transforming-growth-factor-beta and Systemic-Inflammatory-Response-Syndrome

The activation, expansion, and survival of regulatory T cells (Tregs) as well as the expression of their suppressive capacities result from distinct signaling pathways involving various membrane receptors and cytokines. Multiple studies have shown that thymus-derived naturally occurring Tregs constitutively express the forkhead/winged helix transcription factor FoxP3 in addition to high levels of CD25, the negative co-stimulatory molecule CTLA-4, and the glucocorticoid-induced TNF receptor-related protein GITR. At variance, adaptive or induced Tregs acquire these phenotypic markers as they differentiate in the periphery, following adequate stimulation in the appropriate environment, together with their capacity to produce immunomodulatory cytokines (mainly, IL-4, IL-10 and TGF-beta) and to display regulatory capacities. However, none of these molecules but FoxP3 are restricted to Tregs since they may also be expressed and upregulated on activated effector T cells. This explains why different hypotheses were proposed to interpret interesting reports showing that in vivo abrogation of CTLA-4 signaling using neutralizing CTLA-4 antibodies triggers different autoimmune or immune-mediated manifestations. Thus, an effect on pathogenic T cell effectors and/or Tregs has been proposed. Here we present and discuss recent results we obtained in the nonobese diabetic (NOD) mouse model of spontaneous autoimmune diabetes, arguing for a key role of CTLA-4 in the functional activity of Tregs. Moreover, data are presented that simultaneous blockade of CTLA4 and TGF-beta further impairs immunoregulatory circuits that control disease progression.

Topics: Animals; Antigens, CD; Autoimmunity; CTLA-4 Antigen; Diabetes Mellitus, Type 1; Disease Progression; Homeostasis; Immune Tolerance; Mice; Mice, Inbred NOD; Signal Transduction; Systemic Inflammatory Response Syndrome; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

The sepsis syndrome is characterized by the acute release of a variety of inflammatory mediators, which often result in detrimental effects to the host. The release of these mediators is regulated and counterbalanced by the coordinated expression of antiinflammatory molecules. It is the balance between the expression of pro- and antiinflammatory mediators that often determines the magnitude of early tissue injury and subsequent risk of infectious complications. As our understanding of the pathophysiology of sepsis continues to evolve, we have gained a greater appreciation for the effects that sepsis and similar states of overwhelming stress have on host antimicrobial immunity. A number of functional defects in leukocytes isolated from sepsis patients have been characterized. These defects include diminished expression of important cell surface antigens, dysregulated cytokine production, alterations in antigen-presenting ability, and accelerated apoptosis. Impaired leukocyte function has important clinical ramifications, as high mortality rates have been observed in patients displaying evidence of sepsis-induced immune deactivation. In this article, we review the current literature supporting evidence of dysregulation of host immunity occurring during sepsis syndrome, characterize the underlying pathophysiology, and describe novel therapeutic interventions directed at augmenting host immunity during sepsis.

Topics: Adjuvants, Immunologic; Apoptosis; Cytokines; Humans; Immune Tolerance; Inflammation Mediators; Interleukin 1 Receptor Antagonist Protein; Interleukins; Leukocytes; Plasmapheresis; Sepsis; Sialoglycoproteins; Systemic Inflammatory Response Syndrome; Transforming Growth Factor beta

Toxoplasma gondii is able to manipulate the host immune system to establish a persistent and efficient infection, contributing to the development of brain abnormalities with behavioral repercussions. In this context, this work aimed to evaluate the effects of T. gondii infection on the systemic inflammatory response and structure of the primary somatosensory cortex (PSC). C57BL/6 and BALB/c mice were infected with T. gondii ME49 strain tissue cysts and accompanied for 30 days. After this period, levels of cytokines IFN-γ, IL-12, TNF-α and TGF-β were measured. After blood collection, mice were perfused and the brains were submitted to immunohistochemistry for perineuronal net (PNN) evaluation and cyst quantification. The results showed that C57BL/6 mice presented higher levels of TNF-α and IL-12, while the levels of TGF-β were similar between the two mouse lineages, associated with the elevated number of tissue cysts, with a higher occurrence of cysts in the posterior area of the PSC when compared to BALB/c mice, which presented a more homogeneous cyst distribution. Immunohistochemistry analysis revealed a greater loss of PNN labeling in C57BL/6 animals compared to BALB/c. These data raised a discussion about the ability of T. gondii to stimulate a systemic inflammatory response capable of indirectly interfering in the brain structure and function.

Topics: Animals; Interleukin-12; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Somatosensory Cortex; Systemic Inflammatory Response Syndrome; Toxoplasma; Toxoplasmosis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Sepsis is a systemic inflammatory response during infection. There are limited therapeutic options for sepsis patients. Interleukin (IL)-33 has been reported recently with a beneficial effect in mouse sepsis.. In this study, we initiated a clinical study to measure serum levels of pro-inflammatory cytokines including IL-33 in sepsis patients. Next, we employed cecal ligation and puncture (CLP) to study the role of IL-33 during sepsis. To further dissect the molecular mechanism, we used in vivo knockout models and in vitro knockdown murine embryonic fibroblasts (MEFs) to investigate the cross-talk between IL-33 and IL-17 signaling, and to identify the potential downstream mediators.. IL-33 and IL-17 were upregulated in both clinical and experimental sepsis. In CLP, IL-33 (-/-) mice showed higher mortality rate, and IL-33 treatment improved the survival rate. Elevated proinflammatory cytokines in sepsis were related to IL-17 from γδT cells. IL-33 treatment suppressed production of these cytokines by targeting IL-17 signaling both in vivo and in vitro. Finally, IL-33 was shown to inhibit the IL-17 pathway via activating suppressor of cytokine signaling (SOCS)-3.. Collectively, the results suggest that IL-33 plays a negative regulatory role in sepsis progression by inhibiting IL-17 pathway through activating SOCS3. This finding would inspire a new therapeutic strategy for treating sepsis.

Topics: Animals; Case-Control Studies; Chemokine CXCL1; Disease Models, Animal; Genetic Vectors; HEK293 Cells; Humans; Interleukin-17; Interleukin-33; Interleukin-6; Lentinula; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Interleukin-17; Sepsis; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Systemic Inflammatory Response Syndrome; Transforming Growth Factor beta; Up-Regulation

Systemic inflammatory responses can severely injure lungs, prompting efforts to explore how to attenuate such injury. Here we explored whether platelets can help attenuate lung injury in mice resulting from extracorporeal circulation (ECC)-induced systemic inflammatory responses. Mice were subjected to ECC for 30 min, then treated with phosphate-buffered saline, platelets, the GPIIb/IIIa inhibitor Tirofiban, or the combination of platelets and Tirofiban. Blood and lung tissues were harvested 60 min later, and lung injury and inflammatory status were assessed. As expected, ECC caused systemic inflammation and pulmonary dysfunction, and platelet transfusion resulted in significantly milder lung injury and higher lung function. It also led to greater numbers of circulating platelet-leukocyte aggregates and greater platelet accumulation in the lung. Platelet transfusion was associated with higher production of transforming growth factor-β and as well as lower levels of tumour necrosis factor-α and neutrophil elastase in plasma and lung. None of these platelet effects was observed in the presence of Tirofiban. Our results suggest that, at least under certain conditions, platelets can protect lung from injury induced by systemic inflammatory responses.

Topics: Animals; Blood Platelets; Disease Models, Animal; Leukocyte Elastase; Lung; Lung Injury; Mice; Systemic Inflammatory Response Syndrome; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Sepsis initially starts with a systemic inflammatory response (SIRS phase) and is followed by a compensatory anti-inflammatory response syndrome (CARS) that causes impaired adaptive T-cell immunity, immune paralysis and an increased susceptibility to secondary infections. In contrast, parasitic filariae release thousands of microfilariae into the peripheral blood without triggering inflammation, as they induce regulatory, anti-inflammatory host responses. Hence, we investigated the impact of chronic filarial infection on adaptive T-cell responses during the SIRS and CARS phases of a systemic bacterial infection and analysed the development of T-cell paralysis following a subsequent adenovirus challenge in BALB/c mice. Chronic filarial infection impaired adenovirus-specific CD8(+) T-cell cytotoxicity and interferon-γ responses in the absence of a bacterial challenge and led to higher numbers of splenic CTLA-4(+)  CD4(+) T cells, whereas splenic T-cell expression of CD69 and CD62 ligand, serum cytokine levels and regulatory T-cell frequencies were comparable to naive controls. Irrespective of filarial infection, the SIRS phase dominated 6-24 hr after intravenous Escherichia coli challenge with increased T-cell activation and pro-inflammatory cytokine production, whereas the CARS phase occurred 6 days post E. coli challenge and correlated with high levels of transforming growth factor-β and increased CD62 ligand T-cell expression. Escherichia coli-induced impairment of adenovirus-specific CD8(+) T-cell cytotoxicity and interferon-γ production was not additionally impaired by chronic filarial infection. This suggests that filarial immunoregulation does not exacerbate E. coli-induced T-cell paralysis.

Topics: Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chronic Disease; Escherichia coli; Escherichia coli Infections; Female; Filariasis; Filarioidea; Interferon-gamma; Mice; Mice, Inbred BALB C; Systemic Inflammatory Response Syndrome; Transforming Growth Factor beta

Much research is now being conducted in order to understand the role of cytokines in the development of the inflammatory response following trauma. The purpose of this study was to evaluate whether serum levels of certain cytokines, measured immediately after initial injury, can be used as potential biomarkers for predicting the development and the degree of severity of the systemic inflammatory response (SIRS) in patients with moderate and severe trauma.. We conducted a prospective study with 71 individuals of whom 13 (18.3 %) were healthy controls and 58 (81.7 %) were traumatized orthopaedic patients who were categorized into two groups: 31 (43.6 %) with moderate injuries and 27 (38.1 %) patients with severe orthopaedic trauma. Thirty cc of heparinized blood were drawn from each individual within a few hours after the injury. Serum levels of pro-inflammatory, regulatory and anti-inflammatory cytokines were measured in each individual participant.. High levels of pro-inflammatory cytokines IL-1β,-6,-8,-12, tumour necrosis factor alpha and interferon gamma were found in all injured patients compared to healthy controls. Only IL-6 and IL-8 were significantly higher in the injured patients. Levels of the regulatory cytokines, transformed growth factor beta (TGF-β) and IL-10 were higher in the injured patients, but significant only for TGF-β. Levels of IL-4 were significantly lower in the injured groups as compared to the controls.. Secretion of large amounts of pro-inflammatory cytokines and decreased level of anti-inflammatory cytokines during the acute phase of trauma may lead to the development of systemic inflammatory response syndrome (SIRS) in unstable polytraumatized patients. SIRS may result in life threatening conditions as acute respiratory distress syndrome (ARDS) and multiple organ failure (MOF). High levels of IL-6, IL-8, TGFβ and low levels of IL-4 were found to be reliable markers for the existence of immune reactivity in trauma patients. More research is needed to study pattern of cytokine levels along the acute period of injury, after surgical interventions and during recovery.

Topics: Adult; Biomarkers; Cytokines; Female; Fractures, Bone; Humans; Interleukin-4; Interleukin-6; Interleukin-8; Male; Middle Aged; Prospective Studies; Systemic Inflammatory Response Syndrome; Transforming Growth Factor beta; Wounds and Injuries; Young Adult

To observe the effect of Huanglian Jiedu IJecoction (HJU) on systemic and vascular immune responses of high fat diet fed apoE deficient (apoE(-/-)) mice.. Eight wild type C57BL6 mice were recruited as the wild type common food group. Totally 24 apoE(-/-) mice were randomly divided into the ApoE'common food group, the ApoE(-/-) hyperlipidemia group, and the ApoE(-/-) hyperlipidemia plus HJD group, 8 in each group. In the present study, the common food mice and high fat fed mice were fed with a chow diet or a high cholesterol diet for 4 weeks. HJD was given to mice in the ApoE(-/-) hyperlipidemia plus HJD group at the daily dose of 5 g/kg by gastrogavage, while equal volume of pure water was given to mice in the rest groups by gastrogavage. Four weeks later, the plasma levels of blood lipids, the ratio of peripheral blood mononuclear cells, and expressions of Toll-like receptor 4 (TLR-4) and CD36 on the monocytes were detected. The pathological changes and expressions of cytokines in local aorta were detected. The plasma cytokine levels in response to lipopolysaccharide (LPS) were analyzed. Results (1) Compared with the wild type common food group, TO, TG, and LDL-O significantly increased in the ApoE(-/-) common food group (P < 0. 05, P < 0.01). Compared with the ApoE(-/-) common food group, TC and LDL-C significantly increased in the hyperlipidemia group (P < 0. 05). There was no statistical difference in each index between the ApoE(-/-) hyperlipidemia group and the ApoE(-/-) hyperlipidemia plus HJD group (P > 0.05). (2) Compared with the wild type common food group, no obvious change of the ratio of peripheral blood mononuclear cells happened, the TLR4 expression level significantly increased in the ApoE'common food group (P < 0. 05). Compared with the ApoE common food group, the ratio of peripheral blood mononuclear cells and the TLR4 expression level significantly increased in the ApoE' hyperlipidemia group (P < 0.05). Compared with the ApoE(-/-) hyperlipidemia group, the ratio of peripheral blood mononuclear cells and the TLR4 expression level significantly decreased. Besides, the CD36 expression level also significantly decreased (P<0.05). (3) After stimulated by LPS for 3 h, compared with the wild type common food group, plasma TNF-ct and IL-b expressions significantly increased in the ApoE(-/-) common food group (P < 0.05). Compared with the ApoE(-/-) common food group, plasma expressions of IL-12, TNF-alpha, MCP-1, and IL-10 increased, but with no statistical difference in the ApoE(-/-) hyperlipidemia group (P > 0.05). After 4-week intervention of HJD, compared with the ApoE(-/-) hyperlipidemia grou. High fat diet induced systemic reaction and inflammatory reactions of local vessels. The local inflammatory response of vessels exceeded systemic inflammatory response. Intervention of HJD could attenuate inflammatory response, especially in local arteries. Meanwhile, it enhanced systemic anti-inflammatory reactions.

Topics: Animals; Aorta; Apolipoproteins E; CD36 Antigens; Chemokine CCL2; Dietary Fats; Drugs, Chinese Herbal; Female; Hyperlipidemias; Inflammation; Interleukin-10; Interleukin-12; Interleukin-1beta; Leukocytes, Mononuclear; Mice; Mice, Inbred C57BL; Mice, Knockout; Systemic Inflammatory Response Syndrome; Toll-Like Receptor 4; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

White smoke inhalation is an uncommon but potentially deadly cause of acute lung injury. No clinical spectrum or treatment protocol have been developed.. Twenty patients accidentally been exposed to white smoke during military training were the subjects of this study. We analyzed clinical manifestations, cytokine changes, and treatment outcomes.. All patients initially presented with fever, dry cough, chest tightness, and shortness of breath. Twenty-five percent of these patients had severe acute lung injury requiring artificial ventilation support. Elevation of serum tumor necrosis factor-alpha was observed before treatment with antibiotics and glucocorticoids, but the elevation of transforming growth factor-beta(1) was delayed for 2 to 4 weeks after the accident. All the patients had leukocytosis, which correlated positively to disease severity and negatively to intensive treatments. Ninety-five percent of patients had varying degrees of restrictive ventilation impairment, and 85% of these patients had a significantly reduced diffusion capacity in the lungs. Seventy percent of these patients had transient impairment of liver function, which did not correlate to disease severity. The respiratory sequela of restrictive ventilation impairment developed in the most severely affected patients, whereas other tissue toxicities were mostly transient. Treatment included glucocorticoids, antibiotics, and respiratory therapy. All of the patients survived.. A proper ventilation strategy, early pharmacologic therapy including glucocorticoids, and complication prevention may contribute to good treatment outcomes after white smoke inhalation.

Topics: Adult; Anti-Bacterial Agents; Chromates; Drug Therapy, Combination; Glucocorticoids; Humans; Military Personnel; Occupational Exposure; Prognosis; Respiratory Function Tests; Respiratory Therapy; Retrospective Studies; Smoke; Smoke Inhalation Injury; Systemic Inflammatory Response Syndrome; Transforming Growth Factor beta; Trauma Severity Indices; Tumor Necrosis Factor-alpha; Zinc Compounds

The objectives of this study were to examine the prevalence of genetic variation for cytokine production (tumor necrosis factor [TNF]-alpha, interleukin-10, transforming growth factor-beta1) in patients with multiple organ dysfunction syndrome, to measure circulating cytokine levels and relate these to genotype, and to identify the relationship between genetic variation and outcome.. Prospective analysis.. Intensive care unit of a university teaching hospital.. Eighty-eight critically ill patients with multiple organ dysfunction syndrome.. The frequency of the different interleukin-10 genotypes (corresponding to high, intermediate, and low interleukin-10 production ) were significantly different between controls and multiple organ dysfunction syndrome patients. High interleukin-10 producers were under-represented in the multiple organ dysfunction syndrome group: This genotype occurred in 30% of controls but in only 6% of patients ( <.001). There was no relationship between interleukin-10 genotype and mortality. The frequency of TNF-alpha genotypes was also significantly different between patients and controls. Intermediate TNF-alpha producers were under-represented (5.7% vs. 23%) and high TNF-alpha producers over-represented (35.2% vs. 16%) in the patient group (p <.001). TNF-alpha genotype was not related to mortality. The distribution of TNF-beta genotypes (homozygous B1, homozygous B2, and heterozygotes) was also different between controls and patients (p =.008). The B2/B2 genotype (associated with high TNF-alpha production) tended to occur less frequently in the intensive care unit population (31% vs. 50%) and was associated with a higher mortality rate than either the B1/B1 or B1/B2 genotypes (48% vs. 11% and 33% respectively, p=.115). The combination of proinflammatory (TNF-alpha/TNF-beta) and anti-inflammatory (interleukin-10/transforming growth factor-beta1) cytokine genotypes was associated with prolonged patient survival time. Patients predisposed to produce a balanced cytokine response (e.g., intermediate interleukin-10/TNF-alpha producers) demonstrated the longest survival times, although overall mortality was no different.. A genetic predisposition to high interleukin-10 production or intermediate TNF-alpha production may be protective of admission to the intensive care unit, although once admitted, any protection provided by these genotypes seems to be lost. TNF-beta genotype conferred no advantage to patients with multiple organ dysfunction syndrome, the TNFB2 allele being associated with increased mortality. The combination of proinflammatory and anti-inflammatory cytokine genotypes supports the idea that a balanced cytokine response is favorable and was associated with prolonged patient survival time.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cytokines; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Interleukin-10; Male; Middle Aged; Multiple Organ Failure; Polymerase Chain Reaction; Polymorphism, Genetic; Prospective Studies; Systemic Inflammatory Response Syndrome; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

The systemic inflammatory response syndrome (SIRS) is an inflammatory process seen in association with a large number of clinical infective and non-infective conditions. The aim of this study was to investigate the role of anti-inflammatory cytokines such as interleukin-4 (IL-4), interleukin-10 (IL-10), and transforming growth factor-beta (TGF-beta). Serum levels of IL-4, IL-10 and TGF-beta were determined in 45 patients with SIRS: 38 patients had SIRS of infectious origin, whereas seven patients had non-infectious SIRS. Twenty healthy subjects were used as controls. Serum levels of IL-4, IL-10 and TGF-beta were determined by an immunoenzyme assay. A significant increase of IL-4 was observed in these patients at the time of diagnosis and 5 days later. In contrast, serum levels of IL-10 were not increased at the time of diagnosis, but a slight decrease was noted after 5 days. Serum levels of TGF-beta were not increased at time of diagnosis, and a slight increase was observed after 5 days. Serum levels of IL-4 were significantly higher in patients with infectious SIRS at the time of diagnosis, whereas no significant difference between infectious and non-infectious SIRS was noted for serum levels of IL-10 and TGF-beta at the time of diagnosis and 5 days later. During SIRS, serum levels of IL-4 were significantly increased with a significant correlation between IL-4 and mortality, and only levels of IL-4 were significantly increased in the SIRS caused by infectious stimuli.

Topics: Adult; Aged; Female; Humans; Infections; Inflammation Mediators; Interleukin-10; Interleukin-4; Male; Middle Aged; Systemic Inflammatory Response Syndrome; Transforming Growth Factor beta

The systemic inflammatory response syndrome (SIRS) is viewed as a system-wide inflammatory response. Up until now, no parameter has been available for predicting the development of septic shock. In the present study, we evaluated the usefulness of serum levels of CD14, vascular cells adhesion molecule-1 (VCAM-1), endothelial leucocyte adhesion molecule-1 (ELAM-1), macrophage inflammatory protein (MIP) 1 alpha and transforming growth factor beta 2 (TGF-beta 2) as early markers of outcome in patients with SIRS.. A group of 28 SIRS patients (13 survivors/15 non-survivors) was compared with a healthy control group and with patients with local inflammation. Blood samples were analysed on days 0, 4 and 7. Proinflammatory parameters such as sCD14, sVCAM-1, sELAM-1, MIP-1 alpha and anti-inflammatory parameters such as TGF-beta 2 were determined using enzyme-linked immunosorbent assay (ELISA).. At the beginning, all evaluated proinflammatory immunological parameters with the exception of sVCAM-1 were significantly increased in patients with SIRS compared with the healthy control group. However, no significant difference could be observed for all immunological parameters comparing survivors and non-survivors, with the exception of interleukin (IL) 6 at day 7.. All evaluated proinflammatory parameters were increased in patients with SIRS during the course of the disease. However, the parameters have no correlation with outcome and prognosis of SIRS patients.

Topics: Adult; Aged; Aged, 80 and over; Antigens, CD; Biomarkers; Chemokine CCL3; Chemokine CCL4; E-Selectin; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-6; Lipopolysaccharide Receptors; Macrophage Inflammatory Proteins; Male; Middle Aged; Prognosis; Systemic Inflammatory Response Syndrome; Time Factors; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1

Cardiovascular surgery with extracorporeal circulation causes a systemic inflammatory response, which can lead to organ failure and increased postoperative morbidity. Advances in knowledge about the interactions between markers of cellular and humoral immunity involved in the inflammatory response to cardiopulmonary bypass (CPB) may reduce the deleterious effects and improve the outcome for patients undergoing cardiac surgery.. To determine the release of immunoinhibiting cytokines during CPB, we measured plasma levels of interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) in 30 patients undergoing elective coronary artery bypass grafting. Arterial blood samples were collected at eight time points before, during and after CPB, using a standardized ELISA-technique.. Plasma IL-10 and TGF-beta increased significantly after weaning off CPB (P < 0.05) and peaked respectively at time of skin closure (IL-10, 308 +/- 180 pg/ml; TGF-beta, 1860 +/- 906 pg/ml; mean peak +/-S.D.). Postoperatively, 6 h, IL-10 decreased to 19.8 +/- 9.8 pg/ml (P < 0.05) and TGF-beta decreased to 1133 +/- 547 pg/ml (P < 0.05).. Both cytokines are major immunoregulatory factors with negative influence on T cell-mediated immunologic response. The significantly elevated levels at the end of CPB indicate that IL-10 and TGF-beta may be important factors of immunologic dysregulation following CPB.

Topics: Adult; Aged; Cardiopulmonary Bypass; Coronary Artery Bypass; Coronary Disease; Humans; Interleukin-10; Male; Middle Aged; Postoperative Complications; Risk Factors; Systemic Inflammatory Response Syndrome; Transforming Growth Factor beta

Topics: Humans; Systemic Inflammatory Response Syndrome; Transforming Growth Factor beta