduced in classically activated polarized cells. Transcriptional analysis indicated that TGF-β-treated microglia closely resembled M0 cells. The tyrosine kinase phagocytic receptor MerTK was one of the most upregulated among a select number of differentially expressed genes in TGF-β-treated microglia. In contrast, MerTK and its known ligands, growth arrest-specific 6 and Protein S, were downregulated in classically activated cells. MerTK expression and myelin phagocytosis were higher in CNS-derived microglia than observed in monocyte-derived macrophages, both basally and under all tested polarization conditions. Specific MerTK inhibitors reduced myelin phagocytosis and the resultant anti-inflammatory biased cytokine responses for both cell types. Defining and modulating the mechanisms that regulate myelin phagocytosis has the potential to impact lesion and disease evolution in multiple sclerosis. Relevant effects would include enhancing myelin clearance, increasing anti-inflammatory molecule production by myeloid cells, and thereby permitting subsequent tissue repair.

Topics: Adult; Brain; c-Mer Tyrosine Kinase; Cell Polarity; Cells, Cultured; Down-Regulation; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Macrophages; Microglia; Multiple Sclerosis; Myelin Sheath; Myeloid Cells; Phagocytosis; Protein S; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Transforming Growth Factor beta; Up-Regulation

Resolvin D1 (RvD1) was shown to be a potent anti-inflammatory and proresolution lipid mediator in several animal models of inflammation, but its mechanism of action in humans is not clear. We show that the RvD1 receptor GPR32 is present on resting, proinflammatory M(LPS) and alternatively activated primary human M(IL-4) macrophages, whereas TGF-β and IL-6 reduce its membrane expression. Accordingly, stimulation of resting primary human macrophages with 10 nM RvD1 for 48 h maximally reduced the secretion of the proinflammatory cytokines IL-1β and IL-8; abolished chemotaxis to several chemoattractants like chemerin, fMLF, and MCP-1; and doubled the phagocytic activity of these macrophages toward microbial particles. In contrast, these functional changes were not accompanied by surface expression of markers specific for alternatively activated M(IL-4) macrophages. Similar proresolution effects of RvD1 were observed when proinflammatory M(LPS) macrophages were treated with RvD1. In addition, we show that these RvD1-mediated effects are GPR32 dependent because reduction of GPR32 expression by small interfering RNA, TGF-β, and IL-6 treatment ablated these proresolution effects in primary human macrophages. Taken together, our results indicate that in humans RvD1 triggers GPR32 to polarize and repolarize macrophages toward a proresolution phenotype, supporting the role of this mediator in the resolution of inflammation in humans.

Topics: Anti-Inflammatory Agents; Cell Migration Inhibition; Cells, Cultured; Chemotaxis; Docosahexaenoic Acids; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Interleukin-8; Macrophages; Phagocytosis; Phenotype; Receptors, G-Protein-Coupled; RNA Interference; RNA, Small Interfering; Transforming Growth Factor beta

We investigated the effects of pan-class I PI3K inhibitor, ZSTK474 on vascular remodeling using a murine model of allergic vasculitis with eosinophil infiltration.. C57BL/6 mice were sensitized with OVA. The positive controls were exposed to aerosolized OVA daily for 7 days. The other group of mice were administered ZSTK474 (30 mg/kg, p.o. daily) in parallel with daily exposure to aerosolized OVA for 7 days. On the 3rd and 7th day, bronchoalveolar lavage (BAL) was performed and the lungs were excised for pathological analysis. Cell differentials were determined and the concentrations of IL-4, IL-5, IL-13 and TGF-βin BAL fluid were measured.. The total cell numbers and eosinophil numbers in BALF were greatly reduced in the ZSTK474-treated group on the 3rd and 7th day after exposure to OVA. The numbers of total white blood cells and eosinophils in the peripheral blood were significantly reduced in the ZSTK474-treated group on the 3rd and 7th day after exposure to OVA. The concentrations of IL-4, IL-5, and IL-13 in BAL fluids were also reduced significantly on the 3rd day in the ZSTK474-treated group. The concentrations of TGF-β in BAL fluids were also reduced significantly on the 3rd and 7th day in the ZSTK474-treated group. The pathological scores reduced significantly in the ZSTK474-treated group compared to the control group.. The PI3K inhibitor, ZSTK474 suppressed pulmonary vascular remodeling in the murine model of allergic vasculitis with eosinophil infiltration. PI3K signal transduction may have a critical role in the immunological process that induces allergic vasculitis.

Topics: Animals; Asthma; Disease Models, Animal; Eosinophils; Female; Hypersensitivity; Inflammation; Interleukin-13; Interleukin-4; Interleukin-5; Leukocyte Count; Lung; Mice; Mice, Inbred C57BL; Ovalbumin; Phosphoinositide-3 Kinase Inhibitors; Transforming Growth Factor beta; Triazines; Vascular Remodeling; Vasculitis

Renal interstitial fibrosis is characterized by excessive accumulation of extracellular matrix, which leads to end-stage renal failure.. The aim of this study was to explore the effect of Elsholtzia ciliata (Thunb.) Hylander ethanol extract (ECE) on renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO).. After quantitative analysis of ECE using the high performance liquid chromatography-photodiode array (HPLC-PDA) method, an in vitro study was performed to assess the anti-inflammatory and anti-fibrotic effects of ECE, using lipopolysaccharide (LPS) and transforming growth factor-ß (TGF-ß), respectively.. For in vivo study, all male Sprague Dawley (SD) rats (n=10/group), except for those in the control group, underwent UUO. The rats were orally treated with water (control), captopril (positive control, 200 mg/kg), and ECE (300 and 500 mg/kg) for 14 days.. In ECE, luteolin and rosmarinic acid were relatively abundant among the other flavonoids and phenolic acids. ECE treatment ameliorated LPS-induced overexpression of nuclear factor-κB, tumor necrosis factor (TNF-α), and interleukin-6 and improved oxidative stress in RAW 264.7 cells. Furthermore, ECE treatment suppressed TGF-ß-induced α-smooth muscle actin and matrix metalloproteinase 9 expression in human renal mesangial cells. In the UUO model, 14 consecutive days of ECE treatment improved UUO-induced renal damage and attenuated histopathological alterations and interstitial fibrosis. Moreover, the renal expression of TNF-α, TGF-ß, and Smad 3 were inhibited by ECE treatment.. Taken together, the effects of ECE may be mediated by blocking the activation of TGF-ß and inflammatory cytokines, leading subsequently to degradation of the ECM accumulation pathway. Based on these findings, ECE might serve as an improved treatment strategy for renal fibrotic disease.

Topics: Animals; Cytokines; Fibrosis; Humans; Inflammation; Kidney; Kidney Diseases; Lamiaceae; Male; Matrix Metalloproteinase 9; Mesangial Cells; Mice; Nephritis; Oxidative Stress; Phytotherapy; Plant Extracts; Polyphenols; Rats; Rats, Sprague-Dawley; RAW 264.7 Cells; Smad3 Protein; Transforming Growth Factor beta; Ureteral Obstruction

Endoglin is an auxiliary receptor for members of the TGF-β superfamily and plays an important role in the homeostasis of the vessel wall. Mutations in endoglin gene (ENG) or in the closely related TGF-β receptor type I ACVRL1/ALK1 are responsible for a rare dominant vascular dysplasia, the Hereditary Hemorrhagic Telangiectasia (HHT), or Rendu-Osler-Weber syndrome. Endoglin is also expressed in human macrophages, but its role in macrophage function remains unknown. In this work, we show that endoglin expression is triggered during the monocyte-macrophage differentiation process, both in vitro and during the in vivo differentiation of blood monocytes recruited to foci of inflammation in wild-type C57BL/6 mice. To analyze the role of endoglin in macrophages in vivo, an endoglin myeloid lineage specific knock-out mouse line (Eng(fl/fl)LysMCre) was generated. These mice show a predisposition to develop spontaneous infections by opportunistic bacteria. Eng(fl/fl)LysMCre mice also display increased survival following LPS-induced peritonitis, suggesting a delayed immune response. Phagocytic activity is impaired in peritoneal macrophages, altering one of the main functions of macrophages which contributes to the initiation of the immune response. We also observed altered expression of TGF-β1 target genes in endoglin deficient peritoneal macrophages. Overall, the altered immune activity of endoglin deficient macrophages could help to explain the higher rate of infectious diseases seen in HHT1 patients.

Topics: Activin Receptors, Type I; Activin Receptors, Type II; Animals; Endoglin; Flow Cytometry; Gene Expression Regulation; Humans; Immunity, Innate; Inflammation; Intracellular Signaling Peptides and Proteins; Macrophages; Mice; Mice, Knockout; Opportunistic Infections; Phagocytosis; Telangiectasia, Hereditary Hemorrhagic; Transforming Growth Factor beta

Narrowband ultraviolet B (NB-UVB) has been widely used in dermatological phototherapy. As for the application of NB-UVB phototherapy to graft-versus-host disease (GVHD), we previously reported that it was highly efficacious for cutaneous lesions of acute GVHD (aGVHD) and that expansion of regulatory T (Treg) cells induced by NB-UVB might be one of the mechanisms. In order to examine whether NB-UVB irradiation through expansion of Treg cells is effective for the treatment of not only cutaneous aGVHD but also aGVHD of inner organs such as the intestine or liver, we conducted experiments in which a murine lethal aGVHD model, characterized by severe involvement of the intestine, was irradiated with NB-UVB. We found that NB-UVB irradiation improved the clinical score and survival rate. The pathological score of aGVHD was improved in all affected organs: intestine, liver, and skin. In the serum of mice irradiated with NB-UVB, the levels of Treg cells-associated cytokines such as transforming growth factor beta (TGFβ) and interleukin-10 (IL-10) were elevated. The numbers of infiltrating Treg cells in inflamed tissue of the intestine and those in spleen were increased in mice treated with NB-UVB. This is the first report demonstrating that NB-UVB phototherapy has the ability to ameliorate intestinal aGVHD through the expansion of Treg cells.

Topics: Animals; Disease Models, Animal; Graft vs Host Disease; Inflammation; Interleukin-10; Intestinal Diseases; Intestines; Mice; Phototherapy; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Ultraviolet Rays

Stroke is a leading cause of disability and currently lacks effective therapy enabling long-term functional recovery. Ischemic brain injury causes local inflammation, which involves both activated resident microglia and infiltrating immune cells, including monocytes. Monocyte-derived macrophages (MDMs) exhibit a high degree of functional plasticity. Here, we determined the role of MDMs in long-term spontaneous functional recovery after middle cerebral artery occlusion in mice. Analyses by flow cytometry and immunocytochemistry revealed that monocytes home to the stroke-injured hemisphere., and that infiltration peaks 3 d after stroke. At day 7, half of the infiltrating MDMs exhibited a bias toward a proinflammatory phenotype and the other half toward an anti-inflammatory phenotype, but during the subsequent 2 weeks, MDMs with an anti-inflammatory phenotype dominated. Blocking monocyte recruitment using the anti-CCR2 antibody MC-21 during the first week after stroke abolished long-term behavioral recovery, as determined in corridor and staircase tests, and drastically decreased tissue expression of anti-inflammatory genes, including TGFβ, CD163, and Ym1. Our results show that spontaneously recruited monocytes to the injured brain early after the insult contribute to long-term functional recovery after stroke.. For decades, any involvement of circulating immune cells in CNS repair was completely denied. Only over the past few years has involvement of monocyte-derived macrophages (MDMs) in CNS repair received appreciation. We show here, for the first time, that MDMs recruited to the injured brain early after ischemic stroke contribute to long-term spontaneous functional recovery through inflammation-resolving activity. Our data raise the possibility that inadequate recruitment of MDMs to the brain after stroke underlies the incomplete functional recovery seen in patients and that boosting homing of MDMs with an anti-inflammatory bias to the injured brain tissue may be a new therapeutic approach to promote long-term improvement after stroke.

Topics: Animals; Antibodies, Blocking; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Behavior, Animal; beta-N-Acetylhexosaminidases; Chimera; Functional Laterality; Infarction, Middle Cerebral Artery; Inflammation; Lectins; Macrophages; Male; Mice; Mice, Inbred C57BL; Monocytes; Neuronal Plasticity; Psychomotor Performance; Receptors, CCR2; Receptors, Cell Surface; Recovery of Function; Stroke; Transforming Growth Factor beta

Post-operative adhesions are a critical problem in pelvic and abdominal surgery despite a multitude of studies dedicated to finding modalities to prevent their occurrence. Ghrelin administration promotes an anti-fibrotic response in a surgical mouse model of adhesion-induction, but the mechanisms mediating this effect have not been established. In the current study, the molecular mechanisms that underlie the anti-adhesion effect of ghrelin were investigated. Post-surgical adhesions were experimentally created in C57BL/6 wild-type mice via a combination of ischemic peritoneal buttons and cecal multiple abrasions. Ghrelin or saline intraperitoneal injections were given twice daily from two days before surgery to selected time points post-surgically to assess the phenotypic and molecular effects of treatment (1 day (n = 20), 4 days (n = 20) and 20 days (n = 40) after surgery). Endpoints included the scoring of adhesions and gene and protein expression analysis of pro-fibrogenic factors conducted on peritoneal ischemic tissue by quantitative PCR and Western blot. Ghrelin administration significantly reduced post-surgical adhesions and down-regulated pro-inflammatory gene and protein expression, including Tgfb3 and Tgfbr2. The up-regulation of inhibitory proteins Smad6 and Smad7 confirmed the ghrelin-induced blockage of TGF-β signaling. Ghrelin is a candidate therapeutic drug for post-operative adhesion prevention, inhibiting inflammatory responses via blockage of the TGF-β signaling pathway at the onset of surgery before the occurrence of the granulation-remodeling phase.

Topics: Animals; Body Weight; Cell Differentiation; Disease Models, Animal; Gene Expression Regulation; Ghrelin; Inflammation; Male; Mice; Mice, Inbred C57BL; Phenotype; Protein Serine-Threonine Kinases; Rats; Real-Time Polymerase Chain Reaction; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad6 Protein; Smad7 Protein; Tissue Adhesions; Transforming Growth Factor beta; Transforming Growth Factor beta3

Bacillus-produced surfactin can inhibit acute inflammation in vitro and in vivo. However, there is no report whether surfactin could inhibit chronic inflammation in the atherosclerotic lesions. Apoliprotein E deficient (ApoE(-/-)) mice (fed on atherogenic diet) were intragastrically administered with surfactin for 9 doses, then the athero-protective effect of surfactin was determined in vivo. The results showed surfactin could induce anti-inflammatory factors such as IgA, transforming growth factor (TGF)-β and interleukin (IL)-10 in the intestine. Further investigation discovered that surfactin also systemically induced CD4(+)CD25(+)FoxP3(+) Tregs in spleen, which could inhibit T cells to produce pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and interferon (IFN)-γ. The IgG subclass pattern with high titer of IgG1 (Th2-type) but low titer of IgG2a (Th1-type) was also found in the surfactin-treated mice. As a result, the attenuation of chronic inflammation was observed in the surfactin-treated groups accompanying with less TNF-α but more IL-10 in the atherosclerotic lesions. Moreover, surfactin could reduce serum total cholesterol and cholesterol in low-density lipoprotein, and increase serum cholesterol in high-density lipoprotein in mice. Collectively, surfactin could significantly attenuate atherosclerotic lesions on the aorta by restoration of the delicate balance of Th1/Th2 response in mice.

Topics: Animals; Apolipoproteins E; Bacillus; Immunomodulation; Inflammation; Interleukin-10; Lipopeptides; Mice; Mice, Knockout; Peptides, Cyclic; Plaque, Atherosclerotic; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Obesity induces white adipose tissue (WAT) dysfunction characterized by unremitting inflammation and fibrosis, impaired adaptive thermogenesis and increased lipolysis. Prostaglandins (PGs) are powerful lipid mediators that influence the homeostasis of several organs and tissues. The aim of the current study was to explore the regulatory actions of PGs in human omental WAT collected from obese patients undergoing laparoscopic bariatric surgery. In addition to adipocyte hypertrophy, obese WAT showed remarkable inflammation and total and pericellular fibrosis. In this tissue, a unique molecular signature characterized by altered expression of genes involved in inflammation, fibrosis and WAT browning was identified by microarray analysis. Targeted LC-MS/MS lipidomic analysis identified increased PGE2 levels in obese fat in the context of a remarkable COX-2 induction and in the absence of changes in the expression of terminal prostaglandin E synthases (i.e. mPGES-1, mPGES-2 and cPGES). IPA analysis established PGE2 as a common top regulator of the fibrogenic/inflammatory process present in this tissue. Exogenous addition of PGE2 significantly reduced the expression of fibrogenic genes in human WAT explants and significantly down-regulated Col1α1, Col1α2 and αSMA in differentiated 3T3 adipocytes exposed to TGF-β. In addition, PGE2 inhibited the expression of inflammatory genes (i.e. IL-6 and MCP-1) in WAT explants as well as in adipocytes challenged with LPS. PGE2 anti-inflammatory actions were confirmed by microarray analysis of human pre-adipocytes incubated with this prostanoid. Moreover, PGE2 induced expression of brown markers (UCP1 and PRDM16) in WAT and adipocytes, but not in pre-adipocytes, suggesting that PGE2 might induce the trans-differentiation of adipocytes towards beige/brite cells. Finally, PGE2 inhibited isoproterenol-induced adipocyte lipolysis. Taken together, these findings identify PGE2 as a regulator of the complex network of interactions driving uncontrolled inflammation and fibrosis and impaired adaptive thermogenesis and lipolysis in human obese visceral WAT.

Topics: Adipocytes; Adipogenesis; Adipose Tissue, White; Cell Differentiation; Cyclooxygenase 2; Dinoprostone; Down-Regulation; Homeostasis; Humans; Inflammation; Interleukin-6; Lipolysis; Obesity; Signal Transduction; Thermogenesis; Transforming Growth Factor beta

Wingless/integrase-1 (WNT) signalling is associated with lung inflammation and repair, but its role in chronic obstructive pulmonary disease (COPD) pathogenesis is unclear. We investigated whether cigarette smoke-induced dysregulation of WNT-5B contributes to airway remodelling in COPD.We analysed WNT-5B protein expression in the lung tissue of COPD patients and (non)smoking controls, and investigated the effects of cigarette smoke exposure on WNT-5B expression in COPD and control-derived primary bronchial epithelial cells (PBECs). Additionally, we studied downstream effects of WNT-5B on remodelling related genes fibronectin, matrix metalloproteinase (MMP)-2, MMP-9 and SnaiI in BEAS-2B and air-liquid interface (ALI)-cultured PBECs.We observed that airway epithelial WNT-5B expression is significantly higher in lung tissue from COPD patients than controls. Cigarette smoke extract significantly increased mRNA expression of WNT-5B in COPD, but not control-derived PBECs. Exogenously added WNT-5B augmented the expression of remodelling related genes in BEAS-2B cells, which was mediated by transforming growth factor (TGF)-β/Smad3 signalling. In addition, WNT-5B upregulated the expression of these genes in ALI-cultured PBECs, particularly PBECs from COPD patients.Together, our results provide evidence that exaggerated WNT-5B expression upon cigarette smoke exposure in the bronchial epithelium of COPD patients leads to TGF-β/Smad3-dependent expression of genes related to airway remodelling.

Topics: Aged; Aged, 80 and over; Bronchi; Case-Control Studies; Cytokines; Epithelial Cells; Epithelium; Female; Fibronectins; Humans; Inflammation; Lung; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Nicotiana; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Signal Transduction; Smad3 Protein; Smoke; Snail Family Transcription Factors; Tobacco Products; Transforming Growth Factor beta; Wnt Proteins

Experimental studies have reported that aerobic exercise after asthma induction reduces lung inflammation and remodeling. Nevertheless, no experimental study has analyzed whether regular/moderate aerobic training before the induction of allergic asthma may prevent these inflammatory and remodeling processes. For this purpose, BALB/c mice (n = 96) were assigned into non-trained and trained groups. Trained animals ran on a motorized treadmill at moderate intensity, 30 min/day, 3 times/week, for 8 weeks, and were further randomized into subgroups to undergo ovalbumin sensitization and challenge or receive saline using the same protocol. Aerobic training continued until the last challenge. Twenty-four hours after challenge, compared to non-trained animals, trained mice exhibited: (a) increased systolic output and left ventricular mass on echocardiography; (b) improved lung mechanics; (c) decreased smooth muscle actin expression and collagen fiber content in airways and lung parenchyma; (d) decreased transforming growth factor (TGF)-β levels in bronchoalveolar lavage fluid (BALF) and blood; (e) increased interferon (IFN)-γ in BALF and interleukin (IL)-10 in blood; and (f) decreased IL-4 and IL-13 in BALF. In conclusion, regular/moderate aerobic training prior to allergic asthma induction reduced inflammation and remodeling, perhaps through increased IL-10 and IFN-γ in tandem with decreased Th2 cytokines.

Topics: Airway Remodeling; Animals; Asthma; Bronchoalveolar Lavage Fluid; Cytokines; Immunohistochemistry; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-13; Interleukin-4; Lung; Male; Mice; Mice, Inbred BALB C; Microscopy, Electron, Transmission; Ovalbumin; Physical Conditioning, Animal; Pneumonia; Transforming Growth Factor beta

To investigate the effects of vitamin D and its receptor on cytokines expression and podocytes apoptosis.. Cultured mouse podocytes were pre-incubated with vitamin D or transiently transfected with small interfering ribonucleic acid (RNA) to knock down the vitamin D receptor. Lipopolysaccharide was used to mimic the inflammation status of diabetes.. In a lipopolysaccharide-induced state, expressions of transforming growth factor-β, angiotensinogen and vascular endothelial growth factor were similarly increased. Transforming growth factor-β and angiotensinogen levels originally elevated by lipopolysaccharide challenge were distinctly reduced after pre-incubation with vitamin D. Whereas after vitamin D receptor small interfering (si)RNA transfection, the aforementioned cytokines had opposite changes as expected. However, neither vitamin D pretreatment nor vitamin D receptor siRNA transfection influenced the previously increased vascular endothelial growth factor expression at messenger RNA or protein levels. When pretreated with vitamin D, decreases were observed for phosphorylated inhibitor-κB and the inhibitor kinase proteins. After siRNA transfection, those proteins levels were further elevated. The originally increased transforming growth factor-β and angiotensinogen levels as a result of lipopolysaccharide stimulation were reduced at both the messenger RNA and protein levels after the specific inhibition of the nuclear factor-κB pathway with pyrrolidine dithiocarbamate. The apoptosis rate of podocytes was decreased in a parallel manner after vitamin D pre-incubation, and increased after siRNA transfection, which was also suppressed by pyrrolidine dithiocarbamate.. Vitamin D and its receptor might be involved in the progression of diabetic nephropathy by regulating transforming growth factor-β, angiotensinogen expression and apoptosis of podocytes. The processes are mediated through the signaling of nuclear factor-κB pathway.

Topics: Angiotensinogen; Animals; Apoptosis; Cells, Cultured; Inflammation; Lipopolysaccharides; Mice; NF-kappa B; Podocytes; Receptors, Calcitriol; Signal Transduction; Transforming Growth Factor beta; Vitamin D

The aim of this study was to examine the role of IL-33/ST2 pathway in a pathogenesis of acute inflammation and its effects on tissue damage, antioxidative capacity, magnesium concentration and cytokine profile in acutely inflamed tissue.. Male mice were randomly divided in four groups: wild-type control group (WT-C), ST2 knockout control group (KO-C), wild-type inflammatory group (WT-I), and ST2 knockout inflammatory group (KO-I). Acute inflammation was induced in WT-I and KO-I by intramuscular injection of turpentine oil, while mice in WT-C and KO-C were treated with saline. After 12h, animals were euthanized, and blood was collected for determination of creatine kinase (CK) and aspartate transaminase (AST) activity. The treated tissue was used for histopathological analysis, determination of volume density of inflammatory infiltrate (Vdii) and necrotic fiber (Vdnf), gene expression of interleukin (IL)-33, ST2, tumor necrosis factor alpha (TNF-alpha), IL-6, IL-12p35, and transforming growth factor beta (TGF-beta), concentration of magnesium (Mg), copper (Cu), selenium (Se), manganese (Mn) and reduced glutathione (GSH), and superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity.. Presence of inflammatory infiltration and necrosis in the treated tissue was histopathologically confirmed in WT-I and KO-I. Vdii was significantly higher in WT-I when compared to KO-I, whereas Vdnf did not significantly differ between WT-I and KO-I. CK and AST significantly increased in both inflammatory groups when compared to corresponding control groups. However, the values of CK and AST were significantly higher in WT-I than in KO-I. Mg in the treated tissue was significantly lower in WT-I in comparison to WT-C and KO-I, while there was no significant difference between KO-C and KO-I. There was no significant difference in Cu, Se, and Mn in the treated tissue between WT-C, KO-C, WT-I and KO-I. Gene expression of IL-33 in the treated tissue increased in both inflammatory groups when compared to the corresponding control groups, but it was significantly higher in KO-I than in WT-I. Gene expression of ST2 in the treated tissue was significantly higher in WT-I than in WT-C. Gene expression of TNF-alpha, IL-6, and IL-12p35 in the treated tissue was significantly higher in WT-I and KO-I than in the corresponding control groups, and IL-6 was significantly higher in KO-C than in WT-C. TGF-beta gene expression in the treated tissue was significantly higher in KO-I when compared to WT-I, while there was no difference between WT-C and KO-C. SOD activity decreased at the site of acute inflammation in both inflammatory groups, while the GPx activity increased. GSH in the treated tissue was significantly higher in KO-I than in KO-C or WT-I.. The results of our study have indicated, to our knowledge for the first time, that IL-33/ST2 pathway plays a role in enhancing inflammation and tissue damage at the site of acute inflammation by affecting the concentration of magnesium and GSH, important for antioxidative capacity, as well as gene expression of anti-inflammatory cytokine TGF-beta.

Topics: Animals; Antioxidants; Aspartate Aminotransferases; Copper; Creatine Kinase; Gene Expression Regulation; Glutathione; Glutathione Peroxidase; Inflammation; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Magnesium; Male; Manganese; Mice, Inbred BALB C; Muscles; Selenium; Signal Transduction; Superoxide Dismutase; Transforming Growth Factor beta

Compelling evidence suggests that benign prostatic hyperplasia (BPH) development involves accumulation of mesenchymal-like cells derived from the prostatic epithelium by epithelial-mesenchymal transition (EMT). Transforming growth factor (TGF)-β induces EMT phenotypes with low E-cadherin and high vimentin expression in prostatic epithelial cells. Here we report that LPS/TLR4 signalling induces down-regulation of the bone morphogenic protein and activin membrane-bound inhibitor (BAMBI), which enhances TGF-β signalling in the EMT process during prostatic hyperplasia. Additionally, we found that the mean TLR4 staining score was significantly higher in BPH tissues with inflammation compared with BPH tissues without inflammation (5.13 ± 1.21 and 2.96 ± 0.73, respectively; P < 0.001). Moreover, patients with inflammatory infiltrate were more likely to have a higher age (P = 0.020), BMI (P = 0.026), prostate volume (P = 0.024), total IPSS score (P = 0.009) and IPSS-S (P < 0.001). Pearson's correlation coefficient and multiple regression analyses demonstrated that TLR4 mRNA expression level was significantly positively associated with age, BMI, serum PSA levels, urgency and nocturia subscores of IPSS in the inflammatory group. These findings provide new insights into the TLR4-amplified EMT process and the association between TLR4 levels and storage LUTS, suggesting chronic inflammation as vital to the pathogenesis of BPH.

Topics: Aged; Aged, 80 and over; Body Mass Index; Cell Line; Epithelial Cells; Epithelial-Mesenchymal Transition; Gene Expression Regulation; Humans; Inflammation; Kallikreins; Lipopolysaccharides; Male; Membrane Proteins; Middle Aged; Prostate; Prostate-Specific Antigen; Prostatic Hyperplasia; Signal Transduction; Toll-Like Receptor 4; Transforming Growth Factor beta; Transurethral Resection of Prostate

The inclusion of plant meals in diets of farmed Atlantic salmon can elicit inflammatory responses in the distal intestine (DI). For the present work, fish were fed a standard fish meal (FM) diet or a diet with partial replacement of FM with solvent-extracted camelina meal (CM) (8, 16, or 24 % CM inclusion) during a 16-week feeding trial. A significant decrease in growth performance was seen in fish fed all CM inclusion diets (Hixson et al. in Aquacult Nutr 22:615-630, 2016). A 4x44K oligonucleotide microarray experiment was carried out and significance analysis of microarrays (SAM) and rank products (RP) methods were used to identify differentially expressed genes between the DIs of fish fed the 24 % CM diet and those fed the FM diet. Twelve features representing six known transcripts and two unknowns were identified as CM responsive by both SAM and RP. The six known transcripts (including thioredoxin and ependymin), in addition to tgfb, mmp13, and GILT, were studied using qPCR with RNA templates from all four experimental diet groups. All six microarray-identified genes were confirmed to be CM responsive, as was tgfb and mmp13. Histopathological analyses identified signs of inflammation in the DI of salmon fed CM-containing diets, including lamina propria and sub-epithelial mucosa thickening, infiltration of eosinophilic granule cells, increased goblet cells and decreased enterocyte vacuolization. All of these were significantly altered in 24 % CM compared to all other diets, with the latter two also altered in 16 % CM compared with 8 % CM and control diet groups. Significant correlation was seen between histological parameters as well as between five of the qPCR analyzed genes and histological parameters. These molecular biomarkers of inflammation arising from long-term dietary CM exposure will be useful in the development of CM-containing diets that do not have deleterious effects on salmon growth or physiology.

Topics: Animal Feed; Animals; Brassicaceae; Diet; Fish Proteins; Gene Expression Profiling; Gene Expression Regulation; Gene Ontology; Inflammation; Intestines; Matrix Metalloproteinase 13; Molecular Sequence Annotation; Nerve Tissue Proteins; Oligonucleotide Array Sequence Analysis; Oxidoreductases Acting on Sulfur Group Donors; RNA, Messenger; Salmo salar; Thioredoxins; Transforming Growth Factor beta

Joint trauma, which is frequently related with mechanical overloading of articular cartilage, is a well-established risk for osteoarthritis (OA) development. Additionally, reports show that trauma leads to synovial joint inflammation. In consequence, after joint trauma, cartilage is influenced by deleterious excessive loading combined with the catabolic activity of proinflammatory mediators. Since the activation of TGF-β signaling by loading is considered to be a key regulatory pathway for maintaining cartilage homeostasis, we tested the effect of proinflammatory conditions on mechanically mediated activation of TGF-β/Smad2/3P signaling in cartilage.. Cartilage explants were subjected to dynamic mechanical compression in the presence of interleukin-1 beta (IL-1β) or osteoarthritic synovium-conditioned medium (OAS-CM). Subsequently, the activation of the Smad2/3P pathway was monitored with QPCR analysis of reporter genes and additionally the expression of receptors activating the Smad2/3P pathway was analyzed. Finally, the ability for mechanically mediated activation of Smad2/3P was tested in human OA cartilage.. IL-1β presence during compression did not impair the upregulation of Smad2/3P reporter genes, however the results were affected by IL-1β-mediated upregulations in unloaded controls. OAS-CM significantly impaired the compression-mediated upregulation of bSmad7 and Tgbfb1. IL-1β suppressed the compression-mediated bAlk5 upregulation where 12 MPa compression applied in the presence of OAS-CM downregulated the bTgfbr2. Mechanically driven upregulation of Smad2/3P reporter genes was present in OA cartilage.. Proinflammatory conditions partly impair the mechanically mediated activation of the protective TGF-β/Smad2/3P pathway. Additionally, the excessive mechanical compression, applied in the presence of proinflammatory conditions diminishes the expression of the type II TGF-β receptor, a receptor critical for maintenance of articular cartilage.

Topics: Animals; Cartilage, Articular; Cattle; Chondrocytes; Gene Expression Profiling; Humans; Inflammation; Organ Culture Techniques; Osteoarthritis; Polymerase Chain Reaction; Signal Transduction; Smad Proteins; Stress, Mechanical; Transcriptome; Transforming Growth Factor beta

Macrophages are key cells in the innate immune system. They phagocytose pathogens and cellular debris, promote inflammation, and have important roles in tumor immunity. Depending on the microenvironment, macrophages can polarize to M1 (inflammatory) or M2 (anti-inflammatory) phenotypes. Extracellular DnaK (the bacterial ortholog of the mammalian Hsp70) from Mycobacterium tuberculosis (Mtb) was described to exert immune modulatory roles in an IL-10 dependent manner. We have previously observed that endotoxin-free DnaK can polarize macrophages to an M2-like phenotype. However, the mechanisms that underlie this polarization need to be further investigated. IL-10 has been described to promote macrophage polarization, so we investigated the involvement of this cytokine in macrophages stimulated with extracellular DnaK. IL-10 was required to induce the expression of M2 markers - Ym1 and Fizz, when macrophages were treated with DnaK. Blockade of IL-10R also impaired DnaK induced polarization, demonstrating the requirement of the IL-10/IL-10R signaling pathway in this polarization. DnaK was able to induce TGF-β mRNA in treated macrophages in an IL-10 dependent manner. However, protein TGF-β could not be detected in culture supernatants. Finally, using an in vivo allogeneic melanoma model, we observed that DnaK-treated macrophages can promote tumor growth in an IL-10-dependent manner. Our results indicate that the IL-10/IL-10R axis is required for DnaK-induced M2-like polarization in murine macrophages.

Topics: Animals; Bacterial Proteins; Female; HSP70 Heat-Shock Proteins; Inflammation; Interleukin-10; Macrophage Activation; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Molecular Chaperones; Mycobacterium tuberculosis; Phagocytosis; Phenotype; Signal Transduction; Transforming Growth Factor beta

CKD is a global public health problem with significant mortality and morbidity.. We examined the multivariable association of plasma levels of IL-1, IL-1 receptor antagonist, IL-6, TNF-α, TGF-β, high-sensitivity C-reactive protein, fibrinogen, and serum albumin with progression of CKD in 3430 Chronic Renal Insufficiency Cohort study participants.. Over a median follow-up time of 6.3 years, 899 participants reached the composite end point of ≥50% decline in eGFR from baseline or onset of ESRD. Elevated plasma levels of fibrinogen, IL-6, and TNF-α and lower serum albumin were associated with a greater decline in eGFR over time. After adjusting for demographics, BP, laboratory variables, medication use, and baseline eGFR, hazard ratios for the composite outcome were greater for the patients in the highest quartile of fibrinogen (hazard ratio, 2.05; 95% confidence interval, 1.64 to 2.55; P<0.001), IL-6 (hazard ratio, 1.44; 95% confidence interval, 1.17 to 1.77; P<0.01), and TNF-α (hazard ratio, 1.94; 95% confidence interval, 1.52 to 2.47; P<0.001) compared with those in the respective lowest quartiles. The hazard ratio was 3.48 (95% confidence interval, 2.88 to 4.21; P<0.001) for patients in the lowest serum albumin quartile relative to those in the highest quartile. When also adjusted for albuminuria, the associations of fibrinogen (hazard ratio, 1.49; 95% confidence interval, 1.20 to 1.86; P<0.001), serum albumin (hazard ratio, 1.52; 95% confidence interval, 1.24 to 1.87; P<0.001), and TNF-α (hazard ratio, 1.42; 95% confidence interval, 1.11 to 1.81; P<0.001) with outcome were attenuated but remained significant.. Elevated plasma levels of fibrinogen and TNF-α and decreased serum albumin are associated with rapid loss of kidney function in patients with CKD.

Topics: Adult; Aged; C-Reactive Protein; Cytokines; Disease Progression; Female; Fibrinogen; Follow-Up Studies; Glomerular Filtration Rate; Humans; Inflammation; Interleukin-1; Interleukin-6; Kidney Failure, Chronic; Male; Middle Aged; Renal Insufficiency, Chronic; Serum Albumin; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The transforming growth factor β (TGFβ) family plays an important role in the pathogenesis of many diseases, including fibrotic pathologies of the eyes. The difficulties of surgical procedures contribute to the search for new treatment strategies for proliferative vitreoretinopathy. Therefore, the aim of this study was to investigate the expression profile of TGFβ isoforms, their receptors, and TGFβ-related genes in human retinal pigment epithelial cells (RPE) after tacrolimus (FK-506) treatment in the presence or absence of lipopolysaccharide (LPS)-induced inflammation.. The expression profile was analyzed using oligonucleotide microarrays and quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR) techniques.. Analysis using oligonucleotide microarrays revealed 20 statistically significant differentially expressed TGFβ-related genes after LPS treatment in relation to control cells, and after tacrolimus and LPS treatment in relation to LPS-treated cells. Moreover, our results showed that mRNA levels for TGFβ2 and TGFβR3 after tacrolimus treatment, and for TGFβR3 after tacrolimus and LPS treatment in RPE cells were decreased. In turn, in the presence of LPS-induced inflammation, TGFβ2 mRNA level was increased.. These results can be important in regard to the treatment of proliferative vitreoretinopathy, pathogenesis of which is associated with processes regulated by TGFβ, such as inflammation, proliferation, epithelial-mesenchymal transition (EMT), and fibrosis.

Topics: Cells, Cultured; Epithelial Cells; Epithelial-Mesenchymal Transition; Humans; Inflammation; Retinal Pigment Epithelium; RNA, Messenger; Signal Transduction; Tacrolimus; Transforming Growth Factor beta; Vitreoretinopathy, Proliferative

Tumor-associated macrophages (TAMs) are a major component of leukocytic infiltrate in tumors, which facilitates tumor progression and promotes inflammation. TGF-β promotes the differentiation of non-activated macrophages into a TAM-like (M2-like) phenotype; however, the underlying mechanisms are not clear. In this study, we found that TGF-β induces a M2-like phenotype characterized by up-regulation of the anti-inflammatory cytokine IL-10, and down-regulation of the pro-inflammatory cytokines TNF-α and IL-12. In human THP-1 macrophages, overexpression of SNAIL caused M2-like differentiation by inhibiting pro-inflammatory cytokine release and promoting the expression of M2-specific markers. By contrast, SNAIL knockdown promoted M1 polarization through up-regulation of pro-inflammatory cytokines and abolished TGF-β-mediated M2-polarization of THP-1 macrophages. The SMAD2/3 and PI3K/AKT signaling pathways were crucial for TGF-β-induced SNAIL overexpression in THP-1 cells. These findings suggest that TGF-β skews macrophage polarization towards a M2-like phenotype via SNAIL up-regulation, and blockade of TGF-β/SNAIL signaling restores the production of pro-inflammatory cytokines. This study provides new understanding of the role of SNAIL in M2 polarization of macrophages, and suggests a potential therapeutic target for antitumor immunity.

Topics: Animals; Cell Differentiation; Cell Line, Tumor; Humans; Inflammation; Macrophages; Mice; Mice, Inbred BALB C; Phenotype; Snail Family Transcription Factors; Transforming Growth Factor beta

Topics: Airway Remodeling; Asthma; Cell Adhesion Molecules; Dexamethasone; Eosinophils; Epithelial Cells; Fibroblasts; Humans; Hypersensitivity; Inflammation; Interleukin-5; Macrophage-1 Antigen; Th2 Cells; Transforming Growth Factor beta; Up-Regulation; Vascular Cell Adhesion Molecule-1

Inflammatory-mediated pathological processes in the endothelium arise as a consequence of the dysregulation of vascular homeostasis. Of particular importance are mediators produced by stimulated monocytes/macrophages inducing activation of endothelial cells (ECs). This is manifested by excessive soluble pro-inflammatory mediator production and cell surface adhesion molecule expression. Nitro-fatty acids are endogenous products of metabolic and inflammatory reactions that display immuno-regulatory potential and may represent a novel therapeutic strategy to treat inflammatory diseases. The purpose of our study was to characterize the effects of nitro-oleic acid (OA-NO2) on inflammatory responses and the endothelial-mesenchymal transition (EndMT) in ECs that is a consequence of the altered healing phase of the immune response.. The effect of OA-NO2 on inflammatory responses and EndMT was determined in murine macrophages and murine and human ECs using Western blotting, ELISA, immunostaining, and functional assays.. OA-NO2 limited the activation of macrophages and ECs by reducing pro-inflammatory cytokine production and adhesion molecule expression through its modulation of STAT, MAPK and NF-κB-regulated signaling. OA-NO2 also decreased transforming growth factor-β-stimulated EndMT and pro-fibrotic phenotype of ECs. These effects are related to the downregulation of Smad2/3.. The study shows the pleiotropic effect of OA-NO2 on regulating EC-macrophage interactions during the immune response and suggests a role for OA-NO2 in the regulation of vascular endothelial immune and fibrotic responses arising during chronic inflammation.. These findings propose the OA-NO2 may be useful as a novel therapeutic agent for treatment of cardiovascular disorders associated with dysregulation of the endothelial immune response.

Topics: Animals; Endothelial Cells; Endothelium, Vascular; Epithelial-Mesenchymal Transition; Humans; Inflammation; Macrophages; MAP Kinase Signaling System; Mice; NF-kappa B; Oleic Acids; Smad Proteins; STAT Transcription Factors; Transforming Growth Factor beta

The airway epithelium is a semi-impermeable barrier whose disruption by growth factor reprogramming is associated with chronic airway diseases of humans. Transforming growth factor beta (TGFβ)-induced epithelial mesenchymal transition (EMT) plays important roles in airway remodeling characteristic of idiopathic lung fibrosis, asthma and chronic obstructive pulmonary disease (COPD). Inflammation of the airways leads to airway injury and tumor necrosis factor alpha (TNFα) plays an important pro-inflammatory role. Little systematic information about the effects of EMT on TNFα signaling is available. Using an in vitro model of TGFβ-induced EMT in primary human small airway epithelial cells (hSAECs), we applied quantitative proteomics and phosphoprotein profiling to understand the molecular mechanism of EMT and the impact of EMT on innate inflammatory responses. We quantified 7925 proteins and 1348 phosphorylation sites by stable isotope labeling with iTRAQ technology. We found that cellular response to TNFα is cell state dependent and the relative TNFα response in mesenchymal state is highly compressed. Combined bioinformatics analyses of proteome and phosphoproteome indicate that the EMT state is associated with reprogramming of kinome, signaling cascade of upstream transcription regulators, phosphor-networks, and NF-κB dependent cell signaling.. Epithelial mesenchymal transition and inflammation have important implications for clinical and physiologic manifestations of chronic airway diseases such as severe asthma, COPD, and lung fibrosis. Little systematic information on the interplay between EMT and innate inflammation is available. This study combined quantitative proteomics and phosphorproteomics approach to obtain systems-level insight into the upstream transcription regulators involved in the TGFβ-induced EMT in primary human small airway epithelial cells and to elucidate how EMT impacts on the TNFα signaling pathways. The proteomics and phosphoproteomics analysis indicates that many signaling pathways involved in TGFβ-induced EMT and EMT has profound reprogramming effects on innate inflammation response.

Topics: Airway Remodeling; Alveolar Epithelial Cells; Cell Line, Transformed; Epithelial-Mesenchymal Transition; Humans; Inflammation; Phosphoproteins; Proteomics; Signal Transduction; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Airway remodeling includes lung structural changes that have a role in the irreversibility of pulmonary dysfunction shown in chronic bronchial asthmatics. The current experiment investigated the effect of the mitochondrial antioxidant, tiron in comparison with dexamethasone (DEXA) on airway remodeling in chronic asthma. Sensitized BALB/c mice were challenged with ovalbumin (OVA) aerosol for 8weeks, OVA sensitized-challenged mice were treated with either DEXA or tiron, respectively. After that, lung tissue and bronchoaveolar lavage fluid (BALF) were used for measurement of different biological markers. Lungs were examined for histopathological changes and immunohistochemistry. Upon comparing with vehicle treated animals, trion or DEXA treatment significantly reduced eosinophils, lymphocytes, neutrophils and macrophages count in the BALF. Both drugs significantly alleviated chronic OVA-induced oxidative stress as illustrated by decreased pulmonary malondialdenhyde (MDA) and increased glutathione (GSH) and superoxide dismutase (SOD) levels. Asthmatic mice exhibited elevated levels of NOx, IL-13 and TGF-β1 that were reduced by DEXA and tiron. Histopathological changes and increased immunoreactivity of nuclear factor-Kappa B (NF-κ B) in OVA-challenged mice were minimized by tiron and DEXA treatment. In conclusion, in this model of chronic asthma DEXA and tiron ameliorated airway remodeling and inflammation in experimental chronic asthma with no difference between the effect of tiron and DEXA. Tiron has a potential role as adjuvant treatment in chronic asthma.

Topics: 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; Airway Remodeling; Animals; Asthma; Dexamethasone; Eosinophils; Female; Inflammation; Lung; Lymphocytes; Macrophages; Mice; Mice, Inbred BALB C; Neutrophils; NF-kappa B; Oxidative Stress; Superoxide Dismutase; Transforming Growth Factor beta

Exposure to ultraviolet (UV) radiation results in skin damage, collagen reduction in the dermis, and consequently, premature skin aging (photoaging). The goal of this study was to examine the effect of gelatin hydrolysate (CH) from pacific cod (Gadus macrocephalus) skin on UV irradiation-induced inflammation and collagen reduction of photoaging mouse skin. The effect of CH on the activities of endogenous antioxidant enzymes was investigated. The expressions of nuclear factor-κB (NF-κB), proinflammatory cytokines, type I and type III procollagen, transforming growth factor-β1 (TGF-β1), type II receptor of TGF-β1 (TGF-βRII), and Smad7 were determined using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) and ELISA. The results showed that oral administration of CH suppressed UV irradiation-induced damages to skin by inhibiting the depletion of endogenous antioxidant enzyme activity, and by suppressing the expression of NF-κB as well as NF-κB-mediated proinflammatory cytokines expression. Furthermore, CH inhibited type I procollagen synthesis reduction by up-regulating TβRII level and down-regulating Smad7 level, which demonstrates that CH is involved in matrix collagen synthesis by activating the TGF-β/Smad pathway in the photoaging skin. Based on these results, we conclude that CH protected skin from UV irradiation-induced photodamages, and CH may be a potentially effective agent for the prevention of photoaging.

Topics: Animals; Antioxidants; Collagen Type I; Collagen Type III; Down-Regulation; Gadiformes; Gelatin; Inflammation; NF-kappa B; Protective Agents; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Signal Transduction; Skin; Skin Aging; Smad7 Protein; Transforming Growth Factor beta; Ultraviolet Rays; Up-Regulation

Chronic obstructive sleep apnea syndrome (OSAS) is considered to be associated with pulmonary diseases. However, the roles and mechanisms of OSA in pulmonary remodeling remain ambiguous. Thus, this study was aimed to elucidate the morphological and mechanical action of OSA in lung remodeling. In the present study, we employed a novel OSA model to mimic the OSA patient and investigate the role of OSA in pulmonary remodeling. We showed that pulmonary artery pressure of OSA group has no significant increased compared with the sham group. Nevertheless, we found that fibrotic tissue was predominantly located around the bronchi and vascular in the lung. Additionally, inflammatory cell infiltration was also detected in the peribonchial and perivascular space. The morphological change in OSA canines was ascertained by ultrastructure variation characterized by mitochondrial swelling, lamellar bodies degeneration and vascular smooth muscle incrassation. Moreover, sympathetic nerve sprouting was markedly increased in OSA group. Mechanistically, we showed that several pivotal proteins including collagen type I(CoLA1), GAP-43, TH and NGF were highly expressed in OSA groups. Furthermore, we found OSA could activated the expression of TGF-β, which subsequently suppressed miR-185 and promoted CoL A1 expression. This signaling cascade leads to pulmonary remodeling. In conclusion, Our data demonstrates that OSA can accelerate the progression of pulmonary remodeling through TGF-β/miR-185/CoLA1 signaling, which would potentially provide therapeutic strategies for chronic OSAS.

Topics: Animals; Bronchi; Cell Line; Chronic Disease; Collagen Type I; Disease Models, Animal; Dogs; Gene Expression Regulation; Humans; Hypertension, Pulmonary; Inflammation; Lung; Male; MicroRNAs; Muscle, Smooth, Vascular; Sleep Apnea, Obstructive; Transforming Growth Factor beta

Recent evidences have unveiled critical roles of cancer stem cells (CSCs) in tumorigenicity, but how interactions between CSC and tumor environments help maintain CSC initiation remains obscure. The small GTPases Rab27A regulates autocrine and paracrine cytokines by monitoring exocytosis of extracellular vesicles, and is reported to promote certain tumor progression. We observe that overexpression of Rab27A increased sphere formation efficiency (SFE) by increasing the proportion of CD44+ and PKH26high cells in HT29 cell lines, and accelerating the growth of colosphere with higher percentage of cells at S phase. Mechanism study revealed that the supernatant derived from HT29 sphere after Rab27A overexpression was able to expand sphere numbers with elevated secretion of VEGF and TGF-β. In tumor implanting nude mice model, tumor initiation rates and tumor sizes were enhanced by Rab27A with obvious angiogenesis. As a contrast, knocking down Rab27A impaired the above effects. More importantly, the correlation between higher p65 level and Rab27A in colon sphere was detected, p65 was sufficient to induce up-regulation of Rab27A and a functional NF-κB binding site in the Rab27A promoter was demonstrated. Altogether, our findings reveal a unique mechanism that tumor environment related NF-κB signaling promotes various colon cancer stem cells (cCSCs) properties via an amplified paracrine mechanism regulated by higher Rab27A level.

Topics: Animals; Caco-2 Cells; Cell Cycle; Cell Line, Tumor; Colonic Neoplasms; Cytokines; Exocytosis; Female; Gene Expression Regulation, Neoplastic; Humans; Hyaluronan Receptors; Inflammation; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; NF-kappa B; Promoter Regions, Genetic; rab27 GTP-Binding Proteins; RNA Interference; Stem Cells; Transcription Factor RelA; Transforming Growth Factor beta; Up-Regulation; Vascular Endothelial Growth Factor A

Inflammation, extracellular matrix proteins (hydroxyproline, connective tissue growth factor, collagen, and fibronectin), stem and progenitor cells (multipotent mesenchymal stromal cells, Clara cells, angiogenesis, precursors, endothelial and epithelial cells) were studied in female C57Bl/6 mice with experimental elastase-induced emphysema. Diffuse emphysema reduced the number of endothelial (CD45(-)CD31(+)CD34(+)) and epithelial (CD45(-)CD117(+)CD49f(+)) cells, induced microcirculation disturbances, and decreased the area occupied by the connective tissue. Emphysematous changes in the lungs were accompanied by infiltration of the alveolar septa with macrophages and lymphocytes, increase in the serum and lung concentrations of transforming growth factor-β, IL-1β, IL-2, IL-5, IL-10, and IL-13, and lung concentration of IL-17. In the lungs, inflammation was associated with marked increase in the number of multipotent mesenchymal stromal cells CD90(+)CD73(+)CD106(+)CD44(+)) and Clara cells (CD45(-)CD34(-)CD31(-)Sca1(+)) and overexpression of extracellular matrix proteins (hydroxyproline, connective tissue growth factor, collagen, fibronectin) and Clara cells protein. On the other hand, elastase reduced the number of angiogenic precursor cells (CD45(-)CD117(+)Flk1(+)).

Topics: Animals; Epithelial Cells; Extracellular Matrix Proteins; Female; Goblet Cells; Immunohistochemistry; Inflammation; Interleukin-10; Interleukin-13; Interleukin-17; Interleukin-2; Interleukin-5; Mice; Mice, Inbred C57BL; Pulmonary Emphysema; Stem Cells; Transforming Growth Factor beta

Type 1 diabetes (T1D) is thought to involve chronic inflammation, which is manifested by the activation and expression of different inflammatory mediators. Th1- and Th17-associated cytokines are factors that have been shown to exert profound pro-inflammatory activities and have been implicated in the pathogenesis of T1D in mice and humans.. Therefore, the aim of this case control study was to determine the serum level of IL-17, IL-21, IL-27, transforming growth factor beta (TGF-β), and IFN-γ and their reciprocal relationship in Iranian T1D patients.. Blood samples were collected from 48 T1D patients and 49 healthy individuals with no history of malignancies or autoimmune disorders based on simple sampling. The serum levels of IL-17, IL-21, IL-27, TGF-β, and IFN-γ were measured by the enzyme linked immunosorbent assay (ELISA).. The serum levels of IL-17 and IL-21 were significantly higher in T1D patients compared to the healthy individuals (p = 0.005 and 0.01, respectively), but interestingly, the opposite was the case for IL-27 (p < 0.0001). However, there were no significant differences in TGF-β and IFN-γ between both groups. In addition, IL-17/IFN-γ and IL-17/IL-27 ratios were higher in patients compared to the control group.. Our results indicated dominant Th17-associated IL-17, suggesting a shift from the Treg and Th1 phenotypes toward the Th17 phenotype. Therefore, it can promote inflammation in β cells in T1D. In addition, it suggests the role of Th17 and Th17/Th1 ratios as a potential contributor to β cells destruction and the Th17/Th1 response ratio may provide a novel biomarker for rapid T1D diagnosis before the destruction of β cells and progression of the disease to the clinical end stages.

Topics: Adolescent; Animals; Case-Control Studies; Child; Child, Preschool; Diabetes Mellitus, Type 1; Female; Humans; Inflammation; Interferon-gamma; Interleukin-17; Interleukins; Iran; Male; Mice; Th1 Cells; Th17 Cells; Transforming Growth Factor beta; Young Adult

Aneurysm-osteoarthritis syndrome characterized by unpredictable aortic aneurysm formation, is caused by SMAD3 mutations. SMAD3 is part of the SMAD2/3/4 transcription factor, essential for TGF-β-activated transcription. Although TGF-β-related gene mutations result in aneurysms, the underlying mechanism is unknown. Here, we examined aneurysm formation and progression in Smad3

Topics: Aneurysm; Animals; Aortic Aneurysm; Cell Proliferation; Connective Tissue; Disease Models, Animal; Echocardiography; Elastin; Extracellular Signal-Regulated MAP Kinases; Female; Immunohistochemistry; Inflammation; Male; Matrix Metalloproteinases; Mice; Mice, Knockout; Models, Biological; Molecular Imaging; Mortality; Muscle, Smooth, Vascular; Signal Transduction; Smad2 Protein; Smad3 Protein; Transcriptional Activation; Transforming Growth Factor beta; X-Ray Microtomography

Pyrazinamide (PZA) is an essential antitubercular drug, but little is still known about its hepatotoxicity potential. This study examined the effects of PZA exposure on zebrafish (Danio rerio) larvae and the mechanisms underlying its hepatotoxicity. A transgenic line of zebrafish larvae that expressed enhanced green fluorescent protein (EGFP) in the liver was incubated with 1, 2.5, and 5 mM PZA from 72 h postfertilization (hpf). Different endpoints such as mortality, morphology changes in the size and shape of the liver, histological changes, transaminase analysis and apoptosis, markers of oxidative and genetic damage, as well as the expression of certain genes were selected to evaluate PZA-induced hepatotoxicity. Our results confirm the manner of PZA dose-dependent hepatotoxicity. PZA was found to induce marked injury in zebrafish larvae, such as liver atrophy, elevations of transaminase levels, oxidative stress, and hepatocyte apoptosis. To further understand the mechanism behind PZA-induced hepatotoxicity, changes in gene expression levels in zebrafish larvae exposed to PZA for 72 h postexposure (hpe) were determined. The results of this study demonstrated that PZA decreased the expression levels of liver fatty acid binding protein (L-FABP) and its target gene, peroxisome proliferator-activated receptor α (PPAR-α), and provoked more severe oxidative stress and hepatitis via the upregulation of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and transforming growth factor β (TGF-β). These findings suggest that L-FABP-mediated PPAR-α downregulation appears to be a hepatotoxic response resulting from zebrafish larva liver cell apoptosis, and L-FABP can be used as a biomarker for the early detection of PZA-induced liver damage in zebrafish larvae.

Topics: Animals; Animals, Genetically Modified; Antitubercular Agents; Apoptosis; Fatty Acid-Binding Proteins; Green Fluorescent Proteins; Hepatitis; Inflammation; Larva; Liver; Oxidative Stress; PPAR alpha; Pyrazinamide; Reactive Oxygen Species; Transaminases; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Zebrafish

As an inhibitor of apoptosis (IAP) family member, Survivin is known for its role during regulation of apoptosis. More recently its function as a cell cycle regulator has become evident. Survivin was shown to play a pivotal role during embryonic development and is highly expressed in regenerative tissue as well as in many cancer types. We examined the function of Survivin during mouse intestinal organogenesis and in gut pathophysiology. We found high expression of Survivin in experimentally induced colon cancer in mice but also in colon tumors of humans. Moreover, Survivin was regulated by TGF-β and was found to be highly expressed during mucosal healing following intestinal inflammation. We identified that expression of Survivin is essential early on in life, as specific deletion of Survivin in Villin expressing cells led to embryonic death around day 12 post coitum. Together with our recent study on the role of Survivin in the gut of adult mice our data demonstrate that Survivin is an essential guardian of embryonic gut development and adult gut homeostasis protecting the epithelium from cell death promoting the proliferation of intestinal stem and progenitor cells.

Topics: Animals; Embryonic Development; Enterocytes; Female; Gene Deletion; Homeostasis; Humans; Inflammation; Inhibitor of Apoptosis Proteins; Intestinal Neoplasms; Intestines; Male; Mice; Mitosis; Repressor Proteins; Stem Cell Niche; Survivin; Transforming Growth Factor beta

Perinatal infection is a well-identified risk factor for a number of neurodevelopmental disorders, including brain white matter injury (WMI) and Autism Spectrum Disorders (ASD). The underlying mechanisms by which early life inflammatory events cause aberrant neural, cytoarchitectural, and network organization, remain elusive. This study is aimed to investigate how systemic lipopolysaccharide (LPS)-induced neuroinflammation affects microglia phenotypes and early neural developmental events in rats. We show here that LPS exposure at early postnatal day 3 leads to a robust microglia activation which is characterized with mixed microglial proinflammatory (M1) and anti-inflammatory (M2) phenotypes. More specifically, we found that microglial M1 markers iNOS and MHC-II were induced at relatively low levels in a regionally restricted manner, whereas M2 markers CD206 and TGFβ were strongly upregulated in a sub-set of activated microglia in multiple white and gray matter structures. This unique microglial response was associated with a marked decrease in naturally occurring apoptosis, but an increase in cell proliferation in the subventricular zone (SVZ) and the dentate gyrus (DG) of hippocampus. LPS exposure also leads to a significant increase in oligodendrocyte lineage population without causing discernible hypermyelination. Moreover, LPS-exposed rats exhibited significant impairments in communicative and cognitive functions. These findings suggest a possible role of M2-like microglial activation in abnormal neural development that may underlie ASD-like behavioral impairments.

Topics: Animal Communication; Animals; Animals, Newborn; Autism Spectrum Disorder; Cognition; Dentate Gyrus; Gray Matter; Inflammation; Lateral Ventricles; Lectins, C-Type; Lipopolysaccharides; Mannose Receptor; Mannose-Binding Lectins; Microglia; Neurogenesis; Oligodendroglia; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Transforming Growth Factor beta; White Matter

To evaluate the contribution of L-arginine oral or topical rout of administration in the surgical wound healing process.. L-arginine was orally or topically administrated to mice after a laparotomy model procedure. The wounds were analyzed to evaluate the granulation tissue by HE analysis, collagen deposition, iNOS and cytokines production by immunochemisyry on wound progress. Mice used in this model were healthy, immunosupressed or diabetic and all of them were treated with different concentration of L-arginine and rout of administration.. Suggested that groups treated with L-arginine orally or topically improved wound repair when compared with non-treatad mice. L- arginine treatment stimulated TGF-β and restricted NO production leading to a mild Th1 response and collagen deposition in injured area, when it was orally administrated. Topical administration decreased IL-8 and CCR1 expression by wound cells but did not interfere with TNF-α and IL-10 production, ratifying the decrease of inflammatory response, the oral administration however, presented a higher iNOS and TGF-β expression then. L-arginine treatment also improved the improved the wound healing in immunosupressed or diabetic mice.. L-arginine administrated orally or topically can be considered an important factor in the recuperation of tissues.

Topics: Administration, Oral; Administration, Topical; Animals; Arginine; Collagen; Cytokines; Diabetes Mellitus, Experimental; Disease Models, Animal; Immunocompromised Host; Inflammation; Male; Mice; Nitric Oxide; Nitric Oxide Synthase Type II; Surgical Wound; Transforming Growth Factor beta; Wound Healing; Wounds and Injuries

T-Helper 17 (T

Topics: Antibodies, Neutralizing; Benzamides; Cell Differentiation; Cell Separation; Cells, Cultured; Cytokines; Dioxoles; Flow Cytometry; Forkhead Transcription Factors; Humans; Inflammation; Inflammation Mediators; Pyrazoles; T-Lymphocyte Subsets; Th17 Cells; Thiosemicarbazones; Transforming Growth Factor beta

Understanding the mechanisms that lead to autoimmunity is critical for defining potential therapeutic pathways. In this regard there have been considerable efforts in investigating the interacting roles of TGF-β and IL-2 on the function regulatory T cells. We have taken advantage of dnTGF-βRII Il2ra

Topics: Animals; Germinal Center; Immunophilins; Inflammation; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Lymphadenopathy; Lymphocyte Activation; Mice, Transgenic; Phenotype; Signal Transduction; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

It is well known that inflammation plays key roles in the development of atherosclerosis and that the transplantation of bone marrow mononuclear cells (BMMNCs) can suppress inflammation in rodent models of ischemic diseases. Here, we explored whether transplantation of autologous BMMNCs could prevent the progression of atherosclerosis by the alleviation of inflammatory responses in a rabbit model of carotid artery atherosclerosis.. The atherosclerotic rabbit model was established by air desiccation followed by a high-cholesterol diet for 8 weeks. Then, 1 × 107 BMMNCs labeled with BrdU or an equal volume of vehicle were injected into the rabbits via the ear vein. Using an ultrasonographic imaging method, we found that autologous BMMNC treatment significantly decreased the area of atherosclerotic plaques compared to the vehicle-treated group (p < 0.05). The results were further confirmed by hematoxylin-eosin staining. RT-PCR results demonstrated that BMMNC treatment significantly reduced the expression of interleukin (IL)-6 and CD147 but increased the expression of IL-10 and transforming growth factor-β compared with vehicle treatment (p < 0.05), which was consistent with Western blot results.. Transplantation of autologous BMMNCs delays the development of atherosclerosis, most probably via the attenuation of inflammatory responses, which could be a new approach for treating carotid atherosclerosis.

Topics: Animals; Basigin; Bone Marrow Transplantation; Carotid Arteries; Carotid Artery Diseases; Diet, High-Fat; Disease Models, Animal; Down-Regulation; Inflammation; Inflammation Mediators; Interleukin-10; Interleukin-6; Male; Plaque, Atherosclerotic; Rabbits; Time Factors; Transforming Growth Factor beta; Transplantation, Autologous

We aimed to investigate any association between hepatitis C virus (HCV) infection and non-Hodgkin’s\ lymphoma (NHL) in the view of cytokines that control inflammation/angiogenesis and their correlation with\ certain CD markers. NHL patients with or without HCV infection were studied. CD5, CD30, CD3, CD20 and\ CD45 were immunohistochemically evaluated. Plasma levels of vascular endothelial and platelet derived growth\ factors (VEGF, and PDGF), tumor necrosis factor (TNF-α), transforming growth factor (TGF-β), interleukin-6\ (IL-6), IL-8, IL-4, IL-12 and interferon gamma (IFN-γ) were detected by enzyme-linked immunosorbent assay\ (ELISA). HCV+ve NHL patients showed a significant reduction in VEGF, PDGF, IFN-γ, CD5 and CD45 and a\ significant increase in IL-12 and IL-8. In conclusion, there was a significant change in cytokine secretion and\ expression of CD markers in HCV+ve NHL patients. Based on our results, HCV infection in NHL patients\ requires more in-depth investigations to explore any role in lymphoma progression.

Topics: Adolescent; Adult; Aged; Antigens, CD; Biomarkers, Tumor; Female; Hepacivirus; Hepatitis C; Humans; Inflammation; Interferon-gamma; Interleukin-12; Interleukin-4; Interleukin-6; Interleukin-8; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neovascularization, Pathologic; Platelet-Derived Growth Factor; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Young Adult

Although indoleamine 2,3-dioxygenase (IDO)-mediated immune suppression of mesenchymal stem cells (MSCs) has been revealed in septic and tumor microenvironments, the role of IDO in suppressing allergic airway inflammation by MSCs is not well documented. We evaluated the effects of adipose-derived stem cells (ASCs) on allergic inflammation in IDO-knockout (KO) asthmatic mice or asthmatic mice treated with ASCs derived from IDO-KO mice.. ASCs were injected intravenously in wild-type (WT) and IDO-KO asthmatic mice. Furthermore, asthmatic mice were injected with ASCs derived from IDO-KO mice. We investigated the immunomodulatory effects of ASCs between WT and IDO-KO mice or IDO-KO ASCs in asthmatic mice. In asthmatic mice, ASCs significantly reduced airway hyperresponsiveness, the number of total inflammatory cells and eosinophils in bronchoalveolar lavage fluid (BALF), eosinophilic inflammation, goblet hyperplasia, and serum concentrations of total and allergen-specific IgE and IgG1. ASCs significantly inhibited Th2 cytokines, such as interleukin (IL)-4, IL-5, and IL-13, and enhanced Th1 cytokine (interferon-γ) and regulatory cytokines (IL-10, TGF-β) in BALF and lung draining lymph nodes (LLNs). ASCs led to significant increases in regulatory T-cells (Tregs) and IL-10+ T cell populations in LLNs. However, the immunosuppressive effects of ASCs did not significantly differ between WT and IDO-KO mice. Moreover, ASCs derived from IDO-KO mice showed immunosuppressive effects in allergic airway inflammation.. IDO did not play a pivotal role in the suppression of allergic airway inflammation through ASCs, suggesting that it is not the major regulator responsible for suppressing allergic airway inflammation.

Topics: Adipose Tissue; Animals; Asthma; Bronchoalveolar Lavage Fluid; Cell- and Tissue-Based Therapy; Cells, Cultured; Eosinophils; Female; Goblet Cells; Hyperplasia; Immunoglobulin E; Immunoglobulin G; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-13; Interleukin-4; Interleukin-5; Lymphocyte Count; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Methacholine Chloride; Mice; Mice, Inbred C57BL; Mice, Knockout; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

To investigate the effects and mechanisms of adipose-derived stem cells (ADSCs) on bleomycin-induced mice of scleroderma.. In the study, 24 C57BL/6J female mice were randomly divided into control group, bleomycin(BLM)group, ADSCs (hypodermic injection) group and ADSCs (intravenous injection) group . BLM [2 mg/(kg×d)] was injected into the mice to establish the model of scleroderma. There were 6 mice in each group .The control group mice were injected with normal saline 2 mL/(kg×d) by subcutaneously. The rest of the three groups were injected with BLM. ADSCs groups were injected with ADSCs (2×10. The proportion of Th17 and Treg increased in BLM group than in control group(15.30%±1.29% vs.4.32%±0.79%; 9.90%±1.95% vs.5.18%±1.35%, P<0.05), the expression of Th17 significantly decreased (5.02%±0.83%, 6.00%±0.82% vs.15.30%±1.29%, P<0.05) and the expression of Treg increased after the ADSCs therapy (14.32%±1.59%, 11.09%±4.31% vs. 9.90%±1.95%, P<0.05). The expression levels of IL-17,IL-6,tumor necrosis factor-α (TNF-α)mRNA in the lung tissue and IL-6 in the serum increased in BLM group than in control group [3.54±0.30, 10.65±0.66, 5.37±0.52 vs. 1.00±0.00; (21.2±1.74) ng/L vs. (16.87±1.09) ng/L, P<0.05]. The expression of these cytokines significant decreased after the ADSCs therapy [1.63±0.45,1.50±0.29 vs.3.54±0.30; 3.11±0.85, 2.98±0.76 vs.10.65±0.66;1.45±0.47, 1.59±0.41 vs. 5.37±0.52; (17.87±1.45) ng/L, (17.61±1.16) ng/L vs. (21.2±1.74) ng/L, P<0.05]. But there was no obvious difference between ADSCs (hypodermic injection) group and ADSCs (intravenous injection) group(P>0.05). The expression of TGF-β in the serum increased in BLM group than in control group[(33.95±2.49) ng/L vs. (28.8± 2.29) ng/L, P<0.05], however, the expression of TGF-β mRNA had no significant differences than that of control group (1.17±0.11 vs.1.00±0.00, P>0.05). The expression of TGF-β mRNA and protein had no significant differences than that of BLM group [1.25±0.11,1.26±0.12 vs.1.17±0.11; (31.84±2.04) ng/L, (31.25±2.36) ng/L vs. (33.95±2.49) ng/L, P>0.05]. HE staining showed that the inflammation of lung tissue was relieved and the dermal thickness and collagen deposition were decreased after the ADSCs therapy.. ADSCs could effectively alleviate inflammation of the lungs and fibrosis of skin; the effects of anti-inflammatory and anti-fibrosis were associated with immune regulating function.

Topics: Adipose Tissue; Adult Stem Cells; Animals; Bleomycin; Cytokines; Female; Fibrosis; Inflammation; Interleukin-17; Interleukin-6; Lung; Mice; Mice, Inbred C57BL; RNA, Messenger; Scleroderma, Systemic; Skin; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Although the relationship between atherosclerosis and overt hypothyroidism has been confirmed, it remains controversial in cases of subclinical hypothyroidism. Higher TSH and similar T4 suggest differences in set-points or differences due to diagnostic limitations regarding subclinical hypothyroidism. Endothelial dysfunction (ED) is a marker rather than a precursor of cardiovascular disease. Asymmetric dimethylarginine (ADMA) and endocan are known as novel markers of ED in various diseases. Transforming growth factor-beta (TGF-β) has a protective role against autoimmune diseases such as thyroiditis. This study aimed to determine the relationships between serum ADMA, endocan, TGF-β, and the high-sensitivity C-reactive protein (hs-CRP) levels, a proven indicator of ED, in patients with SH.. Thirty-five patients with SH and 21 age- and sex-matched euthyroid subjects were included in the study. The levels of TSH, FT4, lipid parameters, endocan, ADMA, TGF-β, and hs-CRP were measured.. No significant differences in age or sex were found between the patient and control groups (p=0.294 and 0.881, respectively). Mean TSH level was higher in the patient group (p=0.005), whereas mean fT4 level was similar in two groups (p=0.455). The average hs-CRP, endocan, TGF-β l level in the patient group was higher than control group (p=0.001; P=0.012; P=0.025; P<0.01 respectively). A positive correlation was found between the endocan and ADMA levels (r=0.760, p=0.000). ADMA levels also were positively correlated with hs-CRP. Both the TSH and low-density lipoprotein cholesterol (LDL-C) levels were positively correlated with the hs-CRP level.. Subclinical hypothyroidism is associated with increased levels of serum endocan, ADMA, and TGF-β, which are new markers for ED. In particular, ADMA was correlated with both endocan and hs-CRP levels. These findings are suggestive for increased risk of ED and subsequent development of atherosclerosis in patients with SH.

Topics: Adult; Arginine; Biomarkers; Demography; Endothelium, Vascular; Female; Humans; Hypothyroidism; Inflammation; Male; Neoplasm Proteins; Proteoglycans; Risk Factors; Thyroid Function Tests; Transforming Growth Factor beta; Vascular Diseases

Myeloid-derived suppressor cells (MDSCs) are well known regulators of regulatory T cells (Treg cells); however, the direct regulation of MDSCs by Treg cells has not been well characterized. We find that colitis caused by functional deficiency of Treg cells leads to altered expansion and reduced function of MDSCs. During differentiation of MDSCs in vitro from bone marrow cells, Treg cells enhanced MDSC function and controlled their differentiation through a mechanism involving transforming growth factor-β (TGF-β). TGF-β-deficient Treg cells were not able to regulate MDSC function in an experimentally induced model of colitis. Finally, we evaluated the therapeutic effect of TGF-β-mediated in-vitro-differentiated MDSCs on colitis. Adoptive transfer of MDSCs that differentiated with TGF-β led to better colitis prevention than the transfer of MDSCs that differentiated without TGF-β. Our results demonstrate an interaction between Treg cells and MDSCs that contributes to the regulation of MDSC proliferation and the acquisition of immunosuppressive functions.

Topics: Adoptive Transfer; Animals; Bone Marrow Cells; Cell Differentiation; Cell Proliferation; Colitis; Dextran Sulfate; Humans; Inflammation; Mice; Myeloid-Derived Suppressor Cells; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

In humans suffering from pulmonary disease and a mouse model, transient receptor potential vanilloid 4 (TRPV4) channel activation contributes to fibrosis. As a corneal alkali burn induces the same response, we determined if such an effect is also attributable to TRPV4 activation in mice. Accordingly, we determined if the alkali burn wound healing responses in wild-type (WT) mice are different than those in their TRPV4-null (KO) counterpart. Stromal opacification due to fibrosis in KO (n = 128) mice was markedly reduced after 20 days relative to that in WT (n = 157) mice. Immunohistochemistry revealed that increases in polymorphonuclear leukocytes and macrophage infiltration declined in KO mice. Semi-quantitative real time RT-PCR of ocular KO fibroblast cultures identified increases in proinflammatory and monocyte chemoattractant protein-1 chemoattractant gene expression after injury. Biomarker gene expression of fibrosis, collagen1a1 and α-smooth muscle actin were attenuated along with macrophage release of interleukin-6 whereas transforming growth factor β, release was unchanged. Tail vein reciprocal bone marrow transplantation between WT and KO chimera mouse models mice showed that reduced scarring and inflammation in KO mice are due to loss of TRPV4 expression on both corneal resident immune cells, fibroblasts and infiltrating polymorphonuclear leukocytes and macrophages. Intraperitoneal TRPV4 receptor antagonist injection of HC-067047 (10 mg/kg, daily) into WT mice reproduced the KO-phenotype. Taken together, alkali-induced TRPV4 activation contributes to inducing fibrosis and inflammation since corneal transparency recovery was markedly improved in KO mice.

Topics: Actins; Alkalies; Animals; Cornea; Corneal Opacity; Eye Burns; Fibrosis; Gene Expression Regulation; Gene Knockout Techniques; Inflammation; Interleukin-6; Mice; Transforming Growth Factor beta; TRPV Cation Channels; Vascular Endothelial Growth Factor A

Coronary artery disease (CAD) and hypertension are the main reasons of ischemic heart diseases (IHDs). Cytokines as the small glycoproteins are the main arm of immune system and manipulate all of the cardiovascular diseases. The aim of the current study was to examine the effects of treatment of hypertension and CAD on serum levels of IL-6, IL-8, TGF-β and TNF-α.. This interventional study was performed on the patients with hypertension without CAD (group 1), hypertension and CAD (group 2), CAD but not hypertension (group 3) and without hypertension and CAD as controls (group 4). The patients received routine treatment for hypertension and CAD. Serum levels of IL-6, IL-8, TGF-β and TNF-α were analyzed in the groups treated with various drugs, using ELISA technique.. With regard to the medications, Atorvastatin, Losartan and Captopril were administered more in patients (groups 1, 2 and 3) than the patients without hypertension and CAD. The results revealed that serum levels of TGF-β and IL-6 were significantly increased and decreased, respectively, in the groups 1, 2 and 3 when compared to group 4. Serum levels of TGF-β were also increased in females in comparison to males in the group 4.. According to the results it seems that Atorvastatin, Losartan and Captopril have reduced inflammation in in vivo conditions via downregulation of IL-6 and upregulation of TGF-β.

Topics: Antihypertensive Agents; Atorvastatin; Captopril; Coronary Artery Disease; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Inflammation; Interleukin-6; Interleukin-8; Iran; Losartan; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Up-Regulation

Dimethylarsinic acid (DMA(V) ), the major urinary metabolite of inorganic arsenic, is a urinary bladder carcinogen and bladder tumor promoter in adult rats. Increased urothelial cellular proliferation has been considered as an earlier phenotype in DMA(V) -induced bladder carcinogenesis. The present study examined the ultrastructural changes of bladder epithelial cells and expressions of proliferation factors, as well as the secretion of inflammatory cytokines in rats exposed to DMA(V) for 10 weeks by transmission electron microscopy (TEM), qRT-PCR, immunohistochemical staining and ELISA methods. The results showed that DMA(V) administered in the drinking water produced urothelial cytotoxicity and ultrastructural changes in rats. PCNA, cyclin D1 and COX-2 mRNA expressions and immunoreactivities were elevated in bladder urothelium. In addition, 200 ppm DMA(V) treatment increased the transforming growth factor-beta 1 (TGF-β1) secretion and decreased tumor necrosis factor-alpha (TNF)-α level in the urine of rats. These data suggest that chronic inflammation, bladder epithelium lesions and proliferation might be the basic process of the chronic toxicity effects in DMA(V) -treated rats.

Topics: Animals; Cacodylic Acid; Cell Proliferation; Cyclin D1; Cyclooxygenase 2; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Inflammation; Interleukin-6; Male; Microscopy, Electron, Transmission; Proliferating Cell Nuclear Antigen; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Urinary Bladder; Urinary Bladder Neoplasms; Urothelium

It is known that surgery-induced tissue damage activates the peripheral immune system resulting in the release of inflammatory mediators and cognitive impairment in aged mice. Vitamin D has been shown to have immunomodulatory function, but the molecular basis for it has not been well understood. In this study, we mainly investigated the efficacy and mechanism of vitamin D against postoperative cognitive dysfunction (POCD). The treatment of C57BL mice with vitamin D significantly preserves postoperative cognitive function, markedly inhibits surgery-induced interleukin (IL)-17, IL-6, transforming growth factor beta (TGF-β), and retinoic acid-related orphan receptor (RORγt) production, and obviously induces IL-10 and forkhead box p3 (Foxp3) expression. These findings indicate that vitamin D amelioration of POCD is, to a large extent, due to inhibit inflammatory CD4_T cell lineage, T helper 17 (Th17) cells, accompanied with expansion in regulatory T cells (Treg cells), a subset of CD4_T cells that are important in inhibiting inflammation. Our results suggest that Th17 and Treg cell imbalance may play a role in the development of POCD. Vitamin D is useful in the control of inflammatory diseases.

Topics: Animals; Cognition; Female; Forkhead Transcription Factors; Hepatectomy; Inflammation; Interleukin-10; Interleukin-17; Interleukin-6; Liver; Lymphocyte Count; Maze Learning; Mice; Mice, Inbred C57BL; Nuclear Receptor Subfamily 1, Group F, Member 3; Postoperative Complications; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta; Vitamin D

The interaction between human gingival fibroblasts (HGFs) and Porphyromonas gingivalis plays an important role in the development and progression of periodontitis. Porphyromonas gingivalis possesses several virulence factors, including cysteine proteases, the arginine-specific (Rgp) and lysine-specific (Kgp) gingipains. Studying the mechanisms that P. gingivalis, and its derived virulence, use to propagate and interact with host cells will increase the understanding of the development and progression of periodontitis. In this study, we aimed to elucidate how P. gingivalis influences the inflammatory events in HGFs regarding transforming growth factor-β1 (TGF-β1 ), CXCL8, secretory leucocyte protease inhibitor (SLPI), c-Jun and indoleamine 2,3-dioxygenase (IDO). HGFs were inoculated for 6 and 24 h with the wild-type strains ATCC 33277 and W50, two gingipain-mutants of W50 and heat-killed ATCC 33277. The P. gingivalis regulated CXCL8 and TGF-β1 in HGFs, and the kgp mutant gave significantly higher immune response with increased CXCL8 (P < 0.001) and low levels of TGF-β1 . We show that HGFs express and secrete SLPI, which was significantly suppressed by P. gingivalis (P < 0.05). This suggests that by antagonizing SLPI, P. gingivalis contributes to the tissue destruction associated with periodontitis. Furthermore, we found that P. gingivalis inhibits the expression of the antimicrobial IDO, as well as upregulating c-Jun (P < 0.05). In conclusion, P. gingivalis both triggers and suppresses the immune response in HGFs. Consequently, we suggest that the pathogenic effects of P. gingivalis, and especially the activity of the gingipains on the inflammatory and immune response of HGFs, are crucial in periodontitis.

Topics: Adhesins, Bacterial; Cells, Cultured; Cysteine Endopeptidases; Enzyme-Linked Immunosorbent Assay; Fibroblasts; Gingipain Cysteine Endopeptidases; Gingiva; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inflammation; Interleukin-8; Periodontitis; Porphyromonas gingivalis; Proto-Oncogene Proteins c-jun; Real-Time Polymerase Chain Reaction; Secretory Leukocyte Peptidase Inhibitor; Transforming Growth Factor beta

Wolbachia is an endosymbiotic bacterium of the filarial nematode Brugia malayi. The symbiotic relationship between Wolbachia and its filarial host is dependent on interactions between the proteins of both organisms. However, little is known about Wolbachia proteins that are involved in the inflammatory pathology of the host during lymphatic filariasis. In the present study, we cloned, expressed and purified Wolbachia surface protein (r-wsp) from Wolbachia and administered it to mice, either alone or in combination with infective larvae of B. malayi (Bm-L3) and monitored the developing immune response in infected animals. Our results show that spleens and mesenteric lymph nodes of mice immunized with either r-wsp or infected with Bm-L3 show increased percentages of CD4(+) T helper type 17 (Th17) cells and Th1 cytokines like interferon-γ and interleukin-2 (IL-2) along with decreased percentages of regulatory T cells, Th2 cytokines like IL-4 and IL-10 and transforming growth factor β (TGF-β) levels in culture supernatants of splenocytes. These observations were stronger in mice immunized with r-wsp alone. Interestingly, when mice were first immunized with r-wsp and subsequently infected with Bm-L3, percentages of CD4(+) Th17 cells and Th1 cytokines increased even further while that of regulatory T cells, Th2 cytokines and TGF-β levels decreased. These results for the first time show that r-wsp acts synergistically with Bm-L3 in promoting a pro-inflammatory response by increasing Th17 cells and at the same time diminishes host immunological tolerance by decreasing regulatory T cells and TGF-β secretion.

Topics: Animals; Bacterial Outer Membrane Proteins; Brugia malayi; Cloning, Molecular; Filariasis; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-2; Interleukin-4; Larva; Lymph Nodes; Male; Mice; Mice, Inbred BALB C; Recombinant Proteins; Spleen; T-Lymphocytes, Regulatory; Th17 Cells; Th2 Cells; Transforming Growth Factor beta; Wolbachia

Diffuse cutaneous leishmaniasis (DCL) is a rare clinical manifestation of tegumentary leishmaniasis. The molecular mechanisms underlying DCL pathogenesis remain unclear, and there is no efficient treatment available. This study investigated the systemic and in situ expression of the inflammatory response that might contribute to suppression in DCL. The plasma levels of arginase I, ornithine decarboxylase (ODC), transforming growth factor β (TGF-β), and prostaglandin E2 (PGE2) were higher in patients with DCL, compared with patients with localized cutaneous leishmaniasis (LCL) or with controls from an area of endemicity. In situ transcriptomic analyses reinforced the association between arginase I expression and enzymes involved in prostaglandin and polyamine synthesis. Immunohistochemistry confirmed that arginase I, ODC, and cyclooxygenase2 expression was higher in lesion biopsy specimens from patients with DCL than in those from patients with LCL. Inhibition of arginase I or ODC abrogates L. amazonensis replication in infected human macrophages. Our data implicate arginase I, ODC, PGE2, and TGF-β in the failure to mount an efficient immune response and suggest perspectives in the development of new strategies for therapeutic intervention for patients with DCL.

Topics: Adolescent; Adult; Aged; Arginase; Child; Child, Preschool; Dinoprostone; Female; Humans; Inflammation; Leishmaniasis, Diffuse Cutaneous; Male; Middle Aged; Ornithine Decarboxylase; Polyamines; Signal Transduction; Transcriptome; Transforming Growth Factor beta; Young Adult

Dendritic cells (DCs) have the tolerogenic potential to regulate adaptive immunity and induce allografts acceptance. Here we investigated whether blockade of the CD40 pathway could enhance the immune tolerance induced by DC2.4 cells modified to express Jagged-1 (JAG1-DC) in heart transplantation. Results showed that JAG1-DC treatment combined with anti-CD40L monoclonal antibody (mAb) administration significantly prolonged cardiac allograft survival in mice, with long-term survival (>110 days) of 50% of the allografts in the recipients. The therapy specifically inhibited the immune response, induced alloantigen-specific T-cell hyporesponsiveness, upregulated transforming growth factor-β synthesis and increased the population of regulatory T cells (Tregs) driven by Jagged-1-Notch activation. These results highlight the potential application of gene therapy to induce alloantigen-specific Tregs effectively by providing the Jagged-1 stimulation.

Topics: Allografts; Animals; Calcium-Binding Proteins; CD40 Antigens; CD40 Ligand; Cell Line; Cell Proliferation; Dendritic Cells; Female; Forkhead Transcription Factors; Graft Survival; Heart Transplantation; Immunosuppression Therapy; Inflammation; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Lymphocyte Activation; Membrane Proteins; Mice, Inbred BALB C; Mice, Inbred C57BL; Receptors, Notch; Serrate-Jagged Proteins; Signal Transduction; Spleen; T-Lymphocytes; Transforming Growth Factor beta

We aimed to evaluate: (1) endometrial and ovarian tissue injury caused by the glucose toxicity in diabetic rat model and (2) the effect of GLP-1 analog (exenatide) on endometrial and ovarian diabetes induced injury with emphasizing the underlying mechanism. The study group composed of 24 female rats assigned randomly into 3 groups. Group 1 was the control group (n = 8) and received no treatment. Diabetes was induced by intraperitoneal injection of streptozocin for 16 rats which are further assigned randomly into 2 groups: 1 ml/kg intraperitoneal saline was given to Group-2 (diabetic non-treated control group, 8 rats) and 10 µg/kg/day of intraperitoneal exenatide was given to Group 3 (exenatide treated group, 8 rats) for four weeks. After four weeks, blood samples were collected and hysterectomy with bilateral oophorectomy was performed for histopathological examination. Diabetes caused endometrial and ovarian tissue injury in rats (p < 0.0001). Serum transforming growth factor beta (TGF-ß), malonylaldehyde (MDA), pentraxin-3 (PTX-3) levels were higher in diabetic rats (p < 0.0001), whereas antimullerian hormone (AMH) was lower (p < 0.001). Serum levels of these markers reflected that Diabetes induced injury in the reproductive tract occured via oxidative stress, fibrosis and severe inflammation. Diabetes diminished ovarian reserve. Exenatide treatment improved the histological degeneration and fibrosis in the endometrium and ovary with concomitant decrease in inflammatory and oxidative stress markers (p < 0.05). Exenatide also improved ovarian reserve (p < 0.05). Glucose toxicity occured severely in ovary and endometrium in DM. After exenatide treatment; ovarian and endometrial injury and fibrosis seems to decrease significantly. The effects of exenatide in rat models give hope to prevent the women with DM from premature ovarian failure and endometrial dysfunction.

Topics: Animals; Anti-Mullerian Hormone; C-Reactive Protein; Diabetes Mellitus, Experimental; Endometrium; Exenatide; Female; Inflammation; Lipid Peroxidation; Malondialdehyde; Ovarian Reserve; Ovary; Oxidative Stress; Peptides; Rats; Rats, Sprague-Dawley; Serum Amyloid P-Component; Transforming Growth Factor beta; Venoms

In the present study, the anti-atherosclerotic effect and the underlying mechanism of curcuma oil (C. oil), a lipophilic fraction from turmeric (Curcuma longa L.), was evaluated in a hamster model of accelerated atherosclerosis and in THP-1 macrophages. Male golden Syrian hamsters were subjected to partial carotid ligation (PCL) or FeCl3-induced arterial oxidative injury (Ox-injury) after 1 week of treatment with a high-cholesterol (HC) diet or HC diet plus C. oil (100 and 300 mg/kg, orally). Hamsters fed with the HC diet were analysed at 1, 3 and 5 weeks following carotid injury. The HC diet plus C. oil-fed group was analysed at 5 weeks. In hyperlipidaemic hamsters with PCL or Ox-injury, C. oil (300 mg/kg) reduced elevated plasma and aortic lipid levels, arterial macrophage accumulation, and stenosis when compared with those subjected to arterial injury alone. Similarly, elevated mRNA transcripts of matrix metalloproteinase-2 (MMP-2), MMP-9, cluster of differentiation 45 (CD45), TNF-α, interferon-γ (IFN-γ), IL-1β and IL-6 were reduced in atherosclerotic arteries, while those of transforming growth factor-β (TGF-β) and IL-10 were increased after the C. oil treatment (300 mg/kg). The treatment with C. oil prevented HC diet- and oxidised LDL (OxLDL)-induced lipid accumulation, decreased the mRNA expression of CD68 and CD36, and increased the mRNA expression of PPARα, LXRα, ABCA1 and ABCG1 in both hyperlipidaemic hamster-derived peritoneal and THP-1 macrophages. The administration of C. oil suppressed the mRNA expression of TNF-α, IL-1β, IL-6 and IFN-γ and increased the expression of TGF-β in peritoneal macrophages. In THP-1 macrophages, C. oil supplementation prevented OxLDL-induced production of TNF-α and IL-1β and increased the levels of TGF-β. The present study shows that C. oil attenuates arterial injury-induced accelerated atherosclerosis, inflammation and macrophage foam-cell formation.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Atherosclerosis; CD36 Antigens; Cholesterol, Dietary; Cricetinae; Curcuma; Diet, High-Fat; Foam Cells; Homeostasis; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-1beta; Interleukin-6; Leukocyte Common Antigens; Lipoproteins, LDL; Macrophages, Peritoneal; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Plant Extracts; Plant Oils; Plaque, Atherosclerotic; PPAR alpha; RNA, Messenger; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

T-helper type 17 (TH17) cells that produce the cytokines interleukin-17A (IL-17A) and IL-17F are implicated in the pathogenesis of several autoimmune diseases. The differentiation of TH17 cells is regulated by transcription factors such as RORγt, but post-translational mechanisms preventing the rampant production of pro-inflammatory IL-17A have received less attention. Here we show that the deubiquitylating enzyme DUBA is a negative regulator of IL-17A production in T cells. Mice with DUBA-deficient T cells developed exacerbated inflammation in the small intestine after challenge with anti-CD3 antibodies. DUBA interacted with the ubiquitin ligase UBR5, which suppressed DUBA abundance in naive T cells. DUBA accumulated in activated T cells and stabilized UBR5, which then ubiquitylated RORγt in response to TGF-β signalling. Our data identify DUBA as a cell-intrinsic suppressor of IL-17 production.

Topics: Animals; Enzyme Stability; Female; Inflammation; Interleukin-17; Intestine, Small; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Nuclear Receptor Subfamily 1, Group F, Member 3; Proteasome Endopeptidase Complex; Protein Binding; Protein Biosynthesis; Signal Transduction; Substrate Specificity; Th17 Cells; Transforming Growth Factor beta; Ubiquitin-Protein Ligases; Ubiquitin-Specific Proteases; Ubiquitination

Classically activated pro-inflammatory (M1) and alternatively activated anti-inflammatory (M2) macrophages populate the local microenvironment after spinal cord injury (SCI). The former type is neurotoxic while the latter has positive effects on neuroregeneration and is less toxic. In addition, while the M1 macrophage response is rapidly induced and sustained, M2 induction is transient. A promising strategy for the repair of SCI is to increase the fraction of M2 cells and prolong their residence time. This study investigated the effect of M2 macrophages induced from bone marrow-derived macrophages on the local microenvironment and their possible role in neuroprotection after SCI. M2 macrophages produced anti-inflammatory cytokines such as interleukin (IL)-10 and transforming growth factor β and infiltrated into the injured spinal cord, stimulated M2 and helper T (Th)2 cells, and produced high levels of IL-10 and -13 at the site of injury. M2 cell transfer decreased spinal cord lesion volume and resulted in increased myelination of axons and preservation of neurons. This was accompanied by significant locomotor improvement as revealed by Basso, Beattie and Bresnahan locomotor rating scale, grid walk and footprint analyses. These results indicate that M2 adoptive transfer has beneficial effects for the injured spinal cord, in which the increased number of M2 macrophages causes a shift in the immunological response from Th1- to Th2-dominated through the production of anti-inflammatory cytokines, which in turn induces the polarization of local microglia and/or macrophages to the M2 subtype, and creates a local microenvironment that is conducive to the rescue of residual myelin and neurons and preservation of neuronal function.

Topics: Adoptive Transfer; Animals; Axons; Female; Inflammation; Interleukin-10; Interleukin-13; Interleukin-1beta; Interleukin-6; Locomotion; Macrophages; Microglia; Myelin Sheath; Nitric Oxide Synthase Type II; Rats; Recovery of Function; Reverse Transcriptase Polymerase Chain Reaction; Spinal Cord Injuries; Th2 Cells; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Paracoccidioidomycosis (PCM) is a systemic mycosis in which the host response to the infectious agent typically consists of a chronic granulomatous inflammatory process. This condition causes lesions that impair lung function and lead to chronic pulmonary insufficiency resulting from fibrosis development, which is a sequel and disabling feature of the disease. The rPb27 protein has been studied for prophylactic and therapeutic treatment against PCM. Previous studies from our laboratory have shown a protective effect of rPb27 against PCM. However, these studies have not determined whether rPb27 immunization prevents lung fibrosis. We therefore conducted this study to investigate fibrosis resulting from infection by Paracoccidioides brasiliensis in the lungs of animals immunized with rPb27. Animals were immunized with rPb27 and subsequently infected with a virulent strain of P. brasiliensis. Fungal load was evaluated by counting colony-forming units, and Masson's trichrome staining was performed to evaluate fibrosis at 30 and 90 days post-infection. The levels of CCR7, active caspase 3, collagen and cytokines were analyzed. At the two time intervals mentioned, the rPb27 group showed lower levels of fibrosis on histology and reduced levels of collagen and the chemokine receptor CCR7 in the lungs. CCR7 was detected at higher levels in the control groups that developed very high levels of pulmonary fibrosis. Additionally, the immunized groups showed high levels of active caspase 3, IFN-γ, TGF-β and IL-10 in the early phase of P. brasiliensis infection. Immunization with Pb27, in addition to its protective effect, was shown to prevent pulmonary fibrosis.

Topics: Animals; Antifungal Agents; Antigens, Fungal; Caspase 3; Collagen; Fluconazole; Fungal Proteins; Fungal Vaccines; Immunization; Inflammation; Interferon-gamma; Interleukin-10; Lung; Male; Mice; Mice, Inbred BALB C; Paracoccidioides; Paracoccidioidomycosis; Propionibacterium acnes; Pulmonary Fibrosis; Receptors, CCR7; Recombinant Proteins; Transforming Growth Factor beta

Alveolar echinococcosis (AE) is a severe chronic helminthic disease that mimics slow-growing liver cancer. Previous studies using murine models suggest that Echinococcus multilocularis (Em) metacestodes have developed mechanisms which impair the natural inflammatory host response. The aim of this study was to investigate in vitro the impact of Em vesicular fluid (VF) on monocytes, monocytes derived dendritic cells and lymphocytes from healthy blood donors.. First, assays were performed to investigate whether or not Em-VF influences monocyte-derived dendritic cell (MoDC) differentiation and maturation. Monocytes during differentiation and immature MoDCs were exposed to Em-VF. The effect of Em-VF was assessed using flow cytometry (CD86, CD83, CD80) and immune assays (IL-10 and TGFβ). Second, assays were performed to investigate the interaction between Em-VF, peripheral blood monocyte cells (PBMC) and Toll-like Receptor (TLR) agonists (LPS, PolyIC, R848 and CpG). PBMC were stimulated by each of the TLR agonists with and without Em-VF. The subsequent TGFβ production was assessed.. Exposure to Em-VF had bearing on both differentiation and maturation of MoDC, but only partially. A decrease in the expression of co-stimulatory molecules was observed; however, levels of immune-regulatory cytokines were stable. PBMC exposed simultaneously to Em-VF and LPS induced a significant increase of TGFβ (p<0.05, Wilcoxon signed-rank test). Further experiments showed that TGFβ production was lymphocyte-dependent.. The assays performed confirmed that Em-VF influences the host immune response. However, only minor changes were observed when investigating the Em-VF impact on cells from healthy blood donors. Assays with TLR agonists suggested that co-stimulation with LPS reinforces the response of healthy blood donors exposed to Em-VF.

Topics: Animals; Antigens, CD; B7-1 Antigen; B7-2 Antigen; CD83 Antigen; Cell Differentiation; Dendritic Cells; Echinococcosis; Echinococcosis, Hepatic; Echinococcus multilocularis; Humans; Immunoglobulins; Inflammation; Interleukin-10; Lipopolysaccharides; Lymphocyte Activation; Lymphocytes; Membrane Glycoproteins; Monocytes; Toll-Like Receptor 2; Toll-Like Receptor 4; Transforming Growth Factor beta

AMP-activated protein kinase (AMPK) is a conserved serine/threonine kinase with a critical function in the regulation of metabolic pathways in eukaryotic cells. Recently, AMPK has been shown to play an additional role as a regulator of inflammatory activity in leukocytes. Treatment of macrophages with chemical AMPK activators, or forced expression of a constitutively active form of AMPK, results in polarization to an anti-inflammatory phenotype. In addition, we reported previously that stimulation of macrophages with anti-inflammatory cytokines such as IL-10, IL-4, and TGF-β results in rapid activation of AMPK, suggesting that AMPK contributes to the suppressive function of these cytokines. In this study, we investigated the role of AMPK in IL-10-induced gene expression and anti-inflammatory function. IL-10-stimulated wild-type macrophages displayed rapid activation of PI3K and its downstream targets Akt and mammalian target of rapamycin complex (mTORC1), an effect that was not seen in macrophages generated from AMPKα1-deficient mice. AMPK activation was not impacted by treatment with either the PI3K inhibitor LY294002 or the JAK inhibitor CP-690550, suggesting that IL-10-mediated activation of AMPK is independent of PI3K and JAK activity. IL-10 induced phosphorylation of both Tyr(705) and Ser(727) residues of STAT3 in an AMPKα1-dependent manner, and these phosphorylation events were blocked by inhibition of Ca(2+)/calmodulin-dependent protein kinase kinase β, an upstream activator of AMPK, and by the mTORC1 inhibitor rapamycin, respectively. The impaired STAT3 phosphorylation in response to IL-10 observed in AMPKα1-deficient macrophages was accompanied by reduced suppressor of cytokine signaling 3 expression and an inadequacy of IL-10 to suppress LPS-induced proinflammatory cytokine production. Overall, our data demonstrate that AMPKα1 is required for IL-10 activation of the PI3K/Akt/mTORC1 and STAT3-mediated anti-inflammatory pathways regulating macrophage functional polarization.

Topics: AMP-Activated Protein Kinases; Animals; Enzyme Activation; Gene Expression Regulation; Inflammation; Interleukin-10; Interleukin-4; Lipopolysaccharides; Macrophages; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Knockout; Multiprotein Complexes; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; STAT3 Transcription Factor; TOR Serine-Threonine Kinases; Transforming Growth Factor beta

Bioactive peptides from milk can impart a wide range of physiological benefits without the allergies and intolerance associated with the consumption of whole milk. The objective of this study was to characterise the anti-inflammatory properties of intact sodium caseinate (NaCAS), a moderately hydrolysed NaCAS enzyme hydrolysate (EH) and its 5 kDa fraction (5kDaR), in both in vitro and ex vivo systems. In vitro, Caco-2 cells were stimulated with tumor necrosis factor (TNF) α and co-treated ± casein hydrolysates or dexamethasone (control). The inflammatory marker interleukin (IL)-8 was measured by ELISA in the supernatant at 24 h. Ex vivo, porcine colonic tissues were stimulated with lipopolysaccharide (LPS) and co-treated with casein hydrolysates for 3 h from which the relative expression of a panel of cytokines was measured in vitro. While the steroid dexamethasone brought about a 41.6% reduction in the IL-8 concentration in the supernatant, the 5kDaR reduced IL-8 by 59% (P < 0.05) when compared to the TNFα stimulated Caco-2 cells. In the ex vivo system, 5kDaR was associated with decreases in IL-1α, IL-1β, IL-8 and TGF-β expression and an increase in IL-17 expression (P < 0.05) relative to the LPS challenged tissues. We concluded, that a 5 kDa casein fraction demonstrates potent anti-inflammatory effects both in in vitro and ex vivo models of the gastrointestinal tract.

Topics: Animals; Anti-Inflammatory Agents; Caco-2 Cells; Caseins; Dexamethasone; Gastrointestinal Tract; Humans; Inflammation; Interleukin-17; Interleukin-1alpha; Interleukin-1beta; Interleukin-8; Lipopolysaccharides; Models, Biological; Molecular Weight; Swine; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Periostin actively contributes to tissue injury, fibrosis, atherosclerosis, and inflammatory diseases; however, its role in hepatic fibrosis is unclear. Herein, we revealed that periostin expression was significantly up-regulated in carbon tetrachloride- and bile duct ligation-induced mice with acute and chronic liver fibrosis. Deficiency in periostin abrogated the development of liver fibrosis in mice. Carbon tetrachloride treatment significantly increased α-smooth muscle actin, fibronectin, and collagen I levels in wild-type mice, which were unaffected in periostin-knockout mice. Periostin-deficient mice showed a significantly reduced area of collagen deposition and decreased levels of serum alanine aminotransferase and aspartate aminotransferase compared with wild-type mice after 2 weeks of carbon tetrachloride administration. Chemokine ligand 2, IL-6, IL-1β, tumor necrosis factor-α, and tissue inhibitor of metalloproteinases 1 mRNA levels were significantly lower in periostin-deficient mice than in wild-type mice after carbon tetrachloride treatment. Periostin colocalized with hepatic stellate cell-derived collagen I and α-smooth muscle actin in mouse acute and chronic fibrotic liver tissues. Transforming growth factor (TGF)-β1 markedly induced periostin expression in primary mouse hepatic stellate cells. Periostin-deficient mice showed significantly lower levels of TGF-β1 and TGF-β2 compared with wild-type mice after carbon tetrachloride treatment. High levels of periostin in patients with acute or chronic hepatitis correlated with TGF-β1 and TGF-β2 expression in serum from patients with hepatitis. Data indicate that periostin is a novel mediator of hepatic fibrosis development.

Topics: Animals; Cell Adhesion Molecules; Chemical and Drug Induced Liver Injury; Collagen; Hepatic Stellate Cells; Hepatitis; Humans; Inflammation; Liver; Liver Cirrhosis; Mice; Mice, Knockout; Transforming Growth Factor beta

Mucin hypersecretion and overproduction are frequent manifestations of respiratory disease. Determining the physiological function of airway mucin is presently considered more important than identifying the relevant signaling pathways. The lack of a full-length human mucin 8 (MUC8) cDNA sequence has hindered the generation of a Muc8 knockout mouse line. Thus, the precise physiological functions of MUC8 are unclear. Herein, we investigated the function of MUC8 using a small-interfering RNA (siRNA)-mediated genetic silencing approach in human airway epithelial cells. Herein, intracellular IL-1α production was stimulated by an ATP/P2Y2 complex. While ATP/P2Y₂ increased IL-1α secretion in a time-dependent manner, treatment with P2Y₂-specific siRNA significantly decreased IL-1α secretion. Moreover, ATP increased P2Y₂-mediated upregulation of MUC8 expression; however, IL-1α significantly decreased the extent to which ATP/P2Y₂ upregulated MUC8 expression. Interestingly, treatment with MUC8-specific siRNA decreased the production of anti-inflammatory cytokines (TGF-β and IL-1 receptor antagonist) and increased the production of inflammatory cytokines (IL-1α and IL-6) in our system. In addition, siRNA-mediated knockdown of MUC8 expression dramatically increased the secretion of inflammatory chemokines and resulted in an approximately threefold decrease in cell chemotaxis. We propose that MUC8 may function as an anti-inflammatory mucin that participates in inflammatory response by attracting immune cells/cytokines to the site of inflammation. Our results provide new insight into the physiological function of MUC8 and enhance our understanding of mucin overproduction during airway inflammation.

Topics: Adenosine Triphosphate; Animals; Cell Line, Tumor; Gene Silencing; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1alpha; Interleukin-6; Mice; Mice, Knockout; Mucins; Receptors, Purinergic P2Y2; Respiratory Tract Diseases; RNA, Small Interfering; Transforming Growth Factor beta

This study evaluates the effect of Trypanosoma cruzi biotherapy 17dH (BIOT) on mice of different ages, infected with the protozoa concerned.. Performing a blind, controlled, randomized by drawing experiment, 110 animals four or eight-week-old, Swiss, male mice were divided into infected control treated hydroalcoholic 7% (CI-4 = 34 or CI-8 = 21 animals) and infected control treated with biotherapy 17dH-0.2 mL/animal/20 consecutive days/oral regimen (BIOT-4 = 33 or BIOT-8 = 21 animals). Animals were inoculated intraperitoneally with 1400 trypomastigote, T. cruzi Y-strain. Parasitological, immunological and histopathologic parameters were evaluated statistically, using Statistica-8.0 and R 3.0.2 program to analysis of survival. The study was approved by the Ethics Committee for Animal Experimentation/UEM.. Four-week-old mice showed no statistical difference in parasitemia (P = 0.5718) between the treated and control group. Eight-week-old mice from the treated group had a higher parasite peak (P = 0.0424) and higher parasitemia (P < 0.005) than the control. To both groups of 4 and 8 weeks of age, treated or untreated, survival of mice was higher in the treated group than in the control, although it was not statistically significant (p-value = 0.32, 0.55 respectively). Four-week-old mice displayed a spleen section with a number of amastigote nests significantly higher in BIOT-4 than CI-4 (P = 0.01). In eight-week-old mice the number of amastigote nests (P < 0.001) and inflammatory foci (P < 0.06-10% significance) in the liver section were smaller in BIOT-8 than CI-8. Spleen giant cells were significantly higher in CI-8 than in BIOT-8 (P < 0.01). Eight-week-old animals treated with biotherapy showed higher parasitemia and lower tissue parasitism. Opposite pattern was observed in four-week-old animals.. There is a difference of high diluted medication effect in four and eight-week-old mice. In the group of animals 8 weeks the immunomodulatory effect seems to have been higher. Hence, treatment with the medicine produced from T. cruzi modulates the inflammatory response with increased apoptosis and decreased serum levels of TGF-β.

Topics: Animals; Biological Therapy; Chagas Disease; Homeopathy; Inflammation; Liver; Male; Mice; Transforming Growth Factor beta; Trypanosoma cruzi

Mesenchymal stromal cells deploy immune suppressive properties amenable for use as cell therapy for inflammatory disorders. It is now recognized that mesenchymal stromal cells necessitate priming with an inflammatory milieu, in particular interferon-γ, to exert augmented immunosuppressive effects. It has been recently suggested that the heme-catabolizing enzyme heme oxygenase-1 is an essential component of the mesenchymal stromal cell-driven immune suppressive response. Because mesenchymal stromal cells upregulate indoleamine 2,3-dioxygenase expression on interferon-γ priming and indoleamine 2,3-dioxygenase requires heme as a cofactor for optimal catabolic function, we investigated the potential antagonism of heme oxygenase-1 activity on indoleamine 2, 3-dioxygenase and the impact on mesenchymal stromal cell immune plasticity. We herein sought to evaluate the molecular genetic effect of cytokine priming on human mesenchymal stromal cell heme oxygenase-1 expression and its functional role in differentially primed mesenchymal stromal cells. Contrary to previous reports, messenger RNA and protein analyses demonstrated that mesenchymal stromal cells derived from normal subjects (n = 6) do not express heme oxygenase-1 at steady state or after interferon-γ, tumor necrosis factor-α, and/or transforming growth factor-β priming. Pharmacological inhibition of heme oxygenase-1 with the use of tin protoporphyrin did not significantly abrogate the ability of mesenchymal stromal cells to suppress T-cell proliferation in vitro. Overall, these results unequivocally demonstrate that under steady state and after cytokine priming, human mesenchymal stromal cells immunoregulate T-cell proliferation independent of heme oxygenase-1.

Topics: Adolescent; Adult; Cell Proliferation; Cell- and Tissue-Based Therapy; Cells, Cultured; Female; Heme; Heme Oxygenase-1; Humans; Immune Tolerance; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inflammation; Interferon-gamma; Lymphocyte Activation; Male; Mesenchymal Stem Cells; Metalloporphyrins; Protoporphyrins; T-Lymphocytes; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Young Adult

Previous studies demonstrated a strong association between low androgen levels and reduced capacity to mount an inflammatory response. However, the mechanisms underlying these observations are largely not understood.. Generation of CD4+CD25+Foxp3+ regulatory T cells in Leydig cell-conditioned media was determined by flow cytometry and ELISA. Influence of testosterone on cytokine response was measured in LPS-stimulated testicular macrophages, Sertoli and peritubular cells.. Leydig cell-conditioned media dose-dependently stimulated expression of transcription factor Foxp3 and secretion of IL-10 in splenic CD4+ T cells, an effect abolished by addition of the anti-androgen flutamide. In isolated Sertoli and peritubular cells, testosterone pre-treatment suppressed the LPS-induced inflammatory response on TNF-α mRNA expression, while no effect was evident in testicular macrophages (TM).. Androgens can influence the immune system under normal conditions by the generation and functional differentiation of regulatory T cells and in testicular inflammation by direct effect on Sertoli and peritubular cells.

Topics: Androgen Antagonists; Animals; Cell Differentiation; Cells, Cultured; Chemokine CCL2; Culture Media, Conditioned; Flutamide; Forkhead Transcription Factors; Inflammation; Interleukin-10; Leydig Cells; Macrophages; Male; Rats; Rats, Wistar; RNA, Messenger; Sertoli Cells; T-Lymphocytes, Regulatory; Testosterone; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Phagocytosis of apoptotic cells (ACs) is usually a potent immunoregulatory signal but can also promote inflammation. In this article, we show that administration of apoptotic dendritic cells (DCs) inhibited inflammation in vivo through increasing production of TGF-β from intrinsic DCs and B cells. However, ACs derived from LPS-activated DCs failed to restrain inflammation because of a short-lived but marked IL-6 response, which abolished the increase in TGF-β. Inhibition of IL-6 restored the protective anti-inflammatory properties of aACs and the TGF-β response. DCs isolated from mice that had received resting but not activated ACs could transfer the suppression of inflammation to recipient mice. These transferred DCs stimulated B cell TGF-β production and relied on an intact B cell compartment to limit inflammation. These results highlight how the activation state of AC governs their ability to control inflammation through reciprocal regulation of IL-6 and TGF-β.

Topics: Animals; Apoptosis; Arthritis, Experimental; Dendritic Cells; Flow Cytometry; Inflammation; Interleukin-6; Macrophages; Mice; Mice, Inbred C57BL; Microscopy, Confocal; Phagocytosis; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta

The immunomodulatory properties of human amnion epithelial cells (hAECs) have been previously described in several disease models. We previously reported on the ability of hAECs to influence macrophage phenotype and chemotaxis. In this study, we aim to elucidate the contribution of regulatory T cells (Tregs) to macrophage polarisation and downstream effects on inflammation and fibrosis in a bleomycin model of lung injury.. Either CD45(+)/FoxP3(+) Tregs or CD45(+)/FoxP3 (-) non-Tregs were adoptively transferred into Rag1 (-/-) mice immediately prior to bleomycin challenge. Four million hAECs were administered 24 hours later. Outcomes were measured 7 or 14 days later.. Mitigation of lung inflammation and fibrosis was observed only in animals that received both hAECs and Tregs. hAEC treatment also induced the maturation of non-Tregs into FoxP3-expressing Tregs. This event was found to be transforming growth factor-beta (TGFβ)-dependent. Furthermore, polarisation of macrophages from M1 to M2 occurred only in animals that received hAECs and Tregs.. This study provides the first evidence that Tregs are required for hAEC-mediated macrophage polarisation and consequential mitigation of bleomycin-induced lung injury. Uncovering the interactions between hAECs, macrophages, and T-cell subsets is central to understanding the mechanisms by which hAECs elicit lung repair.

Topics: Amnion; Animals; Bleomycin; Cell Differentiation; Cells, Cultured; Coculture Techniques; Disease Models, Animal; Epithelial Cells; Fibrosis; Forkhead Transcription Factors; Homeodomain Proteins; Inflammation; Leukocyte Common Antigens; Lung; Lung Injury; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Increasing evidence shows that microRNAs play an important role in kidney disease. However, functions of long noncoding RNAs (lncRNAs) in kidney diseases remain undefined. We have previously shown that TGF-β1 plays a diverse role in renal inflammation and fibrosis and Smad3 is a key mediator in this process. In this study, we used RNA-sequencing to identify lncRNAs related to renal inflammation and fibrosis in obstructive nephropathy induced in Smad3 wild-type and knockout mice. We found that Arid2-IR was a Smad3-associated lncRNA as a Smad3 binding site was found in the promoter region of Arid2-IR and deletion of Smad3 abolished upregulation of Arid2-IR in the diseased kidney. In vitro knockdown of Arid2-IR from tubular epithelial cells produced no effect on TGF-β-induced Smad3 signaling and fibrosis but inhibited interleukin-1β-stimulated NF-κB-dependent inflammatory response. In contrast, overexpression of Arid2-IR promoted interleukin-1β-induced NF-κB signaling and inflammatory cytokine expression without alteration of TGF-β1-induced fibrotic response. Furthermore, treatment of obstructed kidney with Arid2-IR shRNA blunted NF-κB-driven renal inflammation without effect on TGF-β/Smad3-mediated renal fibrosis. Thus, Arid2-IR is a novel lncRNA that functions to promote NF-κB-dependent renal inflammation. Blockade of Arid2-IR may represent a novel and specific therapy for renal inflammatory disease.

Topics: Animals; Cells, Cultured; Gene Knockdown Techniques; Genetic Therapy; Inflammation; Interleukin-1beta; Kidney; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; NF-kappa B; RNA, Long Noncoding; Sequence Analysis, RNA; Signal Transduction; Smad3 Protein; Transcription Factors; Transforming Growth Factor beta

Hyperuricemia is an independent risk factor for CKD and contributes to kidney fibrosis. In this study, we investigated the effect of EGF receptor (EGFR) inhibition on the development of hyperuricemic nephropathy (HN) and the mechanisms involved. In a rat model of HN induced by feeding a mixture of adenine and potassium oxonate, increased EGFR phosphorylation and severe glomerular sclerosis and renal interstitial fibrosis were evident, accompanied by renal dysfunction and increased urine microalbumin excretion. Administration of gefitinib, a highly selective EGFR inhibitor, prevented renal dysfunction, reduced urine microalbumin, and inhibited activation of renal interstitial fibroblasts and expression of extracellular proteins. Gefitinib treatment also inhibited hyperuricemia-induced activation of the TGF-β1 and NF-κB signaling pathways and expression of multiple profibrogenic cytokines/chemokines in the kidney. Furthermore, gefitinib treatment suppressed xanthine oxidase activity, which mediates uric acid production, and preserved expression of organic anion transporters 1 and 3, which promotes uric acid excretion in the kidney of hyperuricemic rats. Thus, blocking EGFR can attenuate development of HN via suppression of TGF-β1 signaling and inflammation and promotion of the molecular processes that reduce uric acid accumulation in the body.

Topics: Animals; Chemokines; Cytokines; Disease Progression; ErbB Receptors; Fibroblasts; Fibrosis; Gefitinib; Hyperuricemia; Inflammation; Kidney; Kidney Diseases; Male; Phosphorylation; Quinazolines; Rats; Rats, Sprague-Dawley; Risk Factors; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1; Uric Acid

The pathological change of kidney in diabetic nephropathy is represented hypertrophy, inflammation, and renal fibrosis. Oryeongsan, traditional oriental herbal formula, is widely used for the treatment of nephrosis, dropsy, and uremia. This study was examined whether Oryeongsan attenuate high-glucose (HG)-promoted rat mesangial cell fibrosis and matrix accumulation, major features of diabetic glomerulosclerosis.. Oryeongsan was mixed traditional herbal medicine, Alisma orientale Juz, Polyporus umbellatus Fries, Atractylodes macrocephala Koidez, Poria cocos Wolf and Cinnamomum Cassia Presl (5:3:3:1). Renoprotective role in diabetic nephropathy of Oryeongsan was evaluated by [(3)H]-thymidine incorporation, Western blot, RT-qPCR and immunofluorescence microscopy assay.. Rat mesangial cell proliferation induced by HG was significantly accelerated, which was inhibited by Oryeongsan in a dose dependent manner. HG enhanced expression of fibrosis biomarkers such as collagen IV and connective tissue growth factor (CTGF), which was markedly attenuated by Oryeongsan. Oryeongsan increased HG-inhibited membrane type-1 matrix metalloproteinase expression (MT1-MMP) and MMP-2 promotor activity, whereas suppressed HG-induced tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) expression. Moreover, Oryeongsan promoted extracellular matrix degradation through disturbing transforming growth factor β (TGF-β)-Smad signaling. This study further revealed that Oryeongsan ameliorated HG-induced mesangial inflammation accompanying induction of intracellular cell adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1). Moreover, pretreatment of Oryeongsan inhibited NF-κB translocation in HG-exposed mesangial cell.. These results demonstrate that Oryeongsan has protective effect against renal proliferation, fibrosis, and inflammation. Therefore Oryeongsan may be specific therapies targeting renal dysfunction leading to diabetic nephropathy.

Topics: Animals; Chemokine CCL2; Diabetic Nephropathies; Fibrosis; Glomerular Mesangium; Glucose; Inflammation; Intercellular Adhesion Molecule-1; Magnoliopsida; Matrix Metalloproteinase 14; Matrix Metalloproteinase 2; Mesangial Cells; NF-kappa B; Phytotherapy; Plant Extracts; Polyporaceae; Rats; Signal Transduction; Smad Proteins; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta

Periodontitis is the most prevalent infectious disease caused by periodontopathic bacteria and is also a chronic inflammatory disease. Gingival crevicular fluid (GCF) is an inflammatory exudate that seeps into the gingival crevices or periodontal pockets around teeth with inflamed gingiva, and contains various materials including leukocytes and cytokines. Since gingival epithelial cells, which form a barrier against bacterial challenges, are affected by GCF, cytokines or other materials contained within GCF are engaged in the maintenance and disruption of the epithelial barrier. Accordingly, its compositional pattern has been employed as a reliable objective index of local inflammation. Transforming growth factor β1 (TGF-β1) levels in GCF were previously shown to be markedly higher in patients with periodontitis than in healthy subject. However, it currently remains unclear how TGF-β1 affects gingival epithelial cell growth or apoptosis; therefore, elucidating the mechanism responsible may lead to a deeper understanding of pathogenic periodontitis. In the present study, the human gingival epithelial cell line, OBA9 cells were stimulated with recombinant TGF-β1. Apoptosis-related protein levels were determined by Western blotting. Caspase-3/7 activity was measured with a Caspase-Glo assay kit. Surviving and apoptotic cells were detected using an MTS assay and TUNEL staining, respectively. TGF-βRI siRNA and smad2 siRNA were transfected into cells using the lipofectamine RNAiMAX reagent. TGF-β1 elevated caspase-3 activity and the number of TUNEL-positive apoptotic cells in OBA9 cells. Furthermore, while the levels of the pro-apoptotic proteins Bax, Bak, Bim, and Bad were increased in OBA9 cells stimulated with TGF-β1, the TGF-β1 treatment also decreased the levels of anti-apoptotic proteins such as Bcl-2 and Bcl-xL in a time-dependent manner. Additionally, TGF-β1 up-regulated the protein levels of cleaved caspase-9. These results indicated that TGF-β1-induced apoptosis was involved in a mitochondria-related intrinsic pathway. TGF-β1 phosphorylated smad2 in OBA9 cells and this phosphorylation was clearly reduced by SB431542 (a TGF-β type I receptor inhibitor). Consistent with this result, SB431542 or smad2 siRNA-induced reductions in smad2 protein expression levels attenuated TGF-β1-induced apoptosis. On the other hand, the ligation of TGF-β1 on its receptor also stimulated the phosphorylation of Erk and Akt, which are smad2-independent pathways. However, the

Topics: Acetylcysteine; Apoptosis; Benzamides; Caspase 3; Caspase 7; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dioxoles; Epithelial Cells; Extracellular Signal-Regulated MAP Kinases; Gingiva; Humans; Inflammation; MAP Kinase Signaling System; Periodontitis; Phosphorylation; Proto-Oncogene Proteins c-akt; RNA, Small Interfering; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta; Transforming Growth Factor beta1

Fibrosis in the old mouse heart arises partly as a result of aberrant mesenchymal fibroblast activation. We have previously shown that endogenous mesenchymal stem cells (MSCs) in the aged heart are markedly resistant to TGF-β signaling. Fibroblasts originating from these MSCs retain their TGF-β unresponsiveness and become inflammatory. In current studies, we found that these inflammatory fibroblasts secreted higher levels of IL-6 (3-fold increase, P < 0.05) when compared with fibroblasts derived from the young hearts. Elevated IL-6 levels in fibroblasts derived from old hearts arose from up-regulated expression of Ras protein-specific guanine nucleotide releasing factor 1 (RasGrf1), a Ras activator (5-fold, P < 0.01). Knockdown of RasGrf1 by gene silencing or pharmacologic inhibition of farnesyltransferase (FTase) or ERK caused reduction of IL-6 mRNA (more than 65%, P < 0.01) and decreased levels of secreted IL-6 (by 44%, P < 0.01). In vitro, IL-6 markedly increased monocyte chemoattractant protein-1-driven monocyte-to-myeloid fibroblast formation after transendothelial migration (TEM; 3-fold, P < 0.01). In conclusion, abnormal expression of RasGrf1 promoted production of IL-6 by mesenchymal fibroblasts in the old heart. Secreted IL-6 supported conversion of monocyte into myeloid fibroblasts. This process promotes fibrosis and contributes to the diastolic dysfunction in the aging heart.

Topics: Aging; Animals; Cells, Cultured; Fibroblasts; Fibrosis; Heart; Inflammation; Interleukin-6; Male; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Monocytes; Myeloid Cells; Transforming Growth Factor beta

Microparticles (MPs) derived from kidney-derived mesenchymal stem cells (KMSCs) have recently been reported to ameliorate rarefaction of peritubular capillaries (PTC) in ischemic kidneys via delivery of proangiogenic effectors. This study aimed to investigate whether KMSC-derived MPs show anti-fibrotic effects by ameliorating endothelial-to-mesenchymal transition (EndoMT) in human umbilical vein endothelial cells (HUVEC) in vitro and by preserving PTC in kidneys with unilateral ureteral obstruction (UUO) in vivo.. MPs isolated from the supernatants of KMSC were co-cultured with HUVEC to assess their in vitro biologic effects on endothelial cells. Mice were treated with MPs via the tail vein after UUO injury to assess their anti-fibrotic and PTC sparing effects. Renal tubulointerstitial damage and inflammatory cell infiltration were examined with Masson's trichrome, F4/80 and α-smooth muscle actin (α-SMA) staining and PTC rarefaction index was determined by CD31 staining.. KMSC-derived MPs significantly ameliorated EndoMT and improved in vitro proliferation of TGF-β1 treated HUVEC. In vivo administration of KMSC-derived MPs significantly inhibited EndoMT of PTC endothelial cells and improved PTC rarefaction in UUO kidneys. Furthermore, administration of KMSC-derived MPs inhibited inflammatory cell infiltration as well as tubulointerstitial fibrosis in UUO mice as demonstrated by decreased F4/80 and α-SMA-positive cells and Masson's trichrome staining, respectively.. Our results suggest that KMSC-derived MPs ameliorate PTC rarefaction via inhibition of EndoMT and protect against progression of renal damage by inhibiting tubulointerstitial fibrosis.

Topics: Actins; Animals; Antigens, Differentiation; Cell Line; Cell Proliferation; Cell-Derived Microparticles; Coculture Techniques; Disease Models, Animal; Epithelial-Mesenchymal Transition; Fibrosis; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Kidney Tubules; Mesenchymal Stem Cells; Mice; Nephritis, Interstitial; Transforming Growth Factor beta; Ureteral Obstruction

Clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS) is the earliest clinically evident phase of the disease, which may provide valuable insight into the molecular mechanisms of the initiation of the autoimmune response in MS. Our results introduce IL-11 as a new cytokine that plays a role in the autoimmune response in the early phase of the disease. IL-11 is the highest upregulated cytokine in the sera and cerebrospinal fluid from CIS patients, which is also increased in patients with clinically definitive relapsing-remitting MS in comparison with healthy control subjects. Serum IL-11 levels are significantly increased during clinical exacerbations in comparison with remissions in the same patients. CD4(+) cells represent a predominant cell source of IL-11 in the peripheral circulation, and the percentage of IL-11(+)CD4(+) cells is significantly increased in CIS patients in comparison with healthy control subjects. Furthermore, we have identified IL-11 as a new Th17-promoting cytokine, because it induces a differentiation of naive CD4(+) T cells into Th17 cells, as well as expansion of Th17 memory cells. Because the Th17 cytokines IL-17F, IL-21 and TNF-α, and TGF-β induce differentiation of naive cells in the IL-11-secreting CD4(+) cells, we propose that cross-talk between IL-11(+)CD4(+) and Th17 cells may play a role in the inflammatory response in relapsing-remitting MS.

Topics: Adult; Autoimmunity; Cell Communication; Cell Differentiation; Female; Humans; Immunologic Memory; Inflammation; Interleukin-11; Interleukin-17; Interleukins; Male; Multiple Sclerosis, Relapsing-Remitting; Th17 Cells; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Percutaneous treatment with carbon dioxide (CO2) mist, CO2 gas dissolved in water, contributes to improved cardiac function after myocardial infarction (MI). In this study, we investigated the effects of repeated pretreatment with CO2 mist on cardiac dysfunction after MI. The CO2 mist was generated by a dry mist production unit. The whole body of rats below the axilla was wrapped in a polyethylene bag, which was sealed and filled with the CO2 mist in the draft cabinet for 30 min daily for 7 days. MI was induced by ligation of the coronary artery in untreated (UT), CO2 gas-pretreated (CG), and CO2 mist-pretreated (CM) rats. The infarct size and the increase in oxidative stress due to MI were significantly smaller in the CM rats than in the UT rats. Furthermore, the expression of inflammation-related genes, such as monocyte chemoattractant protein-1, and fibrosis-related genes, such as transforming growth factor-β1, was significantly suppressed in the CM rats. The CM rats had a better left ventricular ejection fraction than the UT rats 7 days after MI. These parameters in the CG rats were the same as in the UT group. Thus, CO2 mist preparative treatment may be potentially useful for the reduction of MI.

Topics: Administration, Topical; Animals; Carbon Dioxide; Chemokine CCL2; Disease Models, Animal; Fibrosis; Gene Expression; Inflammation; Male; Myocardial Infarction; Rats, Wistar; Stroke Volume; Transforming Growth Factor beta; Treatment Outcome; Water

In this study, we investigated the molecular mechanisms underlying the anti-inflammatory effects of α-chaconine in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and in LPS-induced septic mice. α-Chaconine inhibited the expressions of cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) at the transcriptional level, and attenuated the transcriptional activity of activator protein-1 (AP-1) by reducing the translocation and phosphorylation of c-Jun. α-Chaconine also suppressed the phosphorylation of TGF-β-activated kinase-1 (TAK1), which lies upstream of mitogen-activated protein kinase kinase 7 (MKK7)/Jun N-terminal kinase (JNK) signaling. JNK knockdown using siRNA prevented the α-chaconine-mediated inhibition of pro-inflammatory mediators. In a sepsis model, pretreatment with α-chaconine reduced the LPS-induced lethality and the mRNA and production levels of pro-inflammatory mediators by inhibiting c-Jun activation. These results suggest that the anti-inflammatory effects of α-chaconine are associated with the suppression of AP-1, and support its possible therapeutic role for the treatment of sepsis.

Topics: Animals; Cell Line; Cyclooxygenase 2; Endotoxins; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Macrophages; Male; MAP Kinase Kinase 4; MAP Kinase Kinase 7; Mice; Mice, Inbred C57BL; Phosphorylation; Solanine; Solanum tuberosum; Transcription Factor AP-1; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Inflammation and fibrosis are implicated in the pathogenesis of hypertensive kidney damage. We previously demonstrated that a nonspecific histone deacetylase (HDAC) inhibitor attenuates cardiac fibrosis in deoxycorticosterone acetate-salt hypertensive rats, which induces HDAC6 protein and enzymatic activity. However, the HDAC inhibitor's effect and mechanism have not yet been demonstrated. We sought to determine whether an HDAC6-selective inhibitor could treat hypertension and kidney damage in angiotensin II-infused mice. Hypertension was induced by infusion of ANG in mice. Tubastatin A, an HDAC6 selective inhibitor, did not regulate blood pressure. Hypertensive stimuli enhanced the expression of HDAC6 in vivo and in vitro. We showed that the inhibition of HDAC6 prevents fibrosis and inflammation as determined by quantitative real-time PCR, western blot, and immunohistochemistry. Small interfering RNA (siRNA) against HDAC6 or Smad3 attenuated hypertensive stimuli-induced fibrosis and inflammation, whereas Smad2 siRNA failed to inhibit fibrosis. Interestingly, the combination of the HDAC6 inhibitor and Smad3 knockdown synergistically blocked transforming growth factor β (TGF-β) or ANG-induced fibrosis. We also demonstrated for the first time, to our knowledge, that acetylation of collagen type I can be regulated by HDAC6/p300 acetyltransferase. The chromatin immunoprecipitation assay revealed that the HDAC6 inhibitor suppressed TGF-β-induced acetylated histone H4 or phospho-Smad2/3 to Smad3 binding elements in the fibrosis-associated gene promoters including collagen type I. These results suggest that HDAC6 may be a valuable therapeutic target for the treatment of hypertension-induced kidney fibrosis and inflammation.

Topics: Angiotensin II; Animals; Cells, Cultured; Collagen Type I; Epigenesis, Genetic; Fibrosis; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Hydroxamic Acids; Indoles; Inflammation; Kidney; Male; Mice; Mice, Inbred ICR; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta

Regulatory T (Treg) cells play a pivotal role in suppressing self-harmful T cell responses, but how Treg cells mediate suppression to maintain immune homeostasis and limit responses during inflammation is unclear. Here we show that effector Treg cells express high amounts of the integrin αvβ8, which enables them to activate latent transforming growth factor-β (TGF-β). Treg-cell-specific deletion of integrin αvβ8 did not result in a spontaneous inflammatory phenotype, suggesting that this pathway is not important in Treg-cell-mediated maintenance of immune homeostasis. However, Treg cells lacking expression of integrin αvβ8 were unable to suppress pathogenic T cell responses during active inflammation. Thus, our results identify a mechanism by which Treg cells suppress exuberant immune responses, highlighting a key role for effector Treg-cell-mediated activation of latent TGF-β in suppression of self-harmful T cell responses during active inflammation.

Topics: Animals; Cell Proliferation; Colitis; Disease Models, Animal; Gene Expression Regulation; Humans; Inflammation; Inflammation Mediators; Integrins; Mice; Models, Immunological; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

TGF-β signaling plays critical roles in the pathogenesis of aneurysms; however, it is still unclear whether its role is protective or destructive. In this study, we investigate the role of SMAD3 in the pathogenesis of calcium chloride (CaCl2)-induced abdominal aortic aneurysms (AAA) in Smad3(-/-), Smad3(+/-) and Smad3(+/+) mice. We find that loss of SMAD3 drastically increases wall thickening of the abdominal aorta. Histological analyses show significant vessel wall remodeling with elastic fiber fragmentation. Remarkably, under polarized light, collagen fibers in the hyperplastic adventitia of Smad3(-/-) mice show extensive reorganization accompanied by loosely packed thin and radial collagen fibers. The expressions of matrix metalloproteinases including MMP2, MMP9, and MMP12 and infiltration of macrophage/T cells are drastically enhanced in the vascular wall of Smad3(-/-) mice. We also observe marked increase of NF-κB and ERK1/2 signaling as well as the expression of nuclear Smad2, Smad4 and TGF-β1 in the vessel wall of Smad3(-/-) mice. In addition, we find that SMAD3 expression is reduced in the dedifferentiated medial smooth muscle-like cells of human AAA patients. These findings provide direct in vivo evidence to support the essential roles of SMAD3 in protecting vessel wall integrity and suppressing inflammation in the pathogenesis of AAAs.

Topics: Animals; Aortic Aneurysm, Abdominal; Atrial Remodeling; Calcium Chloride; Collagen; Disease Models, Animal; Elastin; Extracellular Matrix; Gene Expression Regulation; Inflammation; Leukocytes; Matrix Metalloproteinases; Mice; Mice, Knockout; NF-kappa B; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta

Inflammation is regulated by endogenous mechanisms, including anti-inflammatory cytokines, adenosine, and the nicotinic acetylcholine receptor α7 subunit (α7nAChR). We investigated the role of α7nAChR in protection against the progression of tissue injury in a model of severe, macrophage-mediated, cytokine-dependent anti-glomerular basement membrane (GBM) glomerulonephritis (GN), in α7nAChR-deficient (α7(-/-)) mice . At d 7 after the injection of anti-GBM antibody, kidneys from α7(-/-) mice displayed severe glomeruli (P < 0.0001) and tubulointerstitial lesions (P < 0.001) compared to kidneys from WT mice. An important finding was the presence of severe glomerulosclerosis in α7(-/-) mice in this early phase of the disease. Kidneys of α7(-/-) mice showed greater accumulation of inflammatory cells and higher expression of chemokines and cytokines than did those of WT mice. In addition, in α7(-/-) fibrotic kidneys, the expression of fibrin, collagen, TGF-β, and tissue inhibitor of metalloproteinase (TIMP)-2 increased, and the expression of TIMP3 declined. The increase in counterregulatory responses to inflammation in α7(-/-) nephritic kidneys did not compensate for the lack of α7nAChR. These findings indicate that α7nAChR plays a key role in regulating the inflammatory response in anti-GBM GN and that disruption of the endogenous protective α7nAChR amplifies inflammation to accelerate kidney damage and fibrosis.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Collagen; Cytokines; Disease Models, Animal; Female; Fibrin; Fibrosis; Glomerular Basement Membrane; Glomerulonephritis; Inflammation; Kidney; Macrophages; Male; Mice; Mice, Inbred C57BL; Protein Subunits; Tissue Inhibitor of Metalloproteinase-2; Tissue Inhibitor of Metalloproteinase-3; Transforming Growth Factor beta

Subclinical rejection diagnosed from protocol biopsies is thought to be a risk factor of long- term allograft dysfunction. The reason why in some patients subclinical rejection does not represent risk for progression is not fully understood.. The intragraft expression of 376 target genes involved in chemokine defense, apoptosis, inflammation, tolerance and TGF-β signalling pathways was measured using quantitative real-time RT-PCR (2(-)∆∆(Ct)) method in subclinical inflammation (SCI, n=10), clinical inflammation in acute T-cell mediated rejection (CI, n=10) and no rejection samples (n=9).. Clinical inflammation group showed a increased expression of genes for chemotaxis mediating cytokines (CCL1, CCL17, CCL24, CCL25, CCL26), cytokine receptors (CCR1, CCRL2, IL1RAPL2, CXCR5), proinflammatory cytokines (IL12A, LTA), inflammatory mediator (PTAFR), complement protein C3, executioner protein of apoptosis (CASP7), growth factor (TGFA), colony stimulating factor (CSF-2), proteins involved in dendritic cells differentiation and interaction (CD209, LAMP3), regulation of immune response (LILRB2, LILBRB4). The quantitative difference in transcripts signature between SCI and CI is consistent with stronger proinflammatory setting of CI. Prostaglandin E2 receptor gene expression was independently associated with lower risk of further graft function deterioration (OR 0.11, CI 0.01-0.78, p<0.0001).. Subclinical acute kidney inflammation has transcriptional profile of immune injury of lower extend compared to clinical acute inflammation.

Topics: Adult; Aged; Apoptosis; Biopsy; Chemokines; Cytokines; Disease Progression; Female; Gene Expression; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Inflammation; Inflammation Mediators; Kidney Transplantation; Male; Middle Aged; Receptors, Cytokine; Risk; RNA; Signal Transduction; Transforming Growth Factor beta; Treatment Outcome

Monocytes (Mos) play an important role in the pathogenesis of intestinal mucosal inflammation. This study aims to investigate the mechanism by which the intestinal epithelial cell-derived thrombospondin 1 (TSP1) modulates Mo properties and regulates intestinal inflammatory responses. In this study, the production of TSP1 by intestinal epithelial cells was evaluated by quantitative real-time PCR and Western blotting. The properties of Mos were analyzed by flow cytometry. A mouse model of colitis was created to assess the role of epithelium-derived TSP1 in the suppression of intestinal inflammation. The results demonstrated that mouse intestinal epithelial cells (IECs) expressed TSP1, which was markedly upregulated by butyrate or feeding with Clostridium butyricum. Coculture of the butyrate-primed IECs and Mos or exposure of Mos to TSP1 in the culture induced the expression of transforming growth factor (TGF)-β in Mos. These TGF-β+ Mos had tolerogenic properties that could promote generation of inducible regulatory T cells. Adoptive transfer with TSP1-primed Mos, or feeding C. butyricum could prevent experimental colitis in mice. In summary, C. butyricum induces intestinal epithelial cells to produce TSP1 and induces TGF-β+ Mos, which further suppress experimental colitis in mice. The results implicate that the administration of C. butyricum or butyrate may have the potential to ameliorate chronic intestinal inflammation through inducing immunosuppressive Mos.

Topics: Animals; Butyrates; Clostridium butyricum; Colitis; Disease Models, Animal; Inflammation; Intestinal Mucosa; Male; Mice; Mice, Knockout; Monocytes; Thrombospondin 1; Transforming Growth Factor beta

Laquinimod, is a potential oral immunomodulatory drug, for relapsing-remitting multiple sclerosis (RRMS). We analyzed the blood-transcriptional changes in RRMS patients (who participated in the ALLEGRO clinical trial) at one and six months after laquinimod treatment using gene expression microarrays. The molecular effects of laquinimod were enhanced by duration of treatment and showed down-regulation of inflammatory responses mainly via TGFb signaling, and of pro-inflammatory cytokines as well as of cellular movement, including adhesion, migration and leukocyte extravasation signaling. Our results demonstrate that laquinimod suppresses inflammation through down-regulation of inflammatory cytokines and arrest of leukocyte extravasation and thereby could attenuate disease activity in RRMS patients.

Topics: Adult; Cell Adhesion; Chemotaxis, Leukocyte; Cytokines; Down-Regulation; Female; Gene Expression Profiling; Gene Expression Regulation; Humans; Immunologic Factors; Inflammation; Male; Multiple Sclerosis, Relapsing-Remitting; NF-kappa B; Quinolones; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta

Chronic rhinosinusitis with (CRSwNP) and without nasal polyps (CRSsNP) should be regarded as distinct clinical entities based on differential inflammatory mediator and remodeling profiles. Activin A, a member of the TGF-β superfamily, plays an important role in inflammation and remodeling in the lower airways, although its expression and release in the upper airways remain undescribed.. To investigate the expression of activin A and its inhibitor follistatin in nasal tissue samples from CRSsNP and CRSwNP patients, and to monitor the spontaneous release of these molecules in a human mucosal model.. Protein levels were determined using ELISA for activin A, follistatin, TGF-β1 and indicator proteins (IL-5, ECP, IFNγ) in 13 CRSsNP, 23 CRSwNP, and 10 control samples. The spontaneous release rate and the release ratios of activin A, follistatin and TGF-β1 were determined in 9 CRSsNP and 7 CRSwNP tissue fragments cultured ex-vivo. The induction of activin A and TGF-β1 by one another was studied in 7 CRSsNP tissue fragments cultured ex-vivo.. Significantly higher concentrations of activin A, follistatin, TGF-β1, and IFNγ were observed in CRSsNP compared with CRSwNP samples, whereas the concentrations of IL-5 and ECP were significantly lower. Follistatin was positively and linearly correlated with activin A in CRSsNP and CRSwNP. Activin A, follistatin and TGF-β1 were all spontaneously released by the samples, although the relative ratios released by tissue fragments from CRSsNP and CRSwNP samples were significantly different, with a higher follistatin/activin A-ratio and a follistatin/TGFß1-ratio (with less overall TGF-β1) in CRSwNP than in CRSsNP. Furthermore, TGF-β1 enhanced activin A secretion in CRSsNP tissue fragments cultured ex-vivo.. The differences in tissue concentrations and spontaneous release rates for activin A and follistatin in different CRS samples support the hypothesis that CRSsNP and CRSwNP are two distinct disease entities with respect to remodeling patterns.

Topics: Activins; Adolescent; Adult; Aged; Aged, 80 and over; Chronic Disease; Extracellular Matrix Proteins; Female; Follistatin; Humans; Inflammation; Interferon-gamma; Interleukin-5; Male; Middle Aged; Nasal Polyps; Sinusitis; Transforming Growth Factor beta; Young Adult

The CCN family member 2 (CCN2, also known as connective tissue growth factor) may behave as a risk biomarker and a potential therapeutic target for renal disease. CCN2 participates in the regulation of inflammation and fibrosis. TGF-β is considered the main fibrogenic cytokine; however, in some pathological settings TGF-β also has anti-inflammatory properties. CCN2 has been proposed as a downstream profibrotic mediator of TGF-β, but data on TGF-β role in CCN2 actions are scarce. Our aim was to evaluate the effect of TGF-β blockade in CCN2-mediated experimental renal damage. Systemic administration of the C-terminal module of CCN2 to mice caused sustained renal inflammation. In these mice, TGF-β blockade, using an anti-TGF-β neutralizing antibody, significantly increased renal expression of the NGAL (a kidney injury biomarker), kidney infiltration by monocytes/macrophages, and upregulation of MCP-1 expression. The anti-inflammatory effect of TGF-β seems to be mediated by a dysregulation of the systemic Treg immune response, shown by decreased levels of circulating CD4(+)/Foxp3(+)Treg cells. Our experimental data support the idea that TGF-β exerts anti-inflammatory actions in the kidney and suggest that it is not an optimal therapeutic target.

Topics: Animals; Connective Tissue Growth Factor; Flow Cytometry; Immunohistochemistry; Inflammation; Kidney; Male; Mice; Mice, Inbred C57BL; Receptors, CCR2; Transforming Growth Factor beta

Areca nut consumption has been implicated in the progression of Oral Submucous fibrosis (OSF); an inflammatory precancerous fibrotic condition. Our previous studies have demonstrated the activation of TGF-β signaling in epithelial cells by areca nut components and also propose a role for epithelial expressed TGF-β in the pathogenesis of OSF. Although the importance of epithelial cells in the manifestation of OSF has been proposed, the actual effectors are fibroblast cells. However, the role of areca nut and TGF-β in the context of fibroblast response has not been elucidated. Therefore, to understand their role in the context of fibroblast response in OSF pathogenesis, human gingival fibroblasts (hGF) were treated with areca nut and/or TGF-β followed by transcriptome profiling. The gene expression profile obtained was compared with the previously published transcriptome profiles of OSF tissues and areca nut treated epithelial cells. The analysis revealed regulation of 4666 and 1214 genes by areca nut and TGF-β treatment respectively. The expression of 413 genes in hGF cells was potentiated by areca nut and TGF-β together. Further, the differentially expressed genes of OSF tissues compared to normal tissues overlapped significantly with areca nut and TGF-β induced genes in epithelial and hGF cells. Several positively enriched pathways were found to be common between OSF tissues and areca nut +TGF-β treated hGF cells. In concordance, areca nut along with TGF-β enhanced fibroblast activation as demonstrated by potentiation of αSMA, γSMA and collagen gel contraction by hGF cells. Furthermore, TGF-β secreted by areca nut treated epithelial cells influenced fibroblast activation and other genes implicated in fibrosis. These data establish a role for areca nut influenced epithelial cells in OSF progression by activation of fibroblasts and emphasizes the importance of epithelial-mesenchymal interaction in OSF.

Topics: Areca; Cluster Analysis; Collagen; Disease Progression; Epithelial Cells; Epithelial-Mesenchymal Transition; Fibroblasts; Gene Expression Profiling; Genome, Human; Gingiva; Humans; Inflammation; Nuts; Oligonucleotide Array Sequence Analysis; Oral Submucous Fibrosis; Precancerous Conditions; Signal Transduction; Transcriptome; Transforming Growth Factor beta

Ultraviolet B (UVB) irradiation may cause inflammation- and oxidative-stress-dependent skin cancer and premature aging. Naringenin (1) has been reported to have anti-inflammatory and antioxidant properties, but its effects and mechanisms on UVB irradiation-induced inflammation and oxidative stress are still not known. Thus, the present study aimed to investigate the potential of naringenin to mitigate UVB irradiation-induced inflammation and oxidative damage in the skin of hairless mice. Skin edema, myeloperoxidase (neutrophil marker) and matrix metalloproteinase-9 (MMP-9) activity, and cytokine production were measured after UVB irradiation. Oxidative stress was evaluated by 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS) scavenging ability, ferric reducing antioxidant power (FRAP), reduced glutathione levels, catalase activity, lipid peroxidation products, superoxide anion production, and gp91phox (NADPH oxidase subunit) mRNA expression by quantitative PCR. The intraperitoneal treatment with naringenin reduced skin inflammation by inhibiting skin edema, neutrophil recruitment, MMP-9 activity, and pro-inflammatory (TNF-α, IFN-γ, IL-1β, IL-4, IL-5, IL-6, IL-12, IL-13, IL-17, IL-22, and IL-23) and anti-inflammatory (TGF-β and IL-10) cytokines. Naringenin also inhibited oxidative stress by reducing superoxide anion production and the mRNA expression of gp91phox. Therefore, naringenin inhibits UVB irradiation-induced skin damage and may be a promising therapeutic approach to control skin disease.

Topics: Animals; Antioxidants; Benzothiazoles; Flavanones; Glutathione; Inflammation; Interleukin-10; Interleukin-12; Interleukin-17; Interleukin-22; Interleukin-4; Interleukin-6; Interleukins; Lipid Peroxidation; Male; Mice; Mice, Hairless; Molecular Structure; Oxidative Stress; Skin; Sulfonic Acids; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Ultraviolet Rays

Prospective in vivo rodent model of bone morphogenetic protein (BMP)-induced inflammation.. To evaluate the effects of the coadministration of the nonsteroidal anti-inflammatory drug, diclofenac, on BMP-induced inflammation using our rodent model.. The use of BMP-2 is associated with inflammation in the neck and back. We have previously reported on a rodent model of BMP-2-induced inflammation.. Seven treatment groups were: Surgery alone; absorbable collagen sponges (ACS) alone; 20 μg rhBMP-2 on ACS with no diclofenac; 20 μg rhBMP-2 on ACS+50 mg diclofenac injections; 20 μg rhBMP-2 on ACS+75 mg diclofenac; 20 μg rhBMP-2 on ACS+100 mg diclofenac; and 20 μg rhBMP-2 on ACS+125 mg diclofenac. Using magnetic resonance imaging, inflammation (soft tissue edema volume) was assessed at 3 hours and at 2, 7, and 14 days after implantation. Western blot analysis, histology, and immunohistochemical staining were performed to compare the inflammatory response between groups. The mass size and tissue density of bone formation were compared between groups using plain radiography.. Soft-tissue edema volumes in all diclofenac-treated groups were significantly lower than those observed in the rhBMP-2 alone. There was no significant difference in soft tissue edema volumes between 4 diclofenac-treated groups. The expression of NF-κB signaling pathway related proteins (p65 and p-p65) were increased in the rhBMP-2+ACS group and decreased in diclofenac treatment groups. Histological findings and immunohistochemical staining were consistent with the Western blot results. There was no significant difference between the rhBMP-2+ACS group and diclofenac treatment groups in terms of the mass size and tissue density of bone formation.. Coadministration of diclofenac sodium can reduce the inflammatory response to BMP-2 without impairing heterotopic bone formation in our rodent model of BMP-2-induced inflammation.. N/A.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Back; Bone Morphogenetic Protein 2; Cytokines; Diclofenac; Drug Implants; Edema; Inflammation; Magnetic Resonance Imaging; Male; Osteogenesis; Porifera; Prospective Studies; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Transforming Growth Factor beta

Pingchuan Formula (PCF) is a traditional Chinese recipe. PCF improves chronic airway inflammation by correcting the imbalance of T-helper cell ratio. The purpose of this study was to investigate the effect of PCF on pathological changes in the lungs of asthmatic mice in terms of Treg/Th17 balance.. A bronchial asthma BALB/c mouse model was established using the ovalbumin excitation method. Distilled water (for MDL group) and drugs (for DEX or PCF group) were administered by gavage immediately after the first excitation. Mice were sacrificed after 7 and 28 d treatment. Lung tissues and bronchoalveolar lavage fluid were collected and lung pathological changes were observed after hematoxylin and eosin staining. Differential cell counts, concentrations of interleukins-6, -17, -23 and TGF-β in bronchoalveolar lavage fluid were determined by enzyme-linked immunosorbent assay. Expression of transcriptional factors Foxp3 and RORγt was determined by immunohistochemistry and immunoblot.. An asthma model was successfully established. After 7 or 28 d treatment, lung pathological changes were improved and concentration of interleukins-6, -17, -23 and TGF-β in bronchoalveolar lavage fluid significantly decreased in the PCF group. RORγt expression in lung tissue was decreased in the PCF group, while Foxp3 expression increased (all P values<0.05 compared with the MDL group). There was no significant difference between the PCF and DEX group except that mice in the PCF group lost less bodyweight.. Treatment with PCF downregulates RORγt, elevates Foxp3 expression, reduces interleukins-6, -17, -23 and TGF-β in bronchoalveolar lavage fluid, thus restoring Th17/Treg balance, improving airway inflammation and reducing asthma symptoms.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Drugs, Chinese Herbal; Enzyme-Linked Immunosorbent Assay; Inflammation; Lung; Magnoliopsida; Male; Mice; Mice, Inbred BALB C; Ovalbumin; Phytotherapy; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

Topics: Extracellular Matrix Proteins; Eye Proteins; Humans; Inflammation; Osteonectin; Tenascin; Transforming Growth Factor beta

The etiology of schistosomiasis-associated pulmonary arterial hypertension (PAH), a major cause of PAH worldwide, is poorly understood. Schistosoma mansoni exposure results in prototypical type-2 inflammation. Furthermore, transforming growth factor (TGF)-β signaling is required for experimental pulmonary hypertension (PH) caused by Schistosoma exposure.. We hypothesized type-2 inflammation driven by IL-4 and IL-13 is necessary for Schistosoma-induced TGF-β-dependent vascular remodeling.. Wild-type, IL-4(-/-), IL-13(-/-), and IL-4(-/-)IL-13(-/-) mice (C57BL6/J background) were intraperitoneally sensitized and intravenously challenged with S. mansoni eggs to induce experimental PH. Right ventricular catheterization was then performed, followed by quantitative analysis of the lung tissue. Lung tissue from patients with schistosomiasis-associated and connective tissue disease-associated PAH was also systematically analyzed.. Mice with experimental Schistosoma-induced PH had evidence of increased IL-4 and IL-13 signaling. IL-4(-/-)IL-13(-/-) mice, but not single knockout IL-4(-/-) or IL-13(-/-) mice, were protected from Schistosoma-induced PH, with decreased right ventricular pressures, pulmonary vascular remodeling, and right ventricular hypertrophy. IL-4(-/-)IL-13(-/-) mice had less pulmonary vascular phospho-signal transducer and activator of transcription 6 (STAT6) and phospho-Smad2/3 activity, potentially caused by decreased TGF-β activation by macrophages. In vivo treatment with a STAT6 inhibitor and IL-4(-/-)IL-13(-/-) bone marrow transplantation also protected against Schistosoma-PH. Lung tissue from patients with schistosomiasis-associated and connective tissue disease-associated PAH had evidence of type-2 inflammation.. Combined IL-4 and IL-13 deficiency is required for protection against TGF-β-induced pulmonary vascular disease after Schistosoma exposure, and targeted inhibition of this pathway is a potential novel therapeutic approach for patients with schistosomiasis-associated PAH.

Topics: Animals; Bone Marrow Transplantation; Cell Adhesion Molecules; Humans; Hypertension, Pulmonary; Inflammation; Intercellular Signaling Peptides and Proteins; Interleukin-13; Interleukin-4; Interleukin-4 Receptor alpha Subunit; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphorylation; Schistosoma mansoni; Schistosomiasis mansoni; Smad2 Protein; Smad3 Protein; STAT6 Transcription Factor; Th1 Cells; Th17 Cells; Transforming Growth Factor beta; Vascular Remodeling

Genetic loss of collagen VII causes recessive dystrophic epidermolysis bullosa (RDEB)-a severe skin fragility disorder associated with lifelong blistering and disabling progressive soft tissue fibrosis. Causative therapies for this complex disorder face major hurdles, and clinical implementation remains elusive. Here, we report an alternative evidence-based approach to ameliorate fibrosis and relieve symptoms in RDEB. Based on the findings that TGF-β activity is elevated in injured RDEB skin, we targeted TGF-β activity with losartan in a preclinical setting. Long-term treatment of RDEB mice efficiently reduced TGF-β signaling in chronically injured forepaws and halted fibrosis and subsequent fusion of the digits. In addition, proteomics analysis of losartan- vs. vehicle-treated RDEB skin uncovered changes in multiple proteins related to tissue inflammation. In line with this, losartan reduced inflammation and diminished TNF-α and IL-6 expression in injured forepaws. Collectively, the data argue that RDEB fibrosis is a consequence of a cascade encompassing tissue damage, TGF-β-mediated inflammation, and matrix remodeling. Inhibition of TGF-β activity limits these unwanted outcomes and thereby substantially ameliorates long-term symptoms.

Topics: Animals; Disease Models, Animal; Epidermolysis Bullosa Dystrophica; Immunologic Factors; Inflammation; Losartan; Mice; Proteome; Transforming Growth Factor beta; Treatment Outcome

Alternative medicines are commonly used for the disease prevention and treatment worldwide. Aristolochic acid (AAI) nephropathy (AAN) is a common and rapidly progressive interstitial nephropathy caused by ingestion of Aristolochia herbal medications. Available data on pathophysiology and molecular mechanisms of AAN are limited and were explored here. SD rats were randomized to AAN and control groups. AAN group was treated with AAI by oral gavage for 12 weeks and observed for additional 12 weeks. Kidneys were processed for histological evaluation, Western blotting, and metabolomics analyses using UPLC-QTOF/HDMS. The concentrations of two phosphatidylcholines, two diglycerides and two acyl-carnitines were significantly altered in AAI treated rats at week 4 when renal function and histology were unchanged. Data obtained on weeks 8 to 24 revealed progressive tubulointerstitial fibrosis, inflammation, renal dysfunction, activation of NF-κB, TGF-β, and oxidative pathways, impaired Nrf2 system, and profound changes in lipid metabolites including numerous PC, lysoPC, PE, lysoPE, ceramides and triglycerides. In conclusion, exposure to AAI results in dynamic changes in kidney tissue fatty acid, phospholipid, and glycerolipid metabolisms prior to and after the onset of detectable changes in renal function or histology. These findings point to participation of altered tissue lipid metabolism in the pathogenesis of AAN.

Topics: Animals; Aristolochic Acids; Disease Models, Animal; Fibrosis; Inflammation; Kidney; Lipids; Male; Metabolomics; Nephritis, Interstitial; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta; Triglycerides

Foxp3(+) T cells regulate inflammation and tumorigenesis. However, little is known about the role of different subsets of Foxp3(+) T cells in malignant or tuberculous hydrothorax.. The numbers of CD4(+)CD25(+)Foxp3(+), CD4(+)CD25(-)Foxp3(+) T cells and the levels of some inflammatory cytokines in patients with tuberculous hydrothorax, malignant hydrothorax, and healthy controls (HCs) were examined by flow cytometry and ELISA. The potential association between the numbers of different subsets of Foxp3 + T cells and the values of clinical measures were analyzed.. The numbers of peripheral blood CD4(+)CD25(+)Foxp3(+) T cells were greater in malignant hydrothorax patients than in HCs, but fewer than those of hydrothorax in patients. The percentages of circulating IL-10(+) or LAP(+) CD4(+)CD25(+)Foxp3(+) T cells were higher than in the hydrothorax in patients with malignant hydrothorax. The numbers of circulating CD4(+)CD25(-)Foxp3(+) T cells were significantly fewer in patients with tuberculous hydrothorax than in HCs, and both the numbers of circulating CD4(+)CD25(+)Foxp3(+) and CD4(+)CD25(-)Foxp3(+) T cells were significantly fewer than in the hydrothorax in patients. Significantly higher percentages of circulating IL-10(+) or LAP(+) CD4(+)CD25(+)Foxp3(+) and CD4(+)CD25(-)Foxp3(+) T cells were detected in tuberculous hydrothorax patients. The numbers of CD4(+)CD25(+)Foxp3(+) and CD4(+)CD25(-)Foxp3(+) T cells were associated with hydrothorax adenosine deaminase (ADA) levels in tuberculous hydrothorax patients, while CD4(+)CD25(+)Foxp3(+) T cells were associated with carcino-embryonic antigen (CEA) in malignant hydrothorax patients. The concentrations of serum IL-6 and TGF-β in the patients were significantly higher than that in the HCs, but lower than that in the corresponding hydrothorax. A similar pattern of IL-10 was observed in different groups, except that there was no significant difference in the levels of serum IL-10 between the tuberculous hydrothorax patients and HCs.. CD4(+)CD25(-)Foxp3(+) T cells, which have lower inhibitory function than CD4(+)CD25(+)Foxp3(+) T cells, may play a role in tuberculous hydrothorax.

Topics: Adenosine Deaminase; Adult; Aged; Case-Control Studies; CD4-Positive T-Lymphocytes; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Forkhead Transcription Factors; Humans; Hydrothorax; Inflammation; Interleukin-10; Interleukin-2 Receptor alpha Subunit; Interleukin-6; Male; Middle Aged; Transforming Growth Factor beta; Young Adult

Invariant NKT (iNKT) cell thymic development can lead to distinct committed effector lineages, namely NKT1, NKT2, and NKT17. However, following identification of IL-9-producing iNKT cells involved in mucosal inflammation, their development remains unaddressed. In this study, we report that although thymic iNKT cells from naive mice do not express IL-9, iNKT cell activation in the presence of TGF-β and IL-4 induces IL-9 secretion in murine and human iNKT cells. Acquisition of IL-9 production was observed in different iNKT subsets defined by CD4, NK1.1, and neuropilin-1, indicating that distinct functional subpopulations are receptive to IL-9 polarization. Transcription factor expression kinetics suggest that regulatory mechanisms of IL-9 expression are shared by iNKT and CD4 T cells, with Irf4 and Batf deficiency deeply affecting IL-9 production. Importantly, adoptive transfer of an enriched IL-9(+) iNKT cell population leads to exacerbated allergic inflammation in the airways upon intranasal immunization with house dust mite, confirming the ability of IL-9-producing iNKT cells to mediate proinflammatory effects in vivo, as previously reported. Taken together, our data show that peripheral iNKT cells retain the capacity of shaping their function in response to environmental cues, namely TGF-β and IL-4, adopting an IL-9-producing NKT cell phenotype able to mediate proinflammatory effects in vivo, namely granulocyte and mast cell recruitment to the lungs.

Topics: Adoptive Transfer; Animals; Antigens, Ly; Basic-Leucine Zipper Transcription Factors; CD4 Antigens; Cells, Cultured; Granulocytes; Humans; Inflammation; Interferon Regulatory Factors; Interleukin-4; Interleukin-9; Leukocytes, Mononuclear; Lung; Mast Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Natural Killer T-Cells; Neuropilin-1; NK Cell Lectin-Like Receptor Subfamily B; Pneumonia; Pyroglyphidae; Thymus Gland; Transforming Growth Factor beta

Fibroblast activation protein α (FAP) is a membrane-bound serine protease expressed by activated fibroblasts during wound healing in the skin. Expression of FAP after myocardial infarction (MI) and potential effects on cardiac wound healing are largely unknown.. MI was induced in rats and FAP expression was analyzed at 3, 7 and 28 days post-MI by microarray, Western blot and immunohistochemistry. In human hearts after MI, a FAP(+) fibroblast population was identified, and characterized by immunohistochemistry for prolyl-4-hydroxylase β, α-smooth muscle actin, Thy-1 and vimentin. Signaling pathways leading to FAP expression were studied in human cardiac fibroblasts by Western blot and ELISA using TGFβ1, TGF-beta type I-receptor (TGFbR1)-inhibitor SB431542 or the MAPK-inhibitor U0126 as well as siRNA targeting SMAD2 and SMAD3. Finally, fibroblasts were assayed for FAP-dependent migration (modified Boyden-chamber), proliferation (BrdU-assay) and gelatinolytic activity by gelatin zymography.. In rats, FAP expression was increased after MI especially in the peri-infarct area peaking at 7 days post-MI. Co-localization analysis identified the majority of FAP(+) cells as activated proto-myofibroblasts and myofibroblasts. Concordantly, FAP(+) fibroblasts were abundant in ischemic tissue of human hearts after MI, but not in healthy control hearts. In vitro, FAP was induced by TGFβ1 via the canonical SMAD2/SMAD3 pathway. Depletion of FAP in fibroblasts reduced migratory capacity, while proliferation was not affected. Gelatin zymography revealed gelatinase activity by fibroblast-derived FAP.. In this study, we show for the first time the expression of FAP in activated fibroblasts after MI and its activation by TGFβ1. Effects of FAP on fibroblast migration and gelatinolytic activity indicate a potential role in cardiac wound healing and remodeling.

Topics: Animals; Endopeptidases; Extracellular Matrix Proteins; Gelatinases; Gene Expression Regulation; Humans; Inflammation; Membrane Proteins; Myocardial Infarction; Myocardium; Myofibroblasts; Rats; Serine Endopeptidases; Signal Transduction; Transforming Growth Factor beta; Wound Healing

The microfracture technique for cartilage repair has limited ability to regenerate hyaline cartilage.. The current study made a direct comparison between microfracture and an osteochondral approach with microsphere-based gradient plugs.. The PLGA-based scaffolds had opposing gradients of chondroitin sulfate and β-tricalcium phosphate. A 1-year repair study in sheep was conducted.. The repair tissues in the microfracture were mostly fibrous and had scattered fissures with degenerative changes. Cartilage regenerated with the gradient plugs had equal or superior mechanical properties; had lacunated cells and stable matrix as in hyaline cartilage.. This first report of gradient scaffolds in a long-term, large animal, osteochondral defect demonstrated potential for equal or better cartilage repair than microfracture.

Topics: Animals; Bone and Bones; Calcium Phosphates; Cartilage, Articular; Chondrocytes; Chondroitin Sulfates; Female; Femur; Finite Element Analysis; Humans; Hyaline Cartilage; Inflammation; Knee Joint; Lactic Acid; Magnetic Resonance Imaging; Microspheres; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Regeneration; Sheep; Stress, Mechanical; Tissue Engineering; Tissue Scaffolds; Transforming Growth Factor beta

The mammalian circadian clock consists of multiple transcriptional regulators that coordinate biological processes in a time-of-day-dependent manner. Cardiomyocyte-specific deletion of the circadian clock component, Bmal1 (aryl hydrocarbon receptor nuclear translocator-like protein 1), leads to age-dependent dilated cardiomyopathy and decreased lifespan in mice. We investigated whether cardiomyocyte-specific Bmal1 knockout (CBK) mice display early alterations in cardiac diastolic function, extracellular matrix (ECM) remodeling, and inflammation modulators by investigating CBK mice and littermate controls at 8 and 28 wk of age (i.e., prior to overt systolic dysfunction). Left ventricles of CBK mice exhibited (P < 0.05): 1) progressive abnormal diastolic septal annular wall motion and reduced pulmonary venous flow only at 28 wk of age; 2) progressive worsening of fibrosis in the interstitial and endocardial regions from 8 to 28 wk of age; 3) increased (>1.5 fold) expression of collagen I and III, as well as the matrix metalloproteinases MMP-9, MMP-13, and MMP-14 at 28 wk of age; 4) increased transcript levels of neutrophil chemotaxis and leukocyte migration genes (Ccl2, Ccl8, Cxcl2, Cxcl1, Cxcr2, Il1β) with no change in Il-10 and Il-13 genes expression; and 5) decreased levels of 5-LOX, HO-1 and COX-2, enzymes indicating impaired resolution of inflammation. In conclusion, genetic disruption of the cardiomyocyte circadian clock results in diastolic dysfunction, adverse ECM remodeling, and proinflammatory gene expression profiles in the mouse heart, indicating signs of early cardiac aging in CBK mice.

Topics: Age Factors; Animals; ARNTL Transcription Factors; Diastole; Disease Progression; Extracellular Matrix; Fibrosis; Gene Expression Regulation; Genotype; Hypertrophy, Left Ventricular; Inflammation; Inflammation Mediators; Male; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; Phenotype; RNA, Messenger; Signal Transduction; Smad2 Protein; Smad3 Protein; Time Factors; Transcription, Genetic; Transforming Growth Factor beta; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

Salmonella is a common intestinal pathogen that causes acute and chronic inflammatory response. Probiotics reduce inflammatory cytokine production and serve as beneficial commensal microorganisms in the human gastrointestinal tract. TGF-β (transforming growth factor β)/SMAD and NF-κB signaling play important roles in inflammation in intestinal cells. However, the involvement of the signaling in regulating inflammation between Salmonella and probiotics is not fully understood.. L. acidophilus and prebiotic inulin were used to treat human intestinal Caco-2 cells prior to infection with Salmonella. The cells were harvested to examine the cytokines and MIR21 expression with immunoblotting and real-time PCR. NF-κB and SMAD3/4 reporter vectors were transfected into cells to monitor inflammation and TGF-β1 signaling, respectively.. In this study, we showed that the probiotic L. acidophilus decreased Salmonella-induced NF-κB activation in human intestinal Caco-2 cells. Expression of the inflammatory cytokines, TNF-α and IL-8, in L. acidophilus-pretreated cells was also significantly lower than that in cells infected with Salmonella alone. Moreover, TGF-β1 and MIR21 expression was elevated in cells pretreated with L. acidophilus or synbiotic, a combination of inulin and L. acidophilus, compared to that in untreated cells or cells infected with S. typhimurium alone. By contrast, expression of SMAD7, a target of MIR21, was accordingly reduced in cells treated with L. acidophilus or synbiotics. Consistent with TGF-β1/MIR21 and SMAD7 expression, SMAD3/4 transcriptional activity was significantly higher in the cells treated with L. acidophilus or synbiotics. Furthermore, TGF-β1 antibody antagonized the SMAD3/4 and NF-κB transcriptional activity modulated by L. acidophilus in intestinal cells.. Our results suggest that the TGF-β1/MIR21 signaling pathway may be involved in the suppressive effects of L. acidophilus on inflammation caused by S. typhimurium in intestinal Caco-2 cells.

Topics: Caco-2 Cells; Cytokines; Gene Expression Profiling; Humans; Immunosuppressive Agents; Inflammation; Inulin; Lactobacillus acidophilus; Models, Biological; NF-kappa B; Probiotics; Real-Time Polymerase Chain Reaction; Salmonella Infections; Signal Transduction; Smad3 Protein; Smad4 Protein; Transforming Growth Factor beta

Pistacia terebinthus is used as a coffee substitute in the East and Southern Anatolia regions of Turkey. It contains unsaturated fatty acids, tocopherols, polyphenols and carotenoids. P. terebinthus has anti-inflammatory and potential antioxidant activity. In this study we evaluated the protective effects of P. terebinthus coffee (PTC) on thioacetamide (TAA)-induced liver injury in rats.. Twenty-eight male Sprague-Dawley rats were equally randomized into four groups. Chronic liver injury was induced with TAA (100 mg/kg i.p. three times weekly). The first group of rats served as control and received only tap water (G1), and the remaining groups of rats received PTC, p.o (G2); TAA (G3); TAA plus PTC, p.o (G4), respectively.. After 8 weeks, PTC intake significantly reduced fibrosis/inflammation scores (p PTC intake reduced transforming growth factor beta (TGF-β) concentrations in the liver (p PTC intake.. PTC intake provided beneficial effects against TAA-induced liver injury in rats. PTC probably suppresses the proinflammatory cytokines through NF-κB signaling pathway.

Topics: Animals; Antioxidants; Disease Models, Animal; Inflammation; Liver; Liver Cirrhosis, Experimental; Male; Noxae; Oxidative Stress; Pistacia; Rats; Rats, Sprague-Dawley; Teas, Herbal; Thioacetamide; Transforming Growth Factor beta; Treatment Outcome; Triterpenes

Multiple mechanisms contribute to progressive cardiac dysfunction after myocardial infarction (MI) and inflammation is an important mediator. Mast cells (MCs) trigger inflammation after MI by releasing bio-active factors that contribute to healing. c-Kit-deficient (Kit(W/W-v) ) mice have dysfunctional MCs and develop severe ventricular dilatation post-MI. We explored the role of MCs in post-MI repair. Mouse wild-type (WT) and Kit(W/W-v) MCs were obtained from bone marrow (BM). MC effects on fibroblasts were examined in vitro by proliferation and gel contraction assays. MCs were implanted into infarcted mouse hearts and their effects were evaluated using molecular, cellular and cardiac functional analyses. In contrast to WT, Kit(W/W-v) MC transplantation into Kit(W/W-v) mice did not improve cardiac function or scar size post-MI. Kit(W/W-v) MCs induced significantly reduced fibroblast proliferation and contraction compared to WT MCs. MC influence on fibroblast proliferation was Basic fibroblast growth factor (bFGF)-dependent and MC-induced fibroblast contractility functioned through transforming growth factor (TGF)-β. WT MCs transiently rescue cardiac function early post-MI, but the benefits of BM cell implantation lasted longer. MCs induced increased inflammation compared to the BM-injected mice, with increased neutrophil infiltration and infarct tumour necrosis factor-α (TNF-α) concentration. This augmented inflammation was followed by increased angiogenesis and myofibroblast formation and reduced scar size at early time-points. Similar to the functional data, these beneficial effects were transient, largely vanishing by day 28. Dysfunctional Kit(W/W-v) MCs were unable to rescue cardiac function post-MI. WT MC implantation transiently enhanced angiogenesis and cardiac function. These data suggest that increased inflammation is beneficial to cardiac repair, but these effects are not persistent.

Topics: Animals; Blood Vessels; Cell Differentiation; Cell Proliferation; Cells, Cultured; Coculture Techniques; Enzyme-Linked Immunosorbent Assay; Fibroblast Growth Factor 2; Fibroblasts; Flow Cytometry; Inflammation; Mast Cells; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Myocardial Infarction; Myocardium; Myofibroblasts; Proto-Oncogene Proteins c-kit; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Thymic stromal lymphopoietin (TSLP) is a cytokine known to mature dendritics cells, lower pro-inflammatory IL-12 secretion, induce differentiation of anti-inflammatory FoxP3+ regulatory T cells (Treg). Moreover, Crohn's disease patients have shown a reduction of intestinal TSLP expression. To understand the role of TSLP in inflammation, we constructed Lactococcus lactis strain producing TSLP (LL-TSLP) and investigated the effect of its administration on dextran sulfate sodium (DSS)-induced colitis model in mice.. LL-TSLP secrete an active molecule which lowers secretion of IL-12 by dendritic cells. Treatment with LL-TSLP, increases the amount of TGF-β secreted by T cells in Mesenteric Lymph Node in healthy mice. In acute DSS-induced colitis, LL-TSLP delayed the Disease Activity Index and lowered histological score and colonic INF-γ production. In a DSS-recovery model, LL-TSLP induced a better protective effect if the strain was administered at the beginning of the colitis. At Day 4 of colitis we observed an induction of Treg by LL-TSLP.. TSLP showed an anti-inflammatory protective role in DSS-induced colitis. We have demonstrated that a short and early administration of LL-TSLP is more efficient than a long lasting treatment.

Topics: Administration, Oral; Animals; Colitis; Colon; Cytokines; Dendritic Cells; Dextran Sulfate; Disease Models, Animal; Inflammation; Interleukin-12; Intestinal Mucosa; Lactococcus lactis; Lymph Nodes; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; T-Lymphocytes, Regulatory; Thymic Stromal Lymphopoietin; Transforming Growth Factor beta

Secretoglobin (SCGB) 3A2 is a novel lung-enriched cytokine, previously shown to exhibit anti-inflammatory, growth factor, and anti-fibrotic activities. The latter activity was demonstrated using exogenously-administered recombinant SCGB3A2 in the bleomycin (BLM)-induced pulmonary fibrosis model. Whether SCGB3A2 exhibits anti-fibrotic activity in vivo is not known.. Mice null for the Scgb3a2 gene were subjected to the BLM-induced pulmonary fibrosis model, and the severity of pulmonary fibrosis determined using histological and biochemical methods.. BLM treatment caused weight loss of both Scgb3a2-null and wild-type mice, however, the loss was far more pronounced in BLM-treated Scgb3a2-null than wild-type mice, and the weight of day 21 of BLM-treated Scgb3a2-null mice was about half of that of BLM-treated wild-type mice. Hematoxylin & Eosin, Masson Trichrome, and Sirius Red staining of lung sections, Ashcroft fibrosis scores, hydroxyproline contents, and the levels of mRNAs encoding various collagens demonstrated that BLM-treated Scgb3a2-null mouse lungs had more severe fibrosis than those of wild-type mouse lungs. Total and differential inflammatory cell numbers in bronchoalveolar lavage fluids, and levels of lung mRNAs including those encoding Th2 cytokines such as IL-4 and profibrotic cytokines such as TGFβ were higher in BLM-treated Scgb3a2-null mouse lungs as compared to those of wild-type mouse lungs. In contrast, mRNAs encoding surfactant proteins A, B, C, and D, and SCGB1A1 did not differ between BLM-treated Scgb3a2-null and wild-type mouse lungs.. The role of SCGB3A2 in fibrosis was revisited using Scgb3a2-null mice and littermate controls in the BLM-induced pulmonary fibrosis model. The pulmonary fibrosis in the Scgb3a2-null mice was more severe than the wild-type controls, thus establishing that SCGB3A2 has anti-fibrotic activity in vivo. Importantly, surfactant proteins and SCGB1A1 appear not to be involved in the susceptibility of Scgb3a2-null mice to BLM-induced pulmonary fibrosis.

Topics: Animals; Bleomycin; Bronchoalveolar Lavage Fluid; Collagen; Collectins; Cytokines; Disease Models, Animal; Hydroxyproline; Inflammation; Interleukin-4; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; Pulmonary Fibrosis; Real-Time Polymerase Chain Reaction; RNA, Messenger; Secretoglobins; Severity of Illness Index; Transforming Growth Factor beta

Experimental autoimmune encephalomyelitis (EAE) is a CD4(+)-mediated autoimmune pathology of the central nervous system (CNS) that is used as a model for the study of the human neuroinflammatory disease, multiple sclerosis. During the development of EAE, auto-reactive Th1 and Th17 CD4(+) T cells infiltrate the CNS promoting inflammatory cells recruitment, focal inflammation and tissue destruction. In this sense, statins, agents used to lower lipid levels, have recently shown to exert interesting immunomodulatory function. In fact, statins promote a bias towards a Th2 response, which ameliorates the clinical outcome of EAE. Additionally, simvastatin can inhibit Th17 differentiation. However, many other effects exerted on the immune system by statins have yet to be clarified, in particular during neuroinflammation. Thus, the aim of this study was to investigate the effects of simvastatin on the development of experimental autoimmune encephalomyelitis.. Mice were immunized with MOG(35-55) and EAE severity was assessed daily and scored using a clinical scale. Cytokine secretion by mononuclear cells infiltrating the CNS was evaluated by flow cytometry.. Simvastatin (5 mg/kg/day) improved clinical outcome, induced an increase in TGF-β mRNA expression and inhibited IL-6, IL-12p40, IL-12p70, RANTES and MIP-1β secretion (p < 0.05). This was accompanied by a significant decrease in CNS inflammatory mononuclear cell infiltration, with reduced frequencies of both Th1 and Th17 cells. Simvastatin inhibited the proliferation of T lymphocytes co-cultured with primary microglial cells.. Simvastatin treatment promotes EAE clinical amelioration by inhibiting T cell proliferation and CNS infiltration by pathogenic Th1 and Th17 cells.

Topics: Animals; Cell Differentiation; Cell Proliferation; Central Nervous System; Chemokine CCL5; Encephalomyelitis, Autoimmune, Experimental; Female; Inflammation; Interleukin-12 Subunit p40; Interleukin-6; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Simvastatin; Th1 Cells; Th17 Cells; Transforming Growth Factor beta

The adoptive transfer of the natural regulatory B cells and macrophages should be a useful treatment for inflammation and autoimmune disease. However, it is usually difficult to isolate these cells from the tissues and expand them. Here, we investigated the feasibility of adoptively transferring peritoneal cells (PCs) as a treatment for DSS-induced colitis. We found that peritoneal cavity can provide an easily accessible site for harvesting enough number of PCs, namely, two-dose PCs for the treatment from a mouse in one operation. Adoptive therapy of these cells from healthy mice or those with disease is effectively in reducing the disease activity score. The natural B cells and macrophages of the infused PCs can selectively migrate to lesion sites and regulate the expression of Stat3, NF-κB, Smad3 and Smad7. Additionally, PCs exert dual activity of IL-10 and TGF-β secreted spontaneously by both peritoneal B cells and macrophages, which in turn enhance the induction of regulatory B cells and Macrophages in microenvironment of inflammation. Moreover, PCs can re-establish immunological tolerance in the OVA-immunized mice. Thus, our findings provide a new strategy for colitis therapy and could be of importance in additional exploration of other inflammation and autoimmune diseases therapy.

Topics: Adoptive Transfer; Animals; B-Lymphocytes; Colitis; Dextran Sulfate; Disease Models, Animal; Female; Inflammation; Interleukin-10; Intestinal Mucosa; Macrophages; Mice; Mice, Inbred C57BL; NF-kappa B; Signal Transduction; Smad Proteins, Receptor-Regulated; Transforming Growth Factor beta

Lung cancer is the leading cause of cancer death worldwide. Adenocarcinoma, the most commonly diagnosed histologic type of lung cancer, is associated with smoking. Cigarette smoke promotes inflammation on the airways, which might be mediated by Th17 cells. This inflammatory environment may contribute to tumor development. In contrast, some reports indicate that tumors may induce immunosuppressive Treg cells to dampen immune reactivity, supporting tumor growth and progression. Thus, we aimed to analyze whether chronic inflammation or immunosuppression predominates at the systemic level in lung adenocarcinoma patients, and several cytokines and Th17 and Treg cells were studied. Higher proportions of IL-17-producing CD4(+) T-cells were found in smoking control subjects and in lung adenocarcinoma patients compared to nonsmoking control subjects. In addition, lung adenocarcinoma patients increased both plasma concentrations of IL-2, IL-4, IL-6, and IL-10, and proportions of Latency Associated Peptide (LAP) TGF-β subset of CD4(+)CD25(+)CD127(-) Treg cells, which overexpressed LAP TGF-β. This knowledge may lead to the development of immunotherapies that could inhibit the suppressor activity mediated by the LAP TGF-β subset of CD4(+)CD25(+)CD127(-) Treg cells to promote reactivity of immune cells against lung adenocarcinoma cells.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Aged; CD4-Positive T-Lymphocytes; Female; Humans; Immune Tolerance; Inflammation; Interleukin-10; Interleukin-17; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Interleukin-4; Interleukin-6; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Peptides; Protein Precursors; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

The Sec13 protein functions in various intracellular compartments including the nuclear pore complex, COPII-coated vesicles, and inside the nucleus as a transcription regulator. Here we developed a mouse model that expresses low levels of Sec13 (Sec13(H/-)) to assess its functions in vivo, as Sec13 knockout is lethal. These Sec13 mutant mice did not present gross defects in anatomy and physiology. However, the reduced levels of Sec13 in vivo yielded specific immunological defects. In particular, these Sec13 mutant mice showed low levels of MHC I and II expressed by macrophages, low levels of INF-γ and IL-6 expressed by stimulated T cells, and low frequencies of splenic IFN-γ+CD8+ T cells. In contrast, the levels of soluble and membrane-bound TGF-β as well as serum immunoglobulin production are high in these mice. Furthermore, frequencies of CD19+CD5-CD95+ and CD19+CD5-IL-4+ B cells were diminished in Sec13(H/-) mice. Upon stimulation or immunization, some of the defects observed in the naïve mutant mice were compensated. However, TGF-β expression remained high suggesting that Sec13 is a negative modulator of TGF-β expression and of its immunosuppressive functions on certain immune cells. In sum, Sec13 regulates specific expression of immune factors with key functions in inflammation.

Topics: Animals; Carrier Proteins; CD8-Positive T-Lymphocytes; Immunologic Factors; Inflammation; Interferon-gamma; Interleukin-6; Macrophages; Mice, Mutant Strains; Mycobacterium tuberculosis; Nuclear Proteins; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tuberculosis

Timely resolution of inflammation is critical for the restoration of homeostasis in injured or infected tissue. Chronic inflammation is often characterized by a persistent increase in the concentrations of inflammatory cells and molecular mediators, whose distinct amount and timing characteristics offer an opportunity to identify effective therapeutic regulatory targets. Here, we used our recently developed computational model of local inflammation to identify potential targets for molecular interventions and to investigate the effects of individual and combined inhibition of such targets. This was accomplished via the development and application of computational strategies involving the simulation and analysis of thousands of inflammatory scenarios. We found that modulation of macrophage influx and efflux is an effective potential strategy to regulate the amount of inflammatory cells and molecular mediators in both normal and chronic inflammatory scenarios. We identified three molecular mediators - tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), and the chemokine CXCL8 - as potential molecular targets whose individual or combined inhibition may robustly regulate both the amount and timing properties of the kinetic trajectories for neutrophils and macrophages in chronic inflammation. Modulation of macrophage flux, as well as of the abundance of TNF-α, TGF-β, and CXCL8, may improve the resolution of chronic inflammation.

Topics: Animals; Computer Simulation; Humans; Immunity, Innate; Inflammation; Interleukin-8; Macrophage Activation; Macrophages; Models, Immunological; Severity of Illness Index; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Human and murine lymphocytes express dopamine (DA) D2-like receptors including DRD2, DRD3, and DRD4. However, their roles in rheumatoid arthritis (RA) are less clear. Here we showed that lymphocyte DRD2 activation alleviates both imbalance of T-helper (Th)17/T-regulatory (Treg) cells and inflamed symptoms in a mouse arthritis model of RA. Collagen-induced arthritis (CIA) was prepared by intradermal injection of chicken collagen type II (CII) in tail base of DBA/1 mice or Drd2 (-/-) C57BL/6 mice. D2-like receptor agonist quinpirole downregulated expression of proinflammatory Th17-related cytokines interleukin- (IL-) 17 and IL-22 but further upregulated expression of anti-inflammatory Treg-related cytokines transforming growth factor- (TGF-) β and IL-10 in lymphocytes in vitro and in ankle joints in vivo in CIA mice. Quinpirole intraperitoneal administration reduced both clinical arthritis score and serum anti-CII IgG level in CIA mice. However, Drd2 (-/-) CIA mice manifested more severe limb inflammation and higher serum anti-CII IgG level and further upregulated IL-17 and IL-22 expression and downregulated TGF-β and IL-10 expression than wild-type CIA mice. In contrast, Drd1 (-/-) CIA mice did not alter limb inflammation or anti-CII IgG level compared with wild-type CIA mice. These results suggest that DRD2 activation is involved in alleviation of CIA symptoms by amelioration of Th17/Treg imbalance.

Topics: Animals; Ankle Joint; Arthritis, Experimental; Arthritis, Rheumatoid; Disease Models, Animal; Gene Expression Regulation; Humans; Inflammation; Interleukin-10; Interleukin-17; Interleukin-22; Interleukins; Lymphocyte Activation; Mice; Mice, Knockout; Receptors, Dopamine D1; Receptors, Dopamine D2; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

Acute inflammation either resolves or proceeds to fibrotic repair that replaces functional tissue. Pro-fibrotic hedgehog signaling and induction of its Gli transcription factor in pericytes induces fibrosis in kidney, but molecular instructions connecting inflammation to fibrosis are opaque. We show acute kidney inflammation resulting from chronic ingestion of the common xenobiotic ethanol initiates Gli1 transcription and hedgehog synthesis in kidney pericytes, and promotes renal fibrosis. Ethanol ingestion stimulated transcription of TGF-ß, collagens I and IV, and alpha-smooth muscle actin with accumulation of these proteins. This was accompanied by deposition of extracellular fibrils. Ethanol catabolism by CYP2E1 in kidney generates local reactive oxygen species that oxidize cellular phospholipids to phospholipid products that activate the Platelet-activating Factor receptor (PTAFR) for inflammatory phospholipids. Genetically deleting this ptafr locus abolished accumulation of mRNA for TGF-ß, collagen IV, and α-smooth muscle actin. Loss of PTAFR also abolished ethanol-stimulated Sonic (Shh) and Indian hedgehog (Ihh) expression, and abolished transcription and accumulation of Gli1. Shh induced in pericytes and Ihh in tubules escaped to urine of ethanol-fed mice. Neutrophil myeloperoxidase (MPO) is required for ethanol-induced kidney inflammation, and Shh was not present in kidney or urine of mpo-/- mice. Shh also was present in urine of patients with acute kidney injury, but not in normal individuals or those with fibrotic liver cirrhosis We conclude neither endogenous PTAFR signaling nor CYP2E1-generated radicals alone are sufficient to initiate hedgehog signaling, but instead PTAFR-dependent neutrophil infiltration with myeloperoxidase activation is necessary to initiate ethanol-induced fibrosis in kidney. We also show fibrogenic mediators escape to urine, defining a new class of urinary mechanistic biomarkers of fibrogenesis for an organ not commonly biopsied.

Topics: Animals; Collagen Type IV; Cytochrome P-450 CYP2E1; Ethanol; Female; Fibroblasts; Fibrosis; Hedgehog Proteins; Inflammation; Kidney; Mice; Mice, Inbred C57BL; Pericytes; Peroxidase; Platelet Membrane Glycoproteins; Receptors, G-Protein-Coupled; Signal Transduction; Transcription Factors; Transforming Growth Factor beta

Sepsis-induced inflammation of the lung leads to acute respiratory distress syndrome (ARDS), which may trigger persistent fibrosis. The pathology of ARDS is complex and poorly understood, and the therapeutic approaches are limited. We used a baboon model of Escherichia coli sepsis that mimics the complexity of human disease to study the pathophysiology of ARDS. We performed extensive biochemical, histological, and functional analyses to characterize the disease progression and the long-term effects of sepsis on the lung structure and function. Similar to humans, sepsis-induced ARDS in baboons displays an early inflammatory exudative phase, with extensive necrosis. This is followed by a regenerative phase dominated by proliferation of type 2 epithelial cells, expression of epithelial-to-mesenchymal transition markers, myofibroblast migration and proliferation, and collagen synthesis. Baboons that survived sepsis showed persistent inflammation and collagen deposition 6-27 months after the acute episodes. Long-term survivors had almost double the amount of collagen in the lung as compared with age-matched control animals. Immunostaining for procollagens showed persistent active collagen synthesis within the fibroblastic foci and interalveolar septa. Fibroblasts expressed markers of transforming growth factor-β and platelet-derived growth factor signaling, suggesting their potential role as mediators of myofibroblast migration and proliferation, and collagen deposition. In parallel, up-regulation of the inhibitors of extracellular proteases supports a deregulated matrix remodeling that may contribute to fibrosis. The primate model of sepsis-induced ARDS mimics the disease progression in humans, including chronic inflammation and long-lasting fibrosis. This model helps our understanding of the pathophysiology of fibrosis and the testing of new therapies.

Topics: Acute Lung Injury; Animals; Collagen; Disease Models, Animal; Escherichia coli; Fibrosis; Humans; Inflammation; Lung; Papio; Respiratory Distress Syndrome; Sepsis; Signal Transduction; Transforming Growth Factor beta

To analyze the levels of oxidized low density lipoprotein (ox-LDL) and inflammatory cytokines in the plasma of gout patients. The levels of ox-LDL, hypersensitive C-reactive protein (hs-CRP), interleukin-1β, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured in the plasma of 41 gout patients [28 in acute phase episode, 13 in intermittent phase (IP)], and in 40 healthy controls. The relationship between ox-LDL and inflammation was also explored by measuring the levels of several pro-inflammatory cytokines in the plasma. The plasma levels of ox-LDL, hs-CRP, IL-6 and TNF-α were significantly increased in patients with gout in the acute phase compared to those in the IP group and healthy controls (P < 0.05), but the levels of TGF-β were significantly lower in the acute phase group than in the IP group and healthy controls (P < 0.01). The levels of ox-LDL in the gout patients in the IP were significantly higher than those in healthy controls (P < 0.05). Correlation analysis indicated that the levels of ox-LDL were positively correlated with hs-CRP, IL-6 and TNF-α (r = 0.343, r = 0.386, r = 0.659, P < 0.01, respectively), but negatively correlated with TGF-β levels in patients in the acute phase (r = -0.240, P < 0.05). The levels of ox-LDL in gout patients were significantly higher than those in healthy controls. The changes in ox-LDL levels may be associated with enhanced inflammation in gout patients.

Topics: Acute Disease; Adult; Aged; C-Reactive Protein; Case-Control Studies; Female; Gout; Humans; Inflammation; Interleukin-6; Lipoproteins, LDL; Male; Middle Aged; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Increase in matrix protein content in the kidney is a cardinal feature of diabetic kidney disease. While renal matrix protein content is increased by chronic hyperglycemia, whether it is regulated by acute elevation of glucose and insulin has not been addressed. In this study, we aimed to evaluate whether short duration of combined hyperglycemia and hyperinsulinemia, mimicking the metabolic environment of prediabetes and early type 2 diabetes, induces kidney injury. Normal rats were subjected to either saline infusion (control, n = 4) or 7 h of combined hyperglycemic-hyperinsulinemic clamp (HG+HI clamp; n = 6). During the clamp, plasma glucose and plasma insulin were maintained at about 350 mg/dl and 16 ng/ml, respectively. HG+HI clamp increased the expression of renal cortical transforming growth factor-β (TGF-β) and renal matrix proteins, laminin and fibronectin. This was associated with the activation of SMAD3, Akt, mammalian target of rapamycin (mTOR) complexes, and ERK signaling pathways and their downstream target events in the initiation and elongation phases of mRNA translation, an important step in protein synthesis. Additionally, HG+HI clamp provoked renal inflammation as shown by the activation of Toll-like receptor 4 (TLR4) and infiltration of CD68-positive monocytes. Urinary F2t isoprostane excretion, an index of renal oxidant stress, was increased in the HG+HI clamp rats. We conclude that even a short duration of hyperglycemia and hyperinsulinemia contributes to activation of pathways that regulate matrix protein synthesis, inflammation, and oxidative stress in the kidney. This finding could have implications for the control of short-term rises in blood glucose in diabetic individuals at risk of developing kidney disease.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enzyme Activation; Fibronectins; Fibrosis; Hyperglycemia; Hyperinsulinism; Inflammation; Kidney; Laminin; Male; MAP Kinase Signaling System; NF-kappa B; Oxidative Stress; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; RNA, Messenger; Smad3 Protein; Toll-Like Receptor 4; TOR Serine-Threonine Kinases; Transforming Growth Factor beta

The generation of CD4⁺Foxp3⁺ Treg cells in the thymus is crucial for immune homeostasis and self-tolerance. Recent studies have shown Treg-cell plasticity when Th-related transcriptional factors and cytokines are present. However, the mechanisms that maintain the stability of Treg cells are poorly understood. Here, using mice with a T-cell-specific deletion of the transforming growth factor-β receptor 2 (Tgfbr2⁻/⁻ mice), we identify the restriction of AKT activation as a key event for the control of Treg-cell stability in Th1 inflammation. AKT regulation was evident in thymic CD4⁺Foxp3⁺ Treg cells before they egressed to peripheral tissues. CD4⁺Foxp3⁺ thymocytes from mice with the Tgfbr2 deletion expressed high levels of CXCR3 and T-bet, and produced IFN-γ and TNF-α. Thymic Tgfbr2⁻/⁻ Treg cells also showed an increase in the activation of AKT pathway. Enhanced AKT activity induced the expression of IFN-γ both in natural and inducible Treg cells. Inhibition of AKT activity markedly attenuated the expression of IFN-γ and TNF-α in thymic Tgfbr2⁻/⁻ Treg cells in vivo. In addition, mixed bone marrow transplantation showed that TGF-β signaling maintained Treg-cell stability in an intrinsic manner. Our results demonstrate that AKT hyperactivation contributes to the conversion of Treg cells to a Th1 phenotype.

Topics: Animals; Bone Marrow Transplantation; CD4-Positive T-Lymphocytes; Down-Regulation; Forkhead Transcription Factors; Gene Expression; Inflammation; Interferon-gamma; Mice; Mice, Inbred C57BL; Phenotype; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Signal Transduction; T-Lymphocytes, Regulatory; Th1 Cells; Thymus Gland; Transforming Growth Factor beta

Disturbance of T-cell homeostasis could lead to intestinal inflammation. Naive CD4 T cells undergoing spontaneous proliferation, a robust proliferative response that occurs under severe lymphopenic conditions, differentiate into effector cells producing Th1- and/or Th17-type cytokines and induce a chronic inflammation in the intestine that resembles human inflammatory bowel disease. In this study, we investigated the key properties of CD4 T cells necessary to induce experimental colitis. α4β7 upregulation was primarily induced by mesenteric lymph node (mLN) resident CD11b(+) dendritic cell subsets via transforming growth factor beta (TGFβ)/retinoic acid-dependent mechanism. Interestingly, α4β7 expression was essential but not sufficient to induce inflammation. In addition to gut-homing specificity, expression of gut Ag specificity was also crucial. T-cell acquisition of the specificity was dramatically enhanced by the presence of γδ T cells, a population previously shown to exacerbate T-cell-mediated colitis. Importantly, interleukin (IL)-23-mediated γδ T cell stimulation was necessary to enhance colitogenicity but not gut antigen reactivity of proliferating CD4 T cells. These findings demonstrate that T-cell colitogenicity is achieved through multiple processes, offering a therapeutic rationale by intervening these pathways.

Topics: Animals; Antineoplastic Agents; CD4-Positive T-Lymphocytes; Colitis; Dendritic Cells; Gastrointestinal Tract; Genes, T-Cell Receptor beta; Homeodomain Proteins; Humans; Inflammation; Integrins; Interleukin-16; Interleukin-23 Subunit p19; Lymph Nodes; Mesenteric Veins; Mice; Mice, Inbred C57BL; Mice, Knockout; Real-Time Polymerase Chain Reaction; Receptors, Antigen, T-Cell, gamma-delta; RNA, Messenger; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta; Tretinoin

1. Chronic oxidative stress and inflammation are major mediators of chronic kidney disease (CKD) and result in impaired activation of the cytoprotective transcription factor Nrf2. Given the role of oxidative stress and inflammation in CKD pathogenesis, strategies aimed at restoring Nrf2 activity may attenuate CKD progression. 2. The present study investigated whether the synthetic triterpenoid RTA dh404 (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid-9,11-dihydro-trifluoroethyl amide or CDDO-dhTFEA) would afford renal protection in a 5/6 nephrectomized rat model of CKD. RTA dh404 (2 mg/kg/day) was orally administered once daily for 12 weeks after 5/6 nephrectomy surgery. 3. The remnant kidneys from the vehicle-treated CKD rats showed activation of nuclear factor kappaB (NF-κB), upregulation of NAD(P)H oxidase, glomerulosclerosis, interstitial fibrosis and inflammation, as well as marked reductions in Nrf2 and its target gene products (i.e. catalase, heme oxygenase-1, thioredoxin 1, thioredoxin reductase 1 and peroxiredoxin 1). The functional and structural deficits in the kidney were associated with increased (∼30%) mean arterial pressure (MAP). Treatment with RTA dh404 restored MAP, increased Nrf2 and expression of its target genes, attenuated activation of NF-κB and transforming growth factor-β pathways, and reduced glomerulosclerosis, interstitial fibrosis and inflammation in the CKD rats. 4. Thus, chronic treatment with RTA dh404 was effective in restoring Nrf2 activity and slowing CKD progression in rats following 5/6 nephrectomy.

Topics: Animals; Blotting, Western; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Gene Expression Regulation; Inflammation; Intracellular Signaling Peptides and Proteins; Kelch-Like ECH-Associated Protein 1; Kidney; Male; NF-E2-Related Factor 2; Oleanolic Acid; Oxidative Stress; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; RNA, Messenger; Signal Transduction; Smad7 Protein; Transforming Growth Factor beta

Toll-like receptors (TLRs) have a crucial role in early host defense against invading pathogens. Recent studies suggest that TLRs play important roles in non-infections inflammation and tissue repair and regeneration.. To determine the roles of TLR2 and TLR4 in mouse wound healing using TLR2-deficient (TLR2(-/-)), TLR4-deficient (TLR4(-/-)), and TLR2/TLR4-deficient (TLR2/4(-/-)) mice.. Open wounds made in TLR2(-/-), TLR4(-/-), and TLR2/4(-/-) mice were examined clinically and histologically. Cytokine expression in the wounded skin was also investigated. TGF-β production from macrophages stimulated by hyaluronan, a ligand for TLR2 and TLR4, was evaluated by real-time PCR.. Wound areas in TLR2(-/-), TLR4(-/-), and TLR2/4(-/-) mice were larger than wild-type mice both at days 3 and 7 after wounding, accompanied by decreased numbers of infiltrating macrophages in the dermis and decreased TGF-β and CCL5 mRNA expression in the wounded skin. Immunohistochemistry showed decreased numbers of macrophages expressing TGF-β and reduced CCL5 expression by keratinocytes in the wounded skin from TLR2(-/-), TLR4(-/-), and TLR2/4(-/-) mice compared to wild-type mice. Moreover, TGF-β production from macrophages induced by hyaluronan stimulation in vitro was significantly decreased in the absence of TLRs, especially TLR4. Interestingly, macrophages and wounded skin from TLR2(-/-) mice showed decreased TLR4 mRNA expression compared to wild-type mice, suggesting that the effect of TLR2 deficiency was at least partially dependent on decrease in TLR4. Topical application of TGF-β and CCL5 significantly improved wound healing in TLR-deficient mice.. TLR4, rather than TLR2, regulates wound healing through TGF-β and CCL5 expression.

Topics: Animals; Chemokine CCL5; Gene Expression Regulation; Hyaluronic Acid; Inflammation; Ligands; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Real-Time Polymerase Chain Reaction; Regeneration; Reverse Transcriptase Polymerase Chain Reaction; Toll-Like Receptor 2; Toll-Like Receptor 4; Transforming Growth Factor beta; Wound Healing

We have previously shown that transforming growth factor-β/Smad3-dependent miRNAs play a critical role in renal inflammation and fibrosis. However, off-target effects of miRNAs limit their therapeutic application. Recently, emerging roles of long noncoding RNAs (lncRNAs) in diseases have been recognized. In this study, we used high-throughput RNA sequencing to identify the Smad3-dependent lncRNAs related to renal inflammation and fibrosis in Smad3 knockout mouse models of unilateral ureteral obstructive nephropathy and immunologically induced anti-glomerular basement membrane glomerulonephritis. Compared with wild-type mice, 151 lncRNAs in the unilateral ureteral obstructive nephropathy kidney and 413 lncRNAs in kidneys with anti-glomerular basement membrane glomerulonephritis were significantly altered in Smad3 knockout mice. Among them, 21 common lncRNAs were up-regulated in wild-type, but down-regulated in Smad3 knockout, kidneys in both disease models in which progressive renal inflammation and fibrosis were abolished when the Smad3 gene was deleted or suppressed. Real-time PCR confirmed these findings and revealed the functional link between Smad3-dependent lncRNAs np_5318/np_17856 and progressive kidney injury. Results demonstrate that the identification and characterization of functional lncRNAs associated with kidney disease may represent a promising research direction into renal disorder and may lead to the development of new lncRNA therapies for kidney diseases.

Topics: Animals; Base Sequence; Binding Sites; Female; Fibrosis; Gene Expression Regulation; Gene Ontology; Glomerulonephritis; Inflammation; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Protein Binding; RNA, Long Noncoding; Sequence Analysis, RNA; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta; Ureteral Obstruction

The reactive stroma surrounding tumor lesions performs critical roles ranging from supporting tumor cell proliferation to inducing tumorigenesis and metastasis. Therefore, it is critical to understand the cellular components and signaling control mechanisms that underlie the etiology of reactive stroma. Previous studies have individually implicated fibroblast growth factor receptor 1 (FGFR1) and canonical WNT/β-catenin signaling in prostate cancer progression and the initiation and maintenance of a reactive stroma; however, both pathways are frequently found to be coactivated in cancer tissue. Using autochthonous transgenic mouse models for inducible FGFR1 (JOCK1) and prostate-specific and ubiquitously expressed inducible β-catenin (Pro-Cat and Ubi-Cat, respectively) and bigenic crosses between these lines (Pro-Cat × JOCK1 and Ubi-Cat × JOCK1), we describe WNT-induced synergistic acceleration of FGFR1-driven adenocarcinoma, associated with a pronounced fibroblastic reactive stroma activation surrounding prostatic intraepithelial neoplasia (mPIN) lesions found both in in situ and reconstitution assays. Both mouse and human reactive stroma exhibited increased transforming growth factor-β (TGF-β) signaling adjacent to pathologic lesions likely contributing to invasion. Furthermore, elevated stromal TGF-β signaling was associated with higher Gleason scores in archived human biopsies, mirroring murine patterns. Our findings establish the importance of the FGFR1-WNT-TGF-β signaling axes as driving forces behind reactive stroma in aggressive prostate adenocarcinomas, deepening their relevance as therapeutic targets.

Topics: Adenocarcinoma; Animals; Biopsy; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Disease Models, Animal; Fibroblasts; Humans; Inflammation; Male; Mice; Mice, Nude; Mice, Transgenic; Prostatic Neoplasms; Receptor, Fibroblast Growth Factor, Type 1; Signal Transduction; Species Specificity; Stromal Cells; Transforming Growth Factor beta; Wnt Proteins

Camel milk has traditionally been used to treat cancer, but this practice awaits scientific scrutiny, in particular its role in tumor angiogenesis, the key step involved in tumor growth and metastasis. We aimed to investigate the effects of camel milk on key components of inflammatory angiogenesis in sponge implant angiogenesis model. Polyester-polyurethane sponges, used as a framework for fibrovascular tissue growth, were implanted in Swiss albino mice and camel milk (25, 50 and 100 mg/kg/day) was administered for 14 days through installed cannula. The implants collected at day 14 post-implantation were processed for the assessment of hemoglobin (Hb), myeloperoxidase (MPO), N-acetylglucosaminidase (NAG), and collagen, which were used as indices for angiogenesis, neutrophil, and macrophage accumulation and extracellular matrix deposition, respectively. Relevant inflammatory, angiogenic, and fibrogenic cytokines were also determined. Camel milk treatment attenuated the main components of the fibrovascular tissue, wet weight, vascularization (Hb content), macrophage recruitment (NAG activity), collagen deposition and the levels of vascular endothelial growth factor (VEGF), interleukin (IL)-1β, IL-6, IL-17, tumor necrosis factor-α, and transforming growth factor-β. A regulatory function of camel milk on multiple parameters of the main components of inflammatory angiogenesis has been revealed, giving insight into the potential therapeutic benefit underlying the anti-cancer actions of camel milk.

Topics: Acetylglucosaminidase; Angiogenesis Inhibitors; Animals; Camelus; Chemoprevention; Collagen; Cytokines; Disease Models, Animal; Hemoglobins; Inflammation; Interleukin-17; Interleukin-1beta; Interleukin-6; Lactation; Macrophages; Male; Mice; Milk; Neoplasms; Neovascularization, Pathologic; Neutrophils; Peroxidase; Polyesters; Polyurethanes; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Chronic inflammation is known to promote metabolic dysregulation in obesity and type 2 diabetes. Although the precise origin of the unchecked inflammatory response in obesity is unclear, it is known that overproduction of proinflammatory cytokines by innate immune cells affects metabolism. For example, TNF-α contributes to the inability of cells to respond to insulin and to the increase in levels of insulin. Whether this hyperinsulinemia itself is part of a feedback loop that affects the progression of chronic adipose inflammation is unknown. In this article, we show that regulatory T cells (Tregs) express the insulin receptor, and that high levels of insulin impair the ability of Tregs to suppress inflammatory responses via effects on the AKT/mTOR signaling pathway. Insulin activated AKT signaling in Tregs, leading to inhibition of both IL-10 production and the ability of Tregs to suppress the production of TNF-α by macrophages in a contact-independent manner. The effect of insulin on Treg suppression was limited to IL-10 production and it did not alter the expression of other proteins associated with Treg function, including CTLA-4, CD39, and TGF-β. In a model of diet-induced obesity, Tregs from the visceral adipose tissue of hyperinsulinemic, obese mice showed a similar specific decrease in IL-10 production, as well as a parallel increase in production of IFN-γ. These data suggest that hyperinsulinemia may contribute to the development of obesity-associated inflammation via a previously unknown effect of insulin on the IL-10-mediated function of Tregs.

Topics: Animals; Antigens, CD; Apyrase; Cells, Cultured; CTLA-4 Antigen; Epithelial Cells; Epithelium; Hyperinsulinism; Inflammation; Insulin; Interferon-gamma; Interleukin-10; Intra-Abdominal Fat; Macrophages; Mice; Mice, Inbred C57BL; Obesity; Proto-Oncogene Proteins c-akt; Receptor, Insulin; Signal Transduction; T-Lymphocytes, Regulatory; TOR Serine-Threonine Kinases; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Hepatic stellate cells (HSCs) are the major cell type involved in liver fibrosis. Lipopolysaccharide (LPS)-mediated signaling through Τoll-like receptor 4 (TLR4) in HSCs has been identified as a key event in liver fibrosis, and as the molecular link between inflammation and liver fibrosis. In this study, we investigated the effects of caffeic acid phenethyl ester (CAPE), one of the main medicinal components of propolis, on the pro-inflammatory and fibrogenic phenotypes of LPS-stimulated HSCs. HSCs from rats were isolated and cultured in Dulbecco's modified Eagle's medium (DMEM). Following treatment with LPS, HSCs showed a strong pro-inflammatory phenotype with an upregulation of pro-inflammatory mediators, and a fibrogenic phenotype with enhanced collagen synthesis, mediated by transforming growth factor-β1 (TGF-β1). CAPE significantly and dose-dependently reduced LPS-induced nitrite production, as well as the transcription and protein synthesis of monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS), as determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blotting and enzyme-linked immunosorbent assays (ELISA). CAPE further reduced the TGF-β1-induced transcription and translation (protein synthesis) of the gene coding for collagen type I α1 (col1A1), in LPS-stimulated HSCs. Following LPS stimulation, the phosphorylation of the nuclear factor-κB (NF-κB) inhibitor IκBα and consequently, the nuclear translocation of NF-κB, were markedly increased in the HSCs, and these changes were reversed by pre-treatment with CAPE. In conclusion, CAPE attenuates the pro-inflammatory phenotype of LPS-stimulated HSCs, as well as the LPS-induced sensitization of HSCs to fibrogenic cytokines by inhibiting NF-κB signaling. Our results provide new insight into the treatment of hepatic fibrosis through regulation of the TLR4 signaling pathway.

Topics: Animals; Caffeic Acids; Collagen Type I; Collagen Type I, alpha 1 Chain; Hepatic Stellate Cells; Humans; Inflammation; Lipopolysaccharides; Liver Cirrhosis; NF-kappa B; Phenylethyl Alcohol; Rats; Signal Transduction; Toll-Like Receptor 4; Transforming Growth Factor beta

Vascular Ehlers-Danlos syndrome (VEDS) causes reduced life expectancy because of arterial dissections/rupture and hollow organ rupture. Although the causative gene, COL3A1, was identified >20 years ago, there has been limited progress in understanding the disease mechanisms or identifying treatments.. We studied inflammatory and transforming growth factor-β (TGF-β) signaling biomarkers in plasma and from dermal fibroblasts from patients with VEDS. Analyses were done in terms of clinical disease severity, genotype-phenotype correlations, and body composition and fat deposition alterations. VEDS subjects had increased circulating TGF-β1, TGF-β2, monocyte chemotactic protein-1, C-reactive protein, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and leptin and decreased interleukin-8 versus controls. VEDS dermal fibroblasts secreted more TGF-β2, whereas downstream canonical/noncanonical TGF-β signaling was not different. Patients with COL3A1 exon skipping mutations had higher plasma intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and VEDS probands had abnormally high plasma C-reactive protein versus affected patients identified through family members before any disease manifestations. Patients with VEDS had higher mean platelet volumes, suggesting increased platelet turnover because of ongoing vascular damage, as well as increased regional truncal adiposity.. These findings suggest that VEDS is a systemic disease with a major inflammatory component. C-reactive protein is linked to disease state and may be a disease activity marker. No changes in downstream TGF-β signaling and increased platelet turnover suggest that chronic vascular damage may partially explain increased plasma TGF-β1. Finally, we found a novel role for dysregulated TGF-β2, as well as adipocyte dysfunction, as demonstrated through reduced interleukin-8 and elevated leptin in VEDS.

Topics: Adipokines; Adolescent; Adult; Biomarkers; Body Composition; C-Reactive Protein; Child; Collagen Type III; Ehlers-Danlos Syndrome; Female; Fibroblasts; Genetic Association Studies; Humans; Inflammation; Male; Middle Aged; RNA, Small Interfering; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Young Adult

The race-specific association of inflammation with adiposity and muscle mass in subjects with chronic kidney disease (CKD) was examined.. Plasma concentration of interleukin (IL)-1β, IL-1 receptor antagonist (IL-1RA), IL-6, IL-10, tumor necrosis factor (TNF)-α, TGF-β, high-sensitivity C-reactive protein (hs-CRP), fibrinogen, and serum albumin was measured in 3,939 Chronic Renal Insufficiency Cohort study participants. Bioelectric impedance analysis was used to determine body fat mass (BFM) and fat-free mass (FFM).. Plasma levels of hs-CRP, fibrinogen, IL-1RA, IL-6, and TNF-α increased and serum albumin decreased across the quartiles of body mass index. In multivariable analysis, BFM and FFM were positively associated with hs-CRP, fibrinogen, IL-1β, IL-1RA, and IL-6. One standard deviation (SD) increase in BFM and FFM was associated with 0.36 (95% confidence interval [CI] = 0.33, 0.39) and 0.26 (95% CI = 0.22, 0.30) SD increase in log-transformed hs-CRP, respectively (P < 0.001). Race stratified analysis showed that the association between biomarkers and BFM and FFM differed by race, with Caucasians, demonstrating a stronger association with markers of inflammation than African Americans.. BFA and FFM are positively associated with markers of inflammation in patients with CKD. Race stratified analysis showed that Caucasians have a stronger association with markers of inflammation compared to African Americans.

Topics: Adiposity; Adult; Aged; Biomarkers; Black or African American; Body Mass Index; C-Reactive Protein; Cohort Studies; Cross-Sectional Studies; Electric Impedance; Fibrinogen; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-10; Interleukin-1beta; Interleukin-6; Kidney Failure, Chronic; Linear Models; Middle Aged; Multivariate Analysis; Serum Albumin; Socioeconomic Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; White People

Diabetes can disrupt endoplasmic reticulum (ER) homeostasis which leads to ER stress. ER stress-induced renal apoptosis seems to be involved in the development of diabetic nephropathy. The present study was designed to investigate the contribution of reduced ER stress to the beneficial effects of an angiotensin receptor blocker. Insulin-dependent diabetes mellitus was induced by streptozotocin injections to hypertensive mRen2-transgenic rats. After 2weeks animals were treated with 0.7mg/kg/day irbesartan. Blood glucose, blood pressure and protein excretion were assessed. Expression of ER stress markers was measured by real-time PCR. Immunohistochemistry was performed to detect markers of ER stress, renal damage and infiltrating cells. Glomerulosclerosis and apoptosis were evaluated. Diabetic mRen2-transgenic rats developed renal injury with proteinuria, tubulointerstitial cell proliferation as well as glomerulosclerosis and podocyte injury. Moreover, an increase in inflammation, podocyte ER stress and apoptosis was detected. Irbesartan somewhat lowered blood pressure and reduced proteinuria, tubulointerstitial cell proliferation and glomerulosclerosis. Podocyte damage was ameliorated but markers of ER stress (calnexin, grp78) and apoptosis were not reduced by irbesartan. On the other hand, inflammatory cell infiltration in the tubulointerstitium and the glomerulus was significantly attenuated. We conclude that irbesartan reduced renal damage even in a very low dose. The beneficial effects of low dose irbesartan were paralleled by a reduction of blood pressure and inflammation but not by a reduction of ER stress and apoptosis. Thus, sustained endoplasmic reticulum stress in the kidney does not necessarily lead to increased inflammation and tubulointerstitial or glomerular injury.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Apoptosis; Biphenyl Compounds; Blood Glucose; Blood Pressure; Diabetic Nephropathies; Endoplasmic Reticulum Stress; Inflammation; Irbesartan; Kidney; Male; Rats; Smad Proteins; Tetrazoles; Transforming Growth Factor beta

Oxidant- and inflammation-induced damage to retinal pigment epithelial (RPE) cells is central to the pathogenesis of age-related macular degeneration (AMD). Thus, developing novel strategies to protect these cells is important. We reported previously on the robust antioxidant and therefore cell-protective effects of the cysteine pro-drug L-2-oxothiazolidine-4-carboxylic acid (OTC) in cultured human RPE cells. New reports citing a novel anti-inflammatory role for OTC in addition to the known glutathione-stimulating and antioxidant properties emerged recently; however, this role has not been evaluated in RPE cells or in intact retina. Given the crucial causative roles of oxidative stress and inflammation in AMD pathogenesis, knowing whether OTC might exhibit a similar benefit in this cell and tissue type has high clinical relevance; thus, we evaluated OTC in the present study.. ARPE-19 and primary RPE cells isolated from wild-type, Gpr109a(-/-) , or Slc5a8(-/-) mouse eyes were exposed to TNF-α in the presence or absence of OTC, followed by analysis of IL-6 and Ccl2 expression with real-time quantitative polymerase chain reaction or enzyme-linked immunosorbent assay. Cellular and molecular markers of inflammation and oxidative stress (i.e., IL-1β, TGF-β, ABCG1, ABCA1, reduced glutathione, and dihydroethidium) were evaluated in Ccl2(-/-)/Cx3cr1(-/-) double knockout mice on rd8 background (DKO rd8) treated with OTC (10 mg/ml) in drinking water for a period of 5 months.. OTC treatment significantly inhibited the expression and secretion of IL-6 and Ccl2 in TNF-α-stimulated ARPE-19 cells. Studies conducted using DKO rd8 animals treated with OTC in drinking water confirmed these findings. Cellular and molecular markers of inflammation were significantly suppressed in the retinas of the OTC-treated DKO rd8 animals. Subsequent in vitro and in vivo studies of the possible mechanism(s) to explain these actions revealed that although OTC is an agonist of the anti-inflammatory G-protein coupled receptor GPR109A and a transportable substrate of the sodium-coupled monocarboxylate transporter SMCT1 (SLC5A8), these properties may play a role but do not explain entirely the anti-inflammatory effects this compound elicits in cultured RPE cells and the intact mouse retina.. This study represents, to our knowledge, the first report of the suppressive effects of OTC on inflammation in cultured RPE cells and on inflammation and oxidative stress in the retina in vivo.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; ATP-Binding Cassette Transporters; Cation Transport Proteins; Cell Line; Chemokine CCL2; Gene Expression Regulation; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocarboxylic Acid Transporters; Oxidative Stress; Pyrrolidonecarboxylic Acid; Receptors, G-Protein-Coupled; Receptors, Nicotinic; Retinal Pigment Epithelium; RNA, Messenger; Thiazolidines; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

T helper type 9 (TH9) cells can mediate tumor immunity and participate in autoimmune and allergic inflammation in mice, but little is known about the TH9 cells that develop in vivo in humans. We isolated T cells from human blood and tissues and found that most memory TH9 cells were skin-tropic or skin-resident. Human TH9 cells coexpressed tumor necrosis factor-α and granzyme B and lacked coproduction of TH1/TH2/TH17 cytokines, and many were specific for Candida albicans. Interleukin-9 (IL-9) production was transient and preceded the up-regulation of other inflammatory cytokines. Blocking studies demonstrated that IL-9 was required for maximal production of interferon-γ, IL-9, IL-13, and IL-17 by skin-tropic T cells. IL-9-producing T cells were increased in the skin lesions of psoriasis, suggesting that these cells may contribute to human inflammatory skin disease. Our results indicate that human TH9 cells are a discrete T cell subset, many are tropic for the skin, and although they may function normally to protect against extracellular pathogens, aberrant activation of these cells may contribute to inflammatory diseases of the skin.

Topics: Animals; Autocrine Communication; Candida albicans; Dermatitis, Atopic; Humans; Inflammation; Interleukin-2; Interleukin-9; Lymphocyte Activation; Mice; Paracrine Communication; Psoriasis; Skin; T-Lymphocytes, Helper-Inducer; Transforming Growth Factor beta

Inflammation and its consequent fibrosis are two main features of diabetic nephropathy (DN), but target therapy on these processes for DN remains yet ineffective. We report here that miR-29b is a novel therapeutic agent capable of inhibiting progressive renal inflammation and fibrosis in type 2 diabetes in db/db mice. Under diabetic conditions, miR-29b was largely downregulated in response to advanced glycation end (AGE) product, which was associated with upregulation of collagen matrix in mesangial cells via the transforming growth factor-β (TGF-β)/Smad3-dependent mechanism. These pathological changes were reversed by overexpressing miR-29b, but enhanced by knocking-down miR-29b. Similarly, loss of renal miR-29b was associated with progressive diabetic kidney injury, including microalbuminuria, renal fibrosis, and inflammation. Restored renal miR-29b by the ultrasound-based gene therapy was capable of attenuating diabetic kidney disease. Further studies revealed that inhibition of Sp1 expression, TGF-β/Smad3-dependent renal fibrosis, NF-κB-driven renal inflammation, and T-bet/Th1-mediated immune response may be mechanisms associated with miR-29b treatment in db/db mice. In conclusion, miR-29b may play a protective role in diabetic kidney disease and may have therapeutic potential for diabetic kidney complication.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Fibrosis; Genetic Therapy; Humans; Inflammation; Mice; MicroRNAs; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

Asthma is a chronic airway disorder characterized by recurrent attacks of breathlessness and wheezing, affecting 300 million people around the world (available at: www.who.int). To date, genetic factors associated with asthma susceptibility have been unable to explain the full etiology of asthma. Recent studies have demonstrated that the epigenetic disruption of gene expression plays an equally important role in the development of asthma through interaction with our environment. We sensitized 6-week-old C57BL/6J mice with house-dust-mite (HDM) extracts intraperitoneally followed by 5 weeks of exposure to HDM challenges (three times a week) intratracheally. HDM-exposed mice showed an increase in airway hyper-responsiveness (AHR) and inflammation together with structural remodeling of the airways. We applied methylated DNA immunoprecipitation-next generation sequencing (MeDIP-seq) for profiling of DNA methylation changes in the lungs in response to HDM. We observed about 20 million reads by a single-run of massive parallel sequencing. We performed bioinformatics and pathway analysis on the raw sequencing data to identify differentially methylated candidate genes in HDM-exposed mice. Specifically, we have revealed that the transforming growth factor beta signaling pathway is epigenetically modulated by chronic exposure to HDM. Here, we demonstrated that a specific allergen may play a role in AHR through an epigenetic mechanism by disrupting the expression of genes in lungs that might be involved in airway inflammation and remodeling. Our findings provide new insights into the potential mechanisms by which environmental allergens induce allergic asthma and such insights may assist in the development of novel preventive and therapeutic options for this debilitative disease.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cells, Cultured; Computational Biology; DNA Methylation; Epigenesis, Genetic; Gene Expression Profiling; High-Throughput Nucleotide Sequencing; Hypersensitivity; Immunoprecipitation; Inflammation; Lung; Male; Mice; Mice, Inbred C57BL; Pyroglyphidae; Signal Transduction; Trachea; Transforming Growth Factor beta

Chronic inflammation is rapidly becoming recognized as a key contributor to numerous pathologies. Despite detailed investigations, understanding of the molecular mechanisms regulating inflammation is incomplete. Knowledge of such critical regulatory processes and informative indicators of chronic inflammation is necessary for efficacious therapeutic interventions and diagnostic support to clinicians. We used a computational modeling approach to elucidate the critical factors responsible for chronic inflammation and to identify robust molecular indicators of chronic inflammatory conditions. Our kinetic model successfully captured experimentally observed cell and cytokine dynamics for both acute and chronic inflammatory responses. Using sensitivity analysis, we identified macrophage influx and efflux rate modulation as the strongest inducing factor of chronic inflammation for a wide range of scenarios. Moreover, our model predicted that, among all major inflammatory mediators, IL-6, TGF-β, and PDGF may generally be considered the most sensitive and robust indicators of chronic inflammation, which is supported by existing, but limited, experimental evidence.

Topics: Computer Simulation; Humans; Inflammation; Interleukin-6; Macrophages; Neutrophils; Platelet-Derived Growth Factor; Transforming Growth Factor beta; Wounds and Injuries

Acellular porcine small intestinal submucosa (SIS) has been successfully used for reconstructing esophagus with half circumferential defects. However, repairing full circumferential esophageal defects with SIS has been restricted due to the latter's poor mechanical properties. In the present study, synthetic polyesters biomaterial poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) and poly(lactide-co-glycolide) (PLGA) have been used to improve the mechanical properties of SIS. Feasibility of SIS/PHBHHx-PLGA composite material scaffold for esophageal tissue engineering has been assessed through a series of testing. The appropriate mixing ratio of PHBHHx and PLGA polymers has been determined as 5:5 by mechanical testing and in vitro degradation experiment. The morphology of constructed membranous and tubular scaffolds was also characterized. As confirmed by enzyme-linked immunosorbent assay, the contents of VEGF and TGF-β have respectively reached 657 ± 18 ng mL(-1) and 130 ± 4 pg mL(-1) within the SIS/PHBHHx-PLGA specimens. Biocompatibility of the SIS/PHBHHx-PLGA specimens with rat bone marrow mesenchymal stem cells (MSCs) was also evaluated by scanning electron microscopy and a live-dead cell viability assay. Actin filaments of MSCs on the composite materials were labeled. Biological safety of the extract from SIS/PHBHHx-PLGA specimens, measured as hemolysis rate, was all lower than 5%. Compared with SIS and SIS/PHBHHx-PLGA specimens, inflammatory reaction provoked by the PHBHHx-PLGA specimens in rats was however more severe. Our results have suggested that SIS/PHBHHx-PLGA composite material can offer a new approach for esophageal tissue engineering.

Topics: 3-Hydroxybutyric Acid; Actins; Animals; Biocompatible Materials; Bone Marrow Cells; Caproates; Cell Survival; Enzyme-Linked Immunosorbent Assay; Esophagus; Inflammation; Intestinal Mucosa; Lactic Acid; Male; Mesenchymal Stem Cells; Microscopy, Electron, Scanning; Polyesters; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Rats; Rats, Sprague-Dawley; Stress, Mechanical; Swine; Tissue Engineering; Tissue Scaffolds; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

In tegumentary leishmaniasis caused by Leishmania braziliensis, there is evidence that increased production of IFN-γ, TNF-α and absence of IL-10 is associated with strong inflammatory reaction and with tissue destruction and development of the lesions observed in cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML). We evaluate the role of regulatory cytokines and cytokine antagonists in the downregulation of immune response in L. braziliensis infection. Peripheral blood mononuclear cells from CL and ML were stimulated with soluble Leishmania antigen in the presence or absence of regulatory cytokines (IL-10, IL-27 and TGF-β) or antagonists of cytokines (α-TNF-α and α-IFN-γ). Cytokines production (IL-10, IL-17, TNF-α and IFN-γ) was measured by ELISA. IL-10 and TGF-β downmodulate TNF-α and IL-17 production, whereas IL-27 had no effect in the production of TNF-α, IFN-γ and IL-17 in these patients. Neutralization of TNF-α decreased IFN-γ level and the neutralization of IFN-γ decreased TNF-α level and increased IL-10 production. This study demonstrate that IL-10 and TGF-β are cytokines that appear to be more involved in modulation of immune response in CL and ML patients. IL-10 might have a protective role, since the neutralization of IFN-γ decreases the production of TNF-α in an IL-10-dependent manner.

Topics: Adult; Cells, Cultured; Female; Humans; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-17; Interleukins; Leishmania braziliensis; Leishmaniasis, Cutaneous; Leukocytes, Mononuclear; Male; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Recent epidemiological studies have identified interferon regulatory factor 8 (IRF8) as a susceptibility factor for multiple sclerosis (MS). However, how IRF8 influences the neuroinflammatory disease has remained unknown. By studying the role of IRF8 in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, we found that Irf8(-/-) mice are resistant to EAE. Furthermore, expression of IRF8 in antigen-presenting cells (APCs, such as macrophages, dendritic cells, and microglia), but not in T cells, facilitated disease onset and progression through multiple pathways. IRF8 enhanced αvβ8 integrin expression in APCs and activated TGF-β signaling leading to T helper 17 (Th17) cell differentiation. IRF8 induced a cytokine milieu that favored growth and maintenance of Th1 and Th17 cells, by stimulating interleukin-12 (IL-12) and IL-23 production, but inhibiting IL-27 during EAE. Finally, IRF8 activated microglia and exacerbated neuroinflammation. Together, this work provides mechanistic bases by which IRF8 contributes to the pathogenesis of MS.

Topics: Animals; Cells, Cultured; Dendritic Cells; Encephalomyelitis, Autoimmune, Experimental; Flow Cytometry; Inflammation; Integrins; Interferon Regulatory Factors; Macrophages; Mice; Mice, Knockout; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta

FTY720, an analogue of sphingosine-1-phosphate, is cardioprotective during acute injury. Whether long-term FTY720 affords cardioprotection is unknown. Here, we report the effects of oral FTY720 on ischemia/reperfusion injury and in hypomorphic apoE mice deficient in SR-BI receptor expression (ApoeR61(h/h)/SRB1(-/- mice), a model of diet-induced coronary atherosclerosis and heart failure. We added FTY720 (0.3 mg·kg(-1)·d(-1)) to the drinking water of C57BL/6J mice. After ex vivo cardiac ischemia/reperfusion injury, these mice had significantly improved left ventricular (LV) developed pressure and reduced infarct size compared with controls. Subsequently, ApoeR61(h/h)/SRB1(-/-) mice fed a high-fat diet for 4 weeks were treated or not with oral FTY720 (0.05 mg·kg(-1)·d(-1)). This sharply reduced mortality (P < 0.02) and resulted in better LV function and less LV remodeling compared with controls without reducing hypercholesterolemia and atherosclerosis. Oral FTY720 reduced the number of blood lymphocytes and increased the percentage of CD4+Foxp3+ regulatory T cells (Tregs) in the circulation, spleen, and lymph nodes. FTY720-treated mice exhibited increased TGF-β and reduced IFN-γ expression in the heart. Also, CD4 expression was increased and strongly correlated with molecules involved in natural Treg activity, such as TGF-β and GITR. Our data suggest that long-term FTY720 treatment enhances LV function and increases longevity in mice with heart failure. These benefits resulted not from atheroprotection but from systemic immunosuppression and a moderate reduction of inflammation in the heart.

Topics: Animals; Apolipoproteins E; Cardiotonic Agents; Coronary Artery Disease; Diet, High-Fat; Disease Models, Animal; Fingolimod Hydrochloride; Immunosuppressive Agents; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocardial Reperfusion Injury; Propylene Glycols; Sphingosine; Survival Rate; T-Lymphocytes, Regulatory; Time Factors; Transforming Growth Factor beta; Ventricular Function, Left

Chronic intestinal inflammation is associated with pathological angiogenesis that further amplifies the inflammatory response. Vascular endothelial growth factor (VEGF), is a major angiogenic cytokine that has been implicated in chronic colitis and inflammatory bowel diseases. Endoglin (CD105), a transforming growth factor-β superfamily co-receptor expressed on endothelial and some myeloid cells, is a modulator of angiogenesis involved in wound healing and potentially in resolution of inflammation. We showed previously that Endoglin heterozygous (Eng (+/-)) mice subjected to dextran sodium sulfate developed severe colitis, abnormal colonic vessels and high tissue VEGF. We therefore tested in the current study if treatment with a monoclonal antibody to VEGF could ameliorate chronic colitis in Eng (+/-) mice. Tissue inflammation and microvessel density (MVD) were quantified on histological slides. Colonic wall thickness, microvascular hemodynamics and targeted MAdCAM-1(+) inflamed vessels were assessed in vivo by ultrasound. Mediators of angiogenesis and inflammation were measured by Milliplex and ELISA assays. Colitic Eng (+/-) mice showed an increase in intestinal inflammation, MVD, colonic wall thickness, microvascular hemodynamics and the number of MAdCAM-1(+) microvessels relative to colitic Eng (+/+) mice; these parameters were all attenuated by anti-VEGF treatment. Of all factors up-regulated in the inflamed gut, granulocyte colony-stimulating factor (G-CSF) and amphiregulin were further increased in colitic Eng (+/-) versus Eng (+/+) mice. Anti-VEGF therapy decreased tissue VEGF and inflammation-induced endoglin, IL-1β and G-CSF in colitic Eng (+/-) mice. Our results suggest that endoglin modulates intestinal angiogenic and inflammatory responses in colitis. Furthermore, contrast-enhanced ultrasound provides an excellent non-invasive imaging modality to monitor gut angiogenesis, inflammation and responses to anti-angiogenic treatment.

Topics: Animals; Antibodies, Monoclonal; Colitis; Colon; Endoglin; Female; Granulocyte Colony-Stimulating Factor; Hemodynamics; Heterozygote; Inflammation; Inflammation Mediators; Interleukin-1beta; Intestines; Intracellular Signaling Peptides and Proteins; Male; Mice, Inbred C57BL; Microvessels; Platelet Endothelial Cell Adhesion Molecule-1; Smad Proteins; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Topics: Ehlers-Danlos Syndrome; Female; Humans; Inflammation; Male; Transforming Growth Factor beta

Left atrial (LA) remodeling associated with atrial fibrillation (AF) is known to be related to inflammation and collagen turnover. We investigated the changes in the biomarkers of inflammation and collagen turnover in relation to LA reverse remodeling during the 1st year after AF ablation.. Biomarkers of inflammation [high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6)] and collagen turnover [matrix metalloproteinase-2 (MMP-2), tissue inhibitor of MMP-2 (TIMP-2), transforming growth factor beta 1 (TGF-β1)], as well as asymmetric dimethylarginine (ADMA) and adiponectin levels were measured, and echocardiographic measurements were obtained before and 3, 6, and 12 months after ablation in 60 AF patients (49 males; age, 57.6 ± 10.9 years).. During a 12.1 (11.5-12.9)-month follow-up period, AF recurred in 29 patients (48 %). Neither the LA volume (LAV) nor the left ventricular ejection fraction (LVEF) changed significantly during the 1st year in this group, but the LAV decreased significantly, and the LVEF increased significantly in the nonrecurrence group. The hs-CRP and IL-6 decreased after ablation but returned near to baseline levels in both groups by 12 months. The MMP-2 remained increased during the 1st year in both groups, whereas the TIMP-2 increased markedly in the nonrecurrence group but did not change substantially in the recurrence group. The TGF-β1 increased in both groups, but the change was less pronounced in the recurrence group. The ADMA and adiponectin levels did not change substantially in either group.. Despite reverse remodeling, the inflammation and collagen turnover biomarker levels are quite progressive during the 1st year after ablation and may explain the late AF recurrence.

Topics: Adiponectin; Arginine; Atrial Fibrillation; Biomarkers; C-Reactive Protein; Catheter Ablation; Diagnostic Imaging; Echocardiography; Electrocardiography; Extracellular Matrix; Female; Humans; Inflammation; Interleukin-6; Male; Matrix Metalloproteinase 2; Middle Aged; Predictive Value of Tests; Recurrence; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta; Treatment Outcome

Determination of signaling pathways that regulate beta-cell replication is critical for beta-cell therapy. Here, we show that blocking pancreatic macrophage infiltration after pancreatic duct ligation (PDL) completely inhibits beta-cell proliferation. The TGFβ superfamily signaling inhibitor SMAD7 was significantly up-regulated in beta cells after PDL. Beta cells failed to proliferate in response to PDL in beta-cell-specific SMAD7 mutant mice. Forced expression of SMAD7 in beta cells by itself was sufficient to promote beta-cell proliferation in vivo. M2, rather than M1 macrophages, seem to be the inducers of SMAD7-mediated beta-cell proliferation. M2 macrophages not only release TGFβ1 to directly induce up-regulation of SMAD7 in beta cells but also release EGF to activate EGF receptor signaling that inhibits TGFβ1-activated SMAD2 nuclear translocation, resulting in TGFβ signaling inhibition. SMAD7 promotes beta-cell proliferation by increasing CyclinD1 and CyclinD2, and by inducing nuclear exclusion of p27. Our study thus reveals a molecular pathway to potentially increase beta-cell mass through enhanced SMAD7 activity induced by extracellular stimuli.

Topics: Animals; Cell Movement; Cell Nucleus; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p27; Disease Models, Animal; ErbB Receptors; Inflammation; Insulin-Secreting Cells; Ligation; Macrophages; Mice; Mice, Inbred C57BL; Models, Biological; Signal Transduction; Smad7 Protein; Transforming Growth Factor beta; Up-Regulation

We recently identified endotrophin as an adipokine with potent tumour-promoting effects. However, the direct effects of local accumulation of endotrophin in adipose tissue have not yet been studied. Here we use a doxycycline-inducible adipocyte-specific endotrophin overexpression model to demonstrate that endotrophin plays a pivotal role in shaping a metabolically unfavourable microenvironment in adipose tissue during consumption of a high-fat diet (HFD). Endotrophin serves as a powerful co-stimulator of pathologically relevant pathways within the 'unhealthy' adipose tissue milieu, triggering fibrosis and inflammation and ultimately leading to enhanced insulin resistance. We further demonstrate that blocking endotrophin with a neutralizing antibody ameliorates metabolically adverse effects and effectively reverses metabolic dysfunction induced during HFD exposure. Collectively, our findings demonstrate that endotrophin exerts a major influence in adipose tissue, eventually resulting in systemic elevation of pro-inflammatory cytokines and insulin resistance, and the results establish endotrophin as a potential target in the context of metabolism and cancer.

Topics: Adipocytes; Adipose Tissue; Adult; Animals; Collagen Type VI; Diabetes Mellitus; Diet, High-Fat; Energy Metabolism; Female; Fibrosis; Gene Expression; Humans; Inflammation; Insulin Resistance; Male; Matrix Metalloproteinase 12; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Confocal; Middle Aged; Obesity; Peptide Fragments; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta

In order to gain further insight on the crosstalk between pancreatic cancer (PDAC) and stromal cells, we investigated interactions occurring between TGFβ1 and the inflammatory proteins S100A8, S100A9 and NT-S100A8, a PDAC-associated S100A8 derived peptide, in cell signaling, intracellular calcium (Cai2+) and epithelial to mesenchymal transition (EMT). NF-κB, Akt and mTOR pathways, Cai2+ and EMT were studied in well (Capan1 and BxPC3) and poorly differentiated (Panc1 and MiaPaCa2) cell lines.. NT-S100A8, one of the low molecular weight N-terminal peptides from S100A8 to be released by PDAC-derived proteases, shared many effects on NF-κB, Akt and mTOR signaling with S100A8, but mainly with TGFβ1. The chief effects of S100A8, S100A9 and NT-S100A8 were to inhibit NF-κB and stimulate mTOR; the molecules inhibited Akt in Smad4-expressing, while stimulated Akt in Smad4 negative cells. By restoring Smad4 expression in BxPC3 and silencing it in MiaPaCa2, S100A8 and NT-S100A8 were shown to inhibit NF-κB and Akt in the presence of an intact TGFβ1 canonical signaling pathway. TGFβ1 counteracted S100A8, S100A9 and NT-S100A8 effects in Smad4 expressing, not in Smad4 negative cells, while it synergized with NT-S100A8 in altering Cai2+ and stimulating PDAC cell growth. The effects of TGFβ1 on both EMT (increased Twist and decreased N-Cadherin expression) and Cai2+ were antagonized by S100A9, which formed heterodimers with TGFβ1 (MALDI-TOF/MS and co-immuno-precipitation).. The effects of S100A8 and S100A9 on PDAC cell signaling appear to be cell-type and context dependent. NT-S100A8 mimics the effects of TGFβ1 on cell signaling, and the formation of complexes between TGFβ1 with S100A9 appears to be the molecular mechanism underlying the reciprocal antagonism of these molecules on cell signaling, Cai2+ and EMT.

Topics: Calcium Signaling; Calgranulin A; Calgranulin B; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Humans; Inflammation; NF-kappa B; Pancreatic Neoplasms; Peptide Fragments; Protein Binding; Proteolysis; Proto-Oncogene Proteins c-akt; Smad4 Protein; Transforming Growth Factor beta

Studies have highlighted the importance of histone deacetylase (HDAC)-mediated epigenetic processes in the development of diabetic complications. Inhibitors of HDAC are a novel class of therapeutic agents in diabetic nephropathy, but currently available inhibitors are mostly nonselective inhibit multiple HDACs, and different HDACs serve very distinct functions. Therefore, it is essential to determine the role of individual HDACs in diabetic nephropathy and develop HDAC inhibitors with improved specificity. First, we identified the expression patterns of HDACs and found that, among zinc-dependent HDACs, HDAC2/4/5 were upregulated in the kidney from streptozotocin-induced diabetic rats, diabetic db/db mice, and in kidney biopsies from diabetic patients. Podocytes treated with high glucose, advanced glycation end products, or transforming growth factor-β (common detrimental factors in diabetic nephropathy) selectively increased HDAC4 expression. The role of HDAC4 was evaluated by in vivo gene silencing by intrarenal lentiviral gene delivery and found to reduce renal injury in diabetic rats. Podocyte injury was associated with suppressing autophagy and exacerbating inflammation by HDAC4-STAT1 signaling in vitro. Thus, HDAC4 contributes to podocyte injury and is one of critical components of a signal transduction pathway that links renal injury to autophagy in diabetic nephropathy.

Topics: Animals; Autophagy; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enzyme Inhibitors; Gene Silencing; Glucose; Glycation End Products, Advanced; Histone Deacetylase 2; Histone Deacetylases; Humans; Inflammation; Male; Mice; Podocytes; Rats; Rats, Sprague-Dawley; Repressor Proteins; RNA, Messenger; Signal Transduction; STAT1 Transcription Factor; Transforming Growth Factor beta; Up-Regulation

The goal was to identify cytokines associated with necrotizing enterocolitis (NEC). Based on our earlier reports of decreased tissue expression of transforming growth factor (TGF)-β, we hypothesized that infants with NEC also have low blood TGF-β levels. We further hypothesized that because fetal inflammation increases the risk of NEC, infants who develop NEC have elevated blood cytokine levels in early neonatal period.. Data on 104 extremely-low-birth-weight infants with NEC and 893 without NEC from 17 centers were analyzed. Clinical information was correlated with blood cytokine levels on postnatal day 1 (D1), D3, D7, D14, and D21.. Male gender, non-Caucasian/non-African American ethnicity, sepsis, lower blood TGF-β and interleukin (IL)-2 levels, and higher IL-8 levels were associated with NEC. The NEC group had lower TGF-β levels than controls since D1. The diagnosis of NEC was associated with elevated IL-1β, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1/CC-motif ligand-2, macrophage inflammatory protein-1β/CC-motif ligand-3, and C-reactive protein.. Clinical characteristics, such as gender and ethnicity, and low blood TGF-β levels are associated with higher risk of NEC. Infants who developed NEC did not start with high blood levels of inflammatory cytokines, but these rose mainly after the onset of NEC.

Topics: Biomarkers; Cytokines; Enterocolitis, Necrotizing; False Positive Reactions; Female; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature; Inflammation; Interleukin-2; Interleukin-8; Male; Reproducibility of Results; Risk; Transforming Growth Factor beta

Virus-specific CD8(+) T cells provide classical adaptive immunity by responding to cognate peptide antigen, but they may also act in an "innate" capacity by responding directly to cytokine stimulation. Here, we examined regulation of these distinct T cell functions by anti-inflammatory cytokines (interleukin-4 [IL-4], IL-10, and transforming growth factor β [TGF-β]). Innate gamma interferon (IFN-γ) production by CD8(+) T cells following exposure to IL-12 plus IL-18, IL-12 plus tumor necrosis factor alpha (TNF-α), or IL-12 plus IL-15 was inhibited by exposure to anti-inflammatory cytokines either before or shortly after stimulation. However, inhibition was not universal, as other activation parameters, including upregulation of CD25 and CD69, remained largely unaltered. In contrast, peptide-specific T cell responses were resistant to inhibition by anti-inflammatory cytokines. This was not due to downregulation of cytokine receptor expression or an inability to signal through cytokine receptors since phosphorylation of STAT proteins remained intact. These results highlight key differences in cytokine-mediated regulation of innate and adaptive T cell functions, which may help balance effective antiviral immune responses while reducing T cell-mediated immunopathology.. This study demonstrates key differences between the regulation of "innate" and "adaptive" CD8(+) T cell functions following activation by innate cytokines or viral peptide. Innate production of IFN-γ by CD8(+) T cells following exposure to IL-12 plus IL-18, IL-12 plus TNF-α, or IL-12 plus IL-15 was inhibited by exposure to anti-inflammatory cytokines (IL-4, IL-10, and TGF-β). However, inhibition was not universal, as other activation parameters, including upregulation of CD25 and CD69, remained largely unaltered. In contrast, peptide-specific T cell responses were resistant to inhibition by anti-inflammatory cytokines. This distinct regulation of innate and adaptive T cell functions may serve to reduce T cell-mediated immunopathology while still allowing for effective antiviral responses at a site of infection.

Topics: Adaptive Immunity; Animals; Blotting, Western; CD8-Positive T-Lymphocytes; Cells, Cultured; Flow Cytometry; Immunity, Innate; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-4; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta

Pulmonary fibrosis (PF) is a common complication in those interstitial lung diseases patients, which will result in poor prognosis and short survival. Traditional therapeutic methods such as glucocorticoid and cytotoxic drugs are insufficient for treating PF and may cause severe side effects. Recent studies showed that traditional Chinese herbal abstraction such as Tanshinone IIA (TIIA) was displayed significant anti-PF effects in animal models. However, the exact mechanisms underlying the protective effects of TIIA were not fully understood. Here we further investigated the protective effects of TIIA and its mechanisms underlying. PF models of rat were induced by bleomycin (BLM); TIIA was administered subsequently. The PF changes were identified by histopathological analyses. The results showed that BLM resulted in severe PF and alveolar inflammation; together with significant elevation of transforming growth factor-β 1 (TGF-β1). Angiotensin-converting enzyme 2 (ACE-2) together with angiotensin-(1-7) [ANG-(1-7)] were both greatly reduced after BLM administration. TIIA treatment notably attenuated BLM induced PF and inflammation, decreased expression of TGF-β1 and reversed ACE-2 and ANG-(1-7) production in rat lungs. Thus we may draw the conclusion that TIIA may exert protective effects on BLM induced PF in rats, and the ACE-2/ANG-(1-7) axis may ascribe to those protective effects.

Topics: Abietanes; Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Bleomycin; Humans; Inflammation; Peptide Fragments; Peptidyl-Dipeptidase A; Pulmonary Fibrosis; Rats; Transforming Growth Factor beta

This study investigated the effects of ascorbic acid and N-acetyl cysteine (NAC) antioxidants on the development of myringosclerosis (MS) in an experimental model.. Myringotomies were performed in the ears of 15 guinea pigs, and Spongostan pieces were placed on the perforated regions of the tympanic membrane. The subjects were divided randomly into three groups and treated with three different solutions on the Spongostan-group 1: (control, 0.9% saline), group 2 (ascorbic acid), and group 3 (NAC). On day 15 after treatment, specimens from the tympanic membranes were obtained and examined via light microscopy. Sclerosis and inflammation scores and the tympanic membrane thicknesses were evaluated. Immunohistochemical methods were used to evaluate the expression of VEGF, TGF-β, iNOS, and IL1-β in all groups.. Lower sclerosis and inflammation scores and reduced tympanic membrane thicknesses were observed in groups treated with NAC or ascorbic acid compared with the control group. Immunohistochemical studies revealed significantly less expression of VEGF, TGF-β, and iNOS in groups 2 and 3 compared with group 1. Additionally, IL1-β expression was significantly less in group 3 than in group 1. Compared with group 1, group 2 animals exhibited reduced inflammation in the lamina propria, fewer active fibroblasts, less leukocyte infiltration, and decreased thickness of the vessels; group 3 animals exhibited decreased numbers of active fibroblasts and collagen fibers in the lamina propria.. Inflammation scores, cellular infiltration, and expression of VEGF, TGF-β, and iNOS were reduced by ascorbic acid and/or NAC treatments, thereby decreasing MS development. Decreased expression of IL1-β was observed only in animals treated with NAC.

Topics: Acetylcysteine; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Female; Fibrin Foam; Fibroblasts; Free Radical Scavengers; Guinea Pigs; Hemostatics; Immunohistochemistry; Inflammation; Leukocytes; Microscopy; Mucous Membrane; Myringosclerosis; Nitric Oxide Synthase; Random Allocation; Transforming Growth Factor beta; Tympanic Membrane; Vascular Endothelial Growth Factor A

High-grade glioma is a malignant tumour; the pathogenesis is to be further investigated. Interleukin (IL)-17 is an inflammatory cytokine. Chronic inflammation is a pathological feature of cancer. This study aimed to characterize the glioma-derived IL-17(+) regulatory T cells (Treg). In this study, single cells were isolated from surgically removed high-grade glioma tissue and examined by flow cytometry. The immune suppressor effect of IL-17(+) Tregs on CD8(+) T cells was assessed in vitro. The results showed that abundant IL-17(+) Tregs were found in high-grade glioma tissue. The immune suppressor molecule, transforming growth factor (TGF)-beta, was detected in the IL-17(+) Tregs. The proliferation of CD8(+) T cells was suppressed by culturing with the IL-17(+) Tregs, which was partially abrogated by neutralizing antibodies of either TGF-beta or IL-17 and completely abrogated by neutralizing antibodies against both TGF-beta and IL-17. In conclusion, IL-17(+) Tregs exist in the high-grade glioma tissue; this subset of T cells can suppress CD8(+) T cell activities via releasing TGF-beta and IL-17.

Topics: Adolescent; Adult; Antibodies, Neutralizing; CD8-Positive T-Lymphocytes; Cell Proliferation; Child; Female; Forkhead Transcription Factors; Glioblastoma; Humans; Immunosuppressive Agents; Inflammation; Interleukin-17; Interleukin-2 Receptor alpha Subunit; Lymphocyte Activation; Male; Middle Aged; Receptors, Interleukin-17; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Young Adult

Blocking the activity of IL-6 can inhibit autoimmune diseases such as rheumatoid arthritis and Crohn's disease.. We examined whether an antibody against IL-6, tocilizumab (TCZ) (Actemra®), used clinically in rheumatoid arthritis (RA) would have similar anti-inflammatory effects in EAE after oral administration.. B6 mice were immunized with MOG peptide 35-55 and gavaged with control saline or TCZ during ongoing disease. Splenocytes, CD4(+) T cells or macrophages/monocyte lineage cells (CD11b(+)) from control fed or TCZ fed mice were adoptively transferred into active MOG peptide 35-55 immunized recipient mice during ongoing disease. Actively fed and recipient mice were examined for disease inhibition, inflammation, and cytokine responses.. Ingested (oral) TCZ inhibited ongoing disease and decreased inflammation. Adoptively transferred cells from TCZ fed donors protected against actively induced disease and decreased inflammation. There was a decrease in IL-6 in actively treated spleen, decrease in TNF-α, Th1-like cytokine IL-12 and increase in Th2-like cytokine IL-10 in active fed and adoptively treated recipients.. Ingested (orally administered) TCZ can inhibit disease, CNS inflammation, decrease pro-inflammatory Th1-like cytokines and increase Th2-like anti-inflammatory cytokines.

Topics: Administration, Oral; Adoptive Transfer; Animals; Antibodies, Monoclonal, Humanized; CD11b Antigen; CD4 Antigens; CD4-Positive T-Lymphocytes; Cytokines; Encephalomyelitis, Autoimmune, Experimental; Female; Forkhead Transcription Factors; Immunization; Inflammation; Interleukin-2 Receptor alpha Subunit; Mice, Inbred C57BL; Spleen; Th1 Cells; Th2 Cells; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The aim of this study was to investigate the effects of systemically administered bone-marrow-derived mesenchymal stromal cells (MSCs) on the early acute phase of inflammation in the alkali-burned eye. Mice with damaged eyes were either untreated or treated 24 h after the injury with an intravenous administration of fluorescent-dye-labeled MSCs that were unstimulated or pretreated with interleukin-1α (IL-1α), transforming growth factor-β (TGF-β), or interferon-γ (IFN-γ). Analysis of cell suspensions prepared from the eyes of treated mice on day 3 after the alkali burn revealed that MSCs specifically migrated to the damaged eye and that the number of labeled MSCs was more than 30-times higher in damaged eyes compared with control eyes. The study of the composition of the leukocyte populations within the damaged eyes showed that all types of tested MSCs slightly decreased the number of infiltrating lymphoid and myeloid cells, but only MSCs pretreated with IFN-γ significantly decreased the percentage of eye-infiltrating cells with a more profound effect on myeloid cells. Determining cytokine and NO production in the damaged eyes confirmed that the most effective immunomodulation was achieved with MSCs pretreated with IFN-γ, which significantly decreased the levels of the proinflammatory molecules IL-1α, IL-6, and NO. Taken together, the results show that systemically administered MSCs specifically migrate to the damaged eye and that IFN-γ-pretreated MSCs are superior in inhibiting the acute phase of inflammation, decreasing leukocyte infiltration, and attenuating the early inflammatory environment.

Topics: Alkalies; Allografts; Animals; Antiviral Agents; Burns, Chemical; Eye Burns; Female; Inflammation; Interferon-gamma; Interleukin-1alpha; Mesenchymal Stem Cell Transplantation; Mice; Mice, Inbred BALB C; Stem Cell Niche; Transforming Growth Factor beta

Glioblastoma multiforme (GBM) represents a very aggressive brain tumor. Angiogenesis is the formation of a network of new blood vessels, from preexisting ones. It plays an important role in the formation of the tumor, as it supplies it with oxygen and nutrients. Angiogenesis and inflammation play essential roles in glioblastoma development. These processes are regulated by the balance of a few molecules, acting as pro- or antiangiogenic and pro- or anti-inflammatory factors. The purpose of our study was to evaluate the expression of 7 markers involved in angiogenesis and inflammation pathways in patients with glioblastoma. VEGF, PDGF-bb, IGF-1, TGF-β, TNF-α, IL-6 and IL-8 levels were measured using the ELISA method, in the preoperative sera of 14 patients with histopathologically confirmed glioblastoma multiforme and 32 healthy patients. Serum levels of PDGF-bb, IGF-1 and IL-8 were significantly higher in patients with GBM, compared to the control group (p-value < 0.01). A statistically significant correlation has been found between IGF-1 and IL-6 levels (rho= -0.53, p-value < 0.05) and also between TNF-α and IL-6 levels (rho=0.60, p-value < 0.05). Statistically significant associations have been found between the presence of low levels of IL-8 and the development of coagulation necrosis (p-value < 0.05), high levels of VEGF and development of ischemic necrosis (p-value < 0.01) and high levels of IL-8 and the development of endothelial hyperplasia (p-value < 0.05). We have observed no statistically significant associations between the serum levels of the markers and the survival rates.

Topics: Becaplermin; Biomarkers; Brain Neoplasms; Case-Control Studies; Disease-Free Survival; Glioblastoma; Humans; Inflammation; Insulin-Like Growth Factor I; Interleukin-6; Interleukin-8; Neovascularization, Physiologic; Predictive Value of Tests; Proto-Oncogene Proteins c-sis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Interleukin (IL)-17 represents a family of cytokines with six members, namely IL-17A, B, C, D, E, and F. IL-17A and IL-17F are best studied proinflammatory cytokines. CD4(+) T helper cells producing IL-17A have been identified as a distinct T helper subset, Th17 cells. IL-17 and Th17 cells are important mediators in tissue inflammation in immune-mediated inflammatory diseases. IL-17 is also produced by other immune cells and plays an important role in host defense against microbial infection. Cell-based assays are sensitive and quantitative, and enable identification of cellular sources of IL-17 production. This chapter describes usage of flow cytometry and ELISPOT assays to quantify IL-17A-producing cells in disease and in vitro experiments to study T cell function.

Topics: Animals; Antibodies; Brefeldin A; Enzyme-Linked Immunospot Assay; Female; Flow Cytometry; Fluorescein-5-isothiocyanate; Fluorescent Dyes; Humans; Inflammation; Interleukin-17; Interleukin-6; Ionomycin; Mice; Mice, Inbred C57BL; Phycoerythrin; Quinolinium Compounds; Tetradecanoylphorbol Acetate; Th17 Cells; Transforming Growth Factor beta

The role of body weight in the pathogenesis of osteoarthritis (OA) - previously considered the sole factor in the association between obesity and OA - is being re-evaluated as the contribution of adiposity to the cartilage degenerative process becomes clearer. The current study has been undertaken to better understand the role of adipose-derived proteins, namely adipokines, in OA. For this purpose, we investigated in patients with OA the relationships between the joint levels of leptin, adiponectin and resistin and those of factors involved in inflammation and cartilage maintenance. The sandwich enzyme-linked immunosorbent assays were used to determine in the synovial fluid (SF) from 35 OA patients, the concentrations of adipokines, interleukin-6 (IL-6) and transforming growth factor-β (TGF-β). The soluble form of leptin receptor (sOb-R) was also examined to evaluate the biological active free form of leptin. Correlation analysis indicate that IL-6 levels are positively related to the levels of resistin and adiponectin. Surprisingly, the free form of leptin, but not the total leptin, is negatively associated with IL-6. Beside, adiponectin is the single adipokine that is correlated with TGF-β. Interestingly, a sexual dimorphism is observed in the study as correlations between adipokines and IL-6 or TGF-β are found only with female OA patients. Taken together, these findings suggest that only adiponectin may contribute to the metabolic changes associated with OA. The three adipokines may also be involved in inflammation, but with opposite effects. Both resistin and adiponectin may exhibit pro-inflammatory activity while the free form of leptin may down-regulate the inflammation.

Topics: Adiponectin; Aged; Aged, 80 and over; Arthroplasty, Replacement, Knee; Cartilage; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Female; Humans; Inflammation; Interleukin-6; Leptin; Male; Middle Aged; Osteoarthritis, Knee; Receptors, Leptin; Resistin; Synovial Fluid; Transforming Growth Factor beta

The crucial role of innate immunity in the pathogenesis of systemic sclerosis (SSc) is well established, and in the past few years the hypothesis that Toll-like receptor 4 (TLR4) activation induced by endogenous ligands is involved in fibrogenesis has been supported by several studies on skin, liver, and kidney fibrosis. These findings suggest that TLR4 activation can enhance transforming growth factor beta (TGF-β) signaling, providing a potential mechanism for TLR4/Myeloid differentiation factor 88 (MyD88)-dependent fibrosis.. The expression of TLR4, CD14 and MD2 genes was analyzed by real-time polymerase chain reaction from skin biopsies of 24 patients with diffuse cutaneous SSc. In order to investigate the effects of the chronic skin exposure to endotoxin (Lipopolysaccharide (LPS)) in vivo we examined the expression of inflammation, TGF-β signaling and cellular markers genes by nanostring. We also identified cellular subsets by immunohistochemistry and flow cytometry.. We found that TLR4 and its co-receptors, MD2 and CD14, are over-expressed in lesional skin from patients with diffuse cutaneous SSc, and correlate significantly with progressive or regressive skin disease as assessed by the Delta Modified Rodnan Skin Score. In vivo, a model of chronic dermal LPS exposure showed overexpression of proinflammatory chemokines, recruitment and activation of macrophages, and upregulation of TGF-β signature genes.. We delineated the role of MyD88 as necessary for the induction not only for the early phase of inflammation, but also for pro-fibrotic gene expression via activation of macrophages. Chronic LPS exposure might be a model of early stage of SSc when inflammation and macrophage activation are important pathological features of the disease, supporting a role for innate immune activation in SSc skin fibrosis.

Topics: Animals; Fibrosis; Flow Cytometry; Humans; Immunohistochemistry; Inflammation; Macrophage Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88; Real-Time Polymerase Chain Reaction; Scleroderma, Systemic; Skin; Toll-Like Receptor 4; Transcriptome; Transforming Growth Factor beta

Changes in lifestyle such as increase in high-fat food consumption are an important cause for vascular diseases. The present study aimed to investigate the involvement of ACE and TGF- β in the aorta stiffness induced by high-fat diet. C57BL/6 male mice were divided in two groups according to their diet for 8 weeks: standard diet (ST) and high-fat diet (HF). At the end of the protocol, body weight gain, adipose tissue content, serum lipids and glucose levels, and aorta morphometric and biochemical measurements were performed. Analysis of collagen fibers by picrosirius staining of aorta slices showed that HF diet promoted increase of thin (55%) and thick (100%) collagen fibers deposition and concomitant disorganization of these fibers orientations in the aorta vascular wall (50%). To unravel the mechanism involved, myeloperoxidase (MPO) and angiotensin I converting enzyme (ACE) were evaluated by protein expression and enzyme activity. HF diet increased MPO (90%) and ACE (28%) activities, as well as protein expression of ACE. TGF-β was also increased in aorta tissue of HF diet mice after 8 weeks. Altogether, we have observed that the HF diet-induced aortic stiffening may be associated with increased oxidative stress damage and activation of the RAS in vascular tissue.

Topics: Animals; Aorta; Biomarkers; Diet, High-Fat; Gene Expression Regulation; Humans; Inflammation; Mice; Oxidative Stress; Peptidyl-Dipeptidase A; Transforming Growth Factor beta; Vascular Stiffness; Weight Gain

FOXP3(+) regulatory T cells (Treg cells) are abundant in the intestine, where they prevent dysregulated inflammatory responses to self and environmental stimuli. It is now appreciated that Treg cells acquire tissue-specific adaptations that facilitate their survival and function; however, key host factors controlling the Treg response in the intestine are poorly understood. The interleukin (IL)-1 family member IL-33 is constitutively expressed in epithelial cells at barrier sites, where it functions as an endogenous danger signal, or alarmin, in response to tissue damage. Recent studies in humans have described high levels of IL-33 in inflamed lesions of inflammatory bowel disease patients, suggesting a role for this cytokine in disease pathogenesis. In the intestine, both protective and pathological roles for IL-33 have been described in murine models of acute colitis, but its contribution to chronic inflammation remains ill defined. Here we show in mice that the IL-33 receptor ST2 is preferentially expressed on colonic Treg cells, where it promotes Treg function and adaptation to the inflammatory environment. IL-33 signalling in T cells stimulates Treg responses in several ways. First, it enhances transforming growth factor (TGF)-β1-mediated differentiation of Treg cells and, second, it provides a necessary signal for Treg-cell accumulation and maintenance in inflamed tissues. Strikingly, IL-23, a key pro-inflammatory cytokine in the pathogenesis of inflammatory bowel disease, restrained Treg responses through inhibition of IL-33 responsiveness. These results demonstrate a hitherto unrecognized link between an endogenous mediator of tissue damage and a major anti-inflammatory pathway, and suggest that the balance between IL-33 and IL-23 may be a key controller of intestinal immune responses.

Topics: Animals; Colitis; Colon; Disease Models, Animal; Female; Immunity, Mucosal; Inflammation; Interleukin-23; Interleukin-33; Interleukins; Intestines; Male; Mice; Mice, Inbred C57BL; Receptors, Interleukin; Signal Transduction; T-Lymphocytes, Regulatory; Thymus Gland; Transforming Growth Factor beta

Aortic valve disease (AVD) is characterized by elastic fiber fragmentation (EFF), fibrosis and aberrant angiogenesis. Emilin1 is an elastin-binding glycoprotein that regulates elastogenesis and inhibits TGF-β signaling, but the role of Emilin1 in valve tissue is unknown. We tested the hypothesis that Emilin1 deficiency results in AVD, mediated by non-canonical (MAPK/phosphorylated Erk1 and Erk2) TGF-β dysregulation. Using histology, immunohistochemistry, electron microscopy, quantitative gene expression analysis, immunoblotting and echocardiography, we examined the effects of Emilin1 deficiency (Emilin1-/-) in mouse aortic valve tissue. Emilin1 deficiency results in early postnatal cell-matrix defects in aortic valve tissue, including EFF, that progress to latent AVD and premature death. The Emilin1-/- aortic valve displays early aberrant provisional angiogenesis and late neovascularization. In addition, Emilin1-/- aortic valves are characterized by early valve interstitial cell activation and proliferation and late myofibroblast-like cell activation and fibrosis. Interestingly, canonical TGF-β signaling (phosphorylated Smad2 and Smad3) is upregulated constitutively from birth to senescence, whereas non-canonical TGF-β signaling (phosphorylated Erk1 and Erk2) progressively increases over time. Emilin1 deficiency recapitulates human fibrotic AVD, and advanced disease is mediated by non-canonical (MAPK/phosphorylated Erk1 and Erk2) TGF-β activation. The early manifestation of EFF and aberrant angiogenesis suggests that these processes are crucial intermediate factors involved in disease progression and therefore might provide new therapeutic targets for human AVD.

Topics: Animals; Aortic Valve; Bicuspid Aortic Valve Disease; Calcinosis; Cell Proliferation; Cutis Laxa; Disease Models, Animal; Disease Progression; Elastic Tissue; Fibrosis; Heart Defects, Congenital; Heart Valve Diseases; Inflammation; Membrane Glycoproteins; Mice; Models, Biological; Myofibroblasts; Neovascularization, Pathologic; Signal Transduction; Transforming Growth Factor beta; Ultrasonography

Pulmonary hypertension is a progressive disease of various origins that is associated with right ventricular dysfunction. In the present study, the protective effect of diosgenin was investigated in monocrotaline-induced pulmonary hypertension in rats. Pulmonary hypertension was induced by a single subcutaneous injection of monocrotaline (60 mg/kg). Diosgenin (100 mg/kg) was given by oral administration once daily for 3 weeks. At the end of the experiment, mean arterial blood pressure, electrocardiography and echocardiography were recorded. Rats were then sacrificed and serum was separated for determination of total nitrate/nitrite level. Right ventricles and lungs were isolated for estimation of oxidative stress markers, tumor necrosis factor-alpha, total nitrate/nitrite and transforming growth factor-beta contents. Myeloperoxidase and caspase-3 activities in addition to endothelial and inducible nitric oxide synthase protein expression were also determined. Moreover, histological analysis of pulmonary arteries and cardiomyocyte cross-sectional area was performed. Diosgenin treatment provided a significant improvement toward preserving hemodynamic changes and alleviating oxidative stress, inflammatory and apoptotic markers induced by monocrotaline in rats. Furthermore, diosgenin therapy prevented monocrotaline-induced changes in nitric oxide production, endothelial and inducible nitric oxide synthase protein expression as well as histological analysis. These findings support the beneficial effect of diosgenin in pulmonary hypertension induced by monocrotaline in rats.

Topics: Animals; Caspase 3; Diosgenin; Glutathione; Heart Ventricles; Hypertension, Pulmonary; Inflammation; Lung; Male; Monocrotaline; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Peroxidase; Protective Agents; Pulmonary Artery; Rats, Wistar; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

We examined whether the loss of transient receptor potential ankyrin 1 (TRPA1), an irritant-sensing ion channel, or TRPA1 antagonist treatment affects the severity inflammation and scarring during tissue wound healing in a mouse cornea injury model. In addition, the effects of the absence of TRPA1 on transforming growth factor β1 (TGF-β1)-signaling activation were studied in cell culture. The lack of TRPA1 in cultured ocular fibroblasts attenuated expression of TGF-β1, interleukin-6, and α-smooth muscle actin, a myofibroblast the marker, but suppressed the activation of Smad3, p38 MAPK, ERK, and JNK. Stroma of the healing corneas of TRPA1(-/-) knockout (KO) mice appeared more transparent compared with those of wild-type mice post-alkali burn. Eye globe diameters were measured from photographs. An examination of the corneal surface and eye globes suggested the loss of TRPA1 suppressed post-alkali burn inflammation and fibrosis/scarring, which was confirmed by histology, immunohistochemistry, and gene expression analysis. Reciprocal bone marrow transplantation between mice showed that KO corneal tissue resident cells, but not KO bone marrow-derived cells, are responsible for KO mouse wound healing with reduced inflammation and fibrosis. Systemic TRPA1 antagonists reproduced the KO phenotype of healing. In conclusion, a loss or blocking of TRPA1 in mice reduces inflammation and fibrosis/scarring in the corneal stroma during wound healing following an alkali burn. The responsible mechanism may include the inhibition of TGF-β1-signaling cascades in fibroblasts by attenuated TRPA1 signaling. Inflammatory cells are considered to have a minimum involvement in the exhibition of the KO phenotype after injury.

Topics: Animals; Corneal Diseases; Eye Burns; Fibrosis; Inflammation; Mice; Mice, Knockout; Real-Time Polymerase Chain Reaction; Signal Transduction; Transforming Growth Factor beta; Transient Receptor Potential Channels; TRPA1 Cation Channel; Wound Healing

Leishmania (Viannia) parasites are etiological agents of cutaneous leishmaniasis in the New World. Infection is characterized by a mixed Th1/Th2 inflammatory response, which contributes to disease pathology. However, the role of regulatory T cells (Tregs) in Leishmania (Viannia) disease pathogenesis is unclear. Using the mouse model of chronic L. (V.) panamensis infection, we examined the hypothesis that Treg functionality contributes to control of pathogenesis. Upon infection, Tregs (CD4(+)Foxp3(+)) presented with a dysregulated phenotype, in that they produced IFN-γ, expressed Tbet, and had a reduced ability to suppress T cell proliferation in vitro. Targeted ablation of Tregs resulted in enlarged lesions, increased parasite load, and enhanced production of IL-17 and IFN-γ, with no change in IL-10 and IL-13 levels. This indicated that an increased inflammatory response was commensurate with disease exacerbation and that the remaining impaired Tregs were important in regulation of disease pathology. Conversely, adoptive transfer of Tregs from naive mice halted disease progression, lowered parasite burden, and reduced cytokine production (IL-10, IL-13, IL-17, IFN-γ). Because Tregs appeared to be important for controlling infection, we hypothesized that their expansion could be used as an immunotherapeutic treatment approach. As a proof of principle, chronically infected mice were treated with rIL-2/anti-IL-2 Ab complex to expand Tregs. Treatment transitorily increased the numbers and percentage of Tregs (draining lymph node, spleen), which resulted in reduced cytokine responses, ameliorated lesions, and reduced parasite load (10(5)-fold). Thus, immunotherapy targeting Tregs could provide an alternate treatment strategy for leishmaniasis caused by Leishmania (Viannia) parasites.

Topics: Animals; Antibodies; Antigen-Antibody Complex; Cell Proliferation; Female; Immunotherapy, Adoptive; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-13; Interleukin-17; Interleukin-2; Leishmania guyanensis; Leishmaniasis, Mucocutaneous; Lymphocyte Count; Mice; Mice, Inbred BALB C; Mice, Transgenic; Parasite Load; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Interest in manipulating the immunosuppressive powers of Foxp3-expressing T regulatory cells as an immunotherapy has been tempered by their reported ability to produce proinflammatory cytokines when manipulated in vitro, or in vivo. Understanding processes that can limit this potentially deleterious effect of Treg cells in a therapeutic setting is therefore important. Here, we have studied this using induced (i) Treg cells in which de novo Foxp3 expression is driven by TCR-stimulation in vitro in the presence of TGF-β. We show that iTreg cells can produce significant amounts of three proinflammatory cytokines (IFN-γ, GM-CSF and TNF-α) upon secondary TCR stimulation. GM-CSF is a critical T-cell derived cytokine for the induction of EAE in mice. Despite their apparent capacity to produce GM-CSF, myelin autoantigen-responsive iTreg cells were unable to provoke EAE. Instead, they maintained strong suppressive function in vivo, preventing EAE induction by their CD4+ Foxp3- counterparts. We identified that although iTreg cells maintained the ability to produce IFN-γ and TNF-α in vivo, their ability to produce GM-CSF was selectively degraded upon antigen stimulation under inflammatory conditions. Furthermore, we show that IL-6 and IL-27 individually, or IL-2 and TGF-β in combination, can mediate the selective loss of GM-CSF production by iTreg cells.

Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Forkhead Transcription Factors; Granulocyte-Macrophage Colony-Stimulating Factor; Immunotherapy; Inflammation; Interferon-gamma; Interleukin-12; Interleukin-2; Interleukin-6; Interleukins; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Antigen, T-Cell; T-Lymphocytes, Regulatory; Th1 Cells; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

This study aimed to investigate any inflammatory effect of nicotine on rat embryo by exposing their mothers to different dosages of nicotine during pregnancy. During this experimental study, 32 pregnant healthy Wistar rats were divided into 4 equal groups, including a control and 3 nicotine exposure groups. Injections were performed subcutaneously starting at the first day of pregnancy until parturition. As the dosages of nicotine were increased, the weight gain by pregnant rats and the mean weight of their newborns were significantly reduced. Mean ± SD of hs-CRP was significantly higher among groups exposed to various dosages of nicotine (2, 4, and 6 mg/kg) compared to the control group (P < 0.0001) and its increasing rate was also dose dependent. Mean ± SD serum level of IL-6 and TNF-α among all groups exposed to nicotine, except for 2 mg/kg nicotine injected group, was increased significantly (P < 0.0001). Mean ± SD of serum level of TGF-β and nitrite oxide among exposure groups showed significant differences compared to the control group only at the dosage of 6 mg/kg (P < 0.0001). The current study showed that exposing pregnant rats to nicotine causes a dose dependent increase in the rate of all the studied inflammatory serum markers among their newborns.

Topics: Animals; Animals, Newborn; C-Reactive Protein; Female; Inflammation; Interleukin-6; Male; Nicotine; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The plant Cecropia pachystachya Trécul has been used in Brazilian folk medicine to treat hypertension, bladder and kidney inflammation and renal diseases. The aim of this study was to evaluate the potential of the aqueous fraction from the ethanolic extract of Cecropia pachystachya (FCP) in the management of hypertension, inflammation and progressive renal disease in rats submitted to 5/6 nephrectomy.. Thirty male Wistar rats submitted to 5/6 nephrectomy (5/6 NE) were untreated (NE) or treated (NE+FCP) with the FCP (0.5g/kg/day). The treatment started 15 days after surgery, and the rats were followed for a period of 60 days. Systolic blood pressure (SBP) and albuminuria were evaluated from 15-60 days after the surgical procedure. Function and estructural renal changes, TGF-β (transforming growth factor β), MCP-1 (monocyte chemoattractant protein-1) and nitric oxide (NO) urinary excretion were analyzed. Expression and activity of the renal enzymes arginase (ARG), angiotensin converting enzyme (ACE), and MAP kinase p-JNK expression also were analyzed.. The nephrectomized rats developed progressive albuminuria and increased SBP that was less intense in the treated group. There was a reduction in the glomerular filtration rate (GFR) in the nephrectomized rats, which was attenuated by treatment with FCP extract. The treatment with FCP also attenuated the histological changes, reduced the expression and activity of renal arginase, the number of macrophages (ED-1 positive cells) and the p-JNK expression in the renal cortex of the rats submitted to 5/6 NE. The urinary excretion of TGF-β was less intense in the treated group and was associated with the reduction of the expression and activity of the renal arginase.. These results suggest that the reduction of renal arginase activity, p-JNK and TGF-β expression can explain the mechanism by which the treatment with C. pachystachya reduced the inflammation and improved renal function. This study presents the potential use of Cecropia pachystachya in the treatment of chronic renal diseases.

Topics: Albuminuria; Animals; Arginase; Brazil; Cecropia Plant; Disease Progression; Glomerular Filtration Rate; Hypertension; Inflammation; JNK Mitogen-Activated Protein Kinases; Kidney; Kidney Diseases; Male; Medicine, Traditional; Nephrectomy; Plant Extracts; Rats; Rats, Wistar; Transforming Growth Factor beta

Silicosis is an occupational lung disease, characterized by irreversible and progressive fibrosis. Silica exposure leads to intense lung inflammation, reactive oxygen production, and extracellular ATP (eATP) release by macrophages. The P2X7 purinergic receptor is thought to be an important immunomodulator that responds to eATP in sites of inflammation and tissue damage. The present study investigates the role of P2X7 receptor in a murine model of silicosis. To that end wild-type (C57BL/6) and P2X7 receptor knockout mice received intratracheal injection of saline or silica particles. After 14 days, changes in lung mechanics were determined by the end-inflation occlusion method. Bronchoalveolar lavage and flow cytometry analyzes were performed. Lungs were harvested for histological and immunochemistry analysis of fibers content, inflammatory infiltration, apoptosis, as well as cytokine and oxidative stress expression. Silica particle effects on lung alveolar macrophages and fibroblasts were also evaluated in cell line cultures. Phagocytosis assay was performed in peritoneal macrophages. Silica exposure increased lung mechanical parameters in wild-type but not in P2X7 knockout mice. Inflammatory cell infiltration and collagen deposition in lung parenchyma, apoptosis, TGF-β and NF-κB activation, as well as nitric oxide, reactive oxygen species (ROS) and IL-1β secretion were higher in wild-type than knockout silica-exposed mice. In vitro studies suggested that P2X7 receptor participates in silica particle phagocytosis, IL-1β secretion, as well as reactive oxygen species and nitric oxide production. In conclusion, our data showed a significant role for P2X7 receptor in silica-induced lung changes, modulating lung inflammatory, fibrotic, and functional changes.

Topics: Animals; Apoptosis; Bronchoalveolar Lavage Fluid; Collagen; Fibroblasts; Immunophenotyping; Inflammation; Interleukin-1beta; Lung; Macrophages, Alveolar; Mice; Mice, Inbred C57BL; NF-kappa B; NIH 3T3 Cells; Nitric Oxide; Nitric Oxide Synthase Type II; Phagocytosis; Pulmonary Fibrosis; Purinergic P2X Receptor Antagonists; Reactive Oxygen Species; Receptors, Purinergic P2X7; Rosaniline Dyes; Signal Transduction; Silicon Dioxide; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta

Cancer cells condition macrophages and other inflammatory cells in the tumor microenvironment so that these cells are more permissive for cancer growth and metastasis. Conditioning of inflammatory cells reflects, at least in part, soluble mediators (such as transforming growth factor β and IL-4) that are released by cancer cells and alter the phenotype of cells of the innate immune system. Signaling pathways in cancer cells that potentiate this activity are incompletely understood. The urokinase receptor (uPAR) is a cell-signaling receptor known to promote cancer cell survival, proliferation, metastasis, and cancer stem cell-like properties. The present findings show that uPAR expression in diverse cancer cells, including breast cancer, pancreatic cancer, and glioblastoma cells, promotes the ability of these cells to condition co-cultured bone marrow-derived macrophages so that the macrophages express significantly increased levels of arginase 1, a biomarker of the alternatively activated M2 macrophage phenotype. Expression of transforming growth factor β was substantially increased in uPAR-expressing cancer cells via a mechanism that requires uPA-initiated cell signaling. uPAR also controlled expression of IL-4 in cancer cells via a mechanism that involves activation of ERK1/2. The ability of uPAR to induce expression of factors that condition macrophages in the tumor microenvironment may constitute an important mechanism by which uPAR promotes cancer progression.

Topics: Animals; Arginase; Biomarkers, Tumor; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Coculture Techniques; Disease Progression; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Inflammation; Interleukin-4; Macrophages; Mice; Neoplasm Metastasis; Pancreatic Neoplasms; Phenotype; Receptors, Urokinase Plasminogen Activator; Signal Transduction; Transforming Growth Factor beta

We sought to determine the mechanisms underlying failure of muscle regeneration that is observed in dystrophic muscle through hypothesis generation using muscle profiling data (human dystrophy and murine regeneration). We found that transforming growth factor β-centered networks strongly associated with pathological fibrosis and failed regeneration were also induced during normal regeneration but at distinct time points. We hypothesized that asynchronously regenerating microenvironments are an underlying driver of fibrosis and failed regeneration. We validated this hypothesis using an experimental model of focal asynchronous bouts of muscle regeneration in wild-type (WT) mice. A chronic inflammatory state and reduced mitochondrial oxidative capacity are observed in bouts separated by 4 d, whereas a chronic profibrotic state was seen in bouts separated by 10 d. Treatment of asynchronously remodeling WT muscle with either prednisone or VBP15 mitigated the molecular phenotype. Our asynchronous regeneration model for pathological fibrosis and muscle wasting in the muscular dystrophies is likely generalizable to tissue failure in chronic inflammatory states in other regenerative tissues.

Topics: Animals; Anti-Inflammatory Agents; Cell Differentiation; Cells, Cultured; Dystrophin; Fibrosis; Humans; Inflammation; Mice; Mice, Transgenic; Mitochondria; Muscle, Skeletal; Muscular Dystrophies, Limb-Girdle; Muscular Dystrophy, Animal; Muscular Dystrophy, Duchenne; Muscular Dystrophy, Emery-Dreifuss; Prednisone; Pregnadienediols; Protein Interaction Mapping; Protein Interaction Maps; Protein Structure, Tertiary; Regeneration; RNA, Messenger; Stem Cells; Transforming Growth Factor beta

MicroRNAs are short non-coding single stranded RNAs that regulate gene expression. While much is known about the effects of individual microRNAs, there is now growing evidence that they can work in co-operative networks. MicroRNAs are known to be dysregulated in many diseases and affect pathways involved in the pathology. We investigated dysregulation of microRNA networks using asthma as the disease model. Asthma is a chronic inflammatory disease of the airways characterized by bronchial hyperresponsiveness and airway remodelling. The airway epithelium is a major contributor to asthma pathology and has been shown to produce an excess of inflammatory and pro-remodelling cytokines such as TGF-β, IL-6 and IL-8 as well as deficient amounts of anti-viral interferons. After performing microRNA arrays, we found that microRNAs -18a, -27a, -128 and -155 are down-regulated in asthmatic bronchial epithelial cells, compared to cells from healthy donors. Interestingly, these microRNAs are predicted in silico to target several components of the TGF-β, IL-6, IL-8 and interferons pathways. Manipulation of the levels of individual microRNAs in bronchial epithelial cells did not have an effect on any of these pathways. Importantly, knock-down of the network of microRNAs miR-18a, -27a, -128 and -155 led to a significant increase of IL-8 and IL-6 expression. Interestingly, despite strong in silico predictions, down-regulation of the pool of microRNAs did not have an effect on the TGF-β and Interferon pathways. In conclusion, using both bioinformatics and experimental tools we found a highly relevant potential role for microRNA dysregulation in the control of IL-6 and IL-8 expression in asthma. Our results suggest that microRNAs may have different roles depending on the presence of other microRNAs. Thus, interpretation of in silico analysis of microRNA function should be confirmed experimentally in the relevant cellular context taking into account interactions with other microRNAs when studying disease.

Topics: Asthma; Base Sequence; Bronchi; Down-Regulation; Epithelial Cells; Gene Expression Regulation; Gene Regulatory Networks; Humans; Inflammation; Interleukin-6; MicroRNAs; Molecular Sequence Data; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta

Topics: Animals; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Cell Activating Factor; B-Lymphocytes, Regulatory; Humans; Inflammation; Interleukin-10; Models, Theoretical; Self Tolerance; Transforming Growth Factor beta

Diabetic nephropathy is one of the most common causes of end-stage kidney disease. Aldosterone and angiotensin II appear to play a crucial role in the pathogenesis of this disease. The present study aimed to investigate effects of the combination therapy with spironolactone and candesartan on diabetic nephropathy and elucidate the underlying mechanism(s) involved. Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (STZ) (55 mg/kg). The diabetic rats were orally treated with spironolactone (50 mg/kg/day) and/or candesartan (1 mg/kg/day) for 8 weeks. Administration of STZ caused a marked elevation in the serum level of creatinine, urea and urinary albumin-creatinine ratio (ACR). This was associated with upregulated renal protein levels of nuclear factor-kappa B (NF-κB), transforming growth factor (TGF)-β, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) alongside increasing the renal superoxide anion (O2(-)) production, malondialdehyde (MDA) level and the systolic blood pressure. There was a marked decrease in nitric oxide (NO) bioavailability and antioxidant enzyme capacity. The combined therapy of spironolactone and candesartan significantly normalized the oxidative stress and fibrotic/inflammatory alterations. Additionally, the elevated blood pressure was attenuated by administration of candesartan alone or in combination. This was associated with improving the renal function parameters. The combined therapy exhibited more profound response compared to the monotherapy. In conclusion, our results demonstrate that the combined therapy of spironolactone and candesartan can confer an additive benefit over the use of either drug alone against STZ-induced diabetic nephropathy, presumably via attenuating the inflammatory responses and oxidative status markers.

Topics: Animals; Antioxidants; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cyclooxygenase 2; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Drug Therapy, Combination; Inflammation; Kidney; Male; Malondialdehyde; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Protective Agents; Rats; Rats, Wistar; Spironolactone; Streptozocin; Superoxides; Tetrazoles; Transforming Growth Factor beta

Naja naja atra venom (NNAV) displays diverse pharmacological actions including analgesia, anti-inflammation and immune regulation.In this study, we investigated the effects of NNAV on pulmonary fibrosis and its mechanisms of action.. To determine if Naja naja atra venom (NNAV) can produce beneficial effects on pulmonary fibrosis, two marine models of pulmonary fibrosis were produced with bleomycin (BLM) and lipopolysaccharide (LPS). NNAV (30, 90, 270 μg/kg) was orally administered once a day started five days before BLM and LPS until to the end of experiment. The effects of NNAV treatment on pulmonary injury were evaluated with arterial blood gas analysis, hydroxyproline (HYP) content assessment and HE/Masson staining. The effects of NNAV treatment on inflammatory related cytokines, fibrosis related TGF-β/Smad signaling pathway and oxidative stress were examined.. The results showed that NNAV improved the lung gas-exchange function and attenuated the fibrotic lesions in lung. NNAV decreased IL-1β and TNF-α levels in serum in both pulmonary fibrosis models. NNAV inhibited the activation of NF-κB in LPS-induced and TGF-β/Smad pathway in BLM-induced pulmonary fibrosis. Additionally, NNAV also increased the levels of SOD and GSH and reduced the levels of MDA in BLM-induced pulmonary fibrosis model.. The present study indicates that NNAV attenuates LPS- and BLM-induced lung fibrosis. Its mechanisms of action are associated with inhibiting inflammatory response and oxidative stress. The study suggests that NNAV might be a potential therapeutic drug for treatment of pulmonary fibrosis.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Bleomycin; Elapid Venoms; Elapidae; Female; Fibrosis; Hydroxyproline; Inflammation; Interleukin-1beta; Lung; Male; Mice; NF-kappa B; Oxidative Stress; Pulmonary Fibrosis; Rats, Sprague-Dawley; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Mucositis induced by anti-neoplastic drugs is an important, dose-limiting and costly side-effect of cancer therapy.. To evaluate the effect of the topical application of S-nitrosoglutathione (GSNO), a nitric oxide donor, on 5-fluorouracil (5-FU)-induced oral mucositis in hamsters.. Oral mucositis was induced in male hamsters by two intraperitoneal administrations of 5-FU on the first and second days of the experiment (60 and 40 mg/kg, respectively) followed by mechanical trauma on the fourth day. Animals received saline, HPMC or HPMC/GSNO (0.1, 0.5 or 2.0 mM) 1 h prior to the 5-FU injection and twice a day for 10 or 14 days. Samples of cheek pouches were harvested for: histopathological analysis, TNF-α and IL-1β levels, immunohistochemical staining for iNOS, TNF-α, IL-1β, Ki67 and TGF-β RII and a TUNEL assay. The presence and levels of 39 bacterial taxa were analyzed using the Checkerboard DNA-DNA hybridization method. The profiles of NO released from the HPMC/GSNO formulations were characterized using chemiluminescence.. The HPMC/GSNO formulations were found to provide sustained release of NO for more than 4 h at concentration-dependent rates of 14 to 80 nmol/mL/h. Treatment with HPMC/GSNO (0.5 mM) significantly reduced mucosal damage, inflammatory alterations and cell death associated with 5-FU-induced oral mucositis on day 14 but not on day 10. HPMC/GSNO administration also reversed the inhibitory effect of 5-FU on cell proliferation on day 14. In addition, we observed that the chemotherapy significantly increased the levels and/or prevalence of several bacterial species.. Topical HPMC/GSNO accelerates mucosal recovery, reduces inflammatory parameters, speeds up re-epithelization and decreases levels of periodontopathic species in mucosal ulcers.

Topics: Administration, Topical; Animals; Cricetinae; Disease Models, Animal; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Interleukin-1beta; Male; Neoplasms; Nitric Oxide Synthase Type II; S-Nitrosoglutathione; Stomatitis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

It has been shown recently that significant number (to 40% from total population) of macrophage foam cells (MFC) is formed during early time (24 h) of zymosan-induced peritonitis resolution and agonists of peroxisome proliferation activated receptors-α, -γ (PPAR-α, -γ) exert anti-inflammatory action, protecting their formation (Dushkin et al., 2007). The work is devoted to investigate of the influence of cholesterol-containing liposomes (CHL) on dinamic of zimozan-induced peritonitis in C57Bl/6 mice. The accumulation of cholesterol, the change of cytokine production, PPAR-γ activity and cholesterol efflux in macrophages of C57Bl/6 mice has been investigated. The infiltration of neutrophils, amounts of mononuclear cells and MFC formation were significantly increased in peritonel cavity of zymosan-induced mice that led to in expansion of the period of inflammatory resolution and of the period of MFC resolution. If macrophages obtained after zymosan injection mainly accumulated triglycerides (TG) and at high speed incorporated [1-14C]oleate into TG, the injection of CHL after zymosan-indused inflammation lead to dramatic promotion MFC containing primarily free cholesterol and Ch ethers and been aggravation of [1-14C]oleate incorporation into cholesterol ethers in macrophages (mainly for 2 days). It has to shown that CHL against a background of inflammation promoted reduction of fluorescent NBD-cholesterol efflux from macrophages throughout the studied period (5 days) whereas zymosan inhibited cholesterol efflux at the early stages of inflammation (1 and 2 days), then, on 3ed day, the cholesterol efflux was recovered and increased on day 5. At the same time CHL stimulated the production of TNFα and TGFβ and inhibited the production of IL-10 and DNA-binding activity of PPAR-γ macrophages obtained at early as well as late stages of zymosan-induced peritonitis (compared with injection zymosan only). Thus, accumulation of cholesterol in inflammatory macrophages and promotion of MFC formation prolog timely resoluti- on of acute inflammation inducing alteration of pro- and anti-inflammatory cytokine balance and evoking the repression of macrophage DNA-binding activity of PPAR-γ and cholesterol efflux.

Topics: 4-Chloro-7-nitrobenzofurazan; Animals; Biological Transport; Cholesterol; Foam Cells; Inflammation; Interleukin-10; Liposomes; Male; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Neutrophils; Oleic Acid; Peritonitis; PPAR gamma; Transforming Growth Factor beta; Triglycerides; Tumor Necrosis Factor-alpha; Zymosan

Leukocyte migration into alveolar space plays a critical role in pulmonary inflammation resulting in lung injury. Acute ethanol (EtOH) exposure exerts anti-inflammatory effects. The clinical use of EtOH is critical due to its side effects. Here, we compared effects of EtOH and ethyl pyruvate (EtP) on neutrophil adhesion and activation of cultured alveolar epithelial cells (A549).. Time course and dose-dependent release of interleukin- (IL-) 6 and IL-8 from A549 were measured after pretreatment of A549 with EtP (2.5-10 mM), sodium pyruvate (NaP, 10 mM), or EtOH (85-170 mM), and subsequent lipopolysaccharide or IL-1beta stimulation. Neutrophil adhesion to pretreated and stimulated A549 monolayers and CD54 surface expression were determined.. Treating A549 with EtOH or EtP reduced substantially the cytokine-induced release of IL-8 and IL-6. EtOH and EtP (but not NaP) reduced the adhesion of neutrophils to monolayers in a dose- and time-dependent fashion. CD54 expression on A549 decreased after EtOH or EtP treatment before IL-1beta stimulation.. EtP reduces secretory and adhesive potential of lung epithelial cells under inflammatory conditions. These findings suggest EtP as a potential treatment alternative that mimics the anti-inflammatory effects of EtOH in early inflammatory response in lungs.