interleukin-8 and Autoimmune-Diseases

Advances in the past two decades have resulted in the recognition of several tumefactive pancreatic lesions that, on histologic evaluation, show a varying combination of inflammation and fibrosis. Autoimmune pancreatitis, the prototypic tumefactive pancreatic fibroinflammatory lesion, is composed of two distinct diseases, type 1 autoimmune pancreatitis and the less common type 2 autoimmune pancreatitis. Although designated as autoimmune pancreatitis, the two diseases show little morphologic or pathogenic overlap. In type 1 disease, subsets of T lymphocytes (type 2 helper T cells, regulatory T cells, and T follicular helper 2 cells) are hypothesized to drive the inflammatory reaction. The B-cell response is characterized by an oligoclonal expansion of plasmablasts, with dominant clones that vary among patients and distinct clones that emerge at the time of relapse. Although the precise role of IgG4 in this condition remains uncertain, recent studies suggest that other IgG subclasses (eg, IgG1) may mediate the immune reactions, whereas IgG4 represents a response to dampen excessive inflammation. A recent study of type 2 autoimmune pancreatitis highlights the role of CXCL8 (alias IL-8), with duct epithelium and infiltrating T lymphocytes expressing this chemokine; the latter may contribute to the distinct form of neutrophilic inflammation in this disease. The review also highlights other forms of mass-forming chronic pancreatitis: follicular pancreatitis, groove pancreatitis, and those associated with rheumatologic diseases.

Topics: Antibodies, Neoplasm; Autoimmune Diseases; Carcinoma, Pancreatic Ductal; Fibrosis; Humans; Immunoglobulin G; Inflammation; Interleukin-8; Neoplasm Proteins; Pancreatic Neoplasms; Pancreatitis, Chronic; Plasma Cells; T-Lymphocytes, Regulatory; Th2 Cells

CXCL8 was the first chemokine shown to be secreted by thyrocytes. Experimental data suggest that CXCL8 plays a role in thyroid homeostasis but its role in thyroid diseases remains poorly investigated. Clinical studies measuring the serum levels of CXCL8 in patients with autoimmune-thyroid-diseases reported conflicting results. Solid evidences support a role of CXCL8 as a tumor-promoting agent in several human cancers. Studies in thyroid cancer are still in their initial stage, but promising. Several evidences indicate that thyroid cancer may share with other human malignancies some of the effects of CXCL8 and highlight the possibility of using CXCL8 as a marker of aggressiveness. Basic and clinical evidences in favor or against a role for CXCL8 in thyroid diseases are discussed.

Topics: Animals; Autoimmune Diseases; Humans; Interleukin-8; Neoplasms; Thyroid Diseases; Thyroid Gland

T helper (Th) 17 cells have crucial functions in host defense, and dysregulated Th17 responses mediate a variety of autoimmune and inflammatory conditions. Th17 cells coexpress interleukin (IL)-22, and its receptor is expressed on epidermal keratinocytes. IL-17 and IL-22 cooperatively enhance some immunological responses. A close relationship between IL-17 and the cutaneous milieu has been suggested by a number of observations. IL-17 induces the production of certain cytokines, chemokines and antimicrobial peptides by keratinocytes, and its cooperation with IL-22 has been documented. Recent findings have suggested that Th17 cells profoundly participate in the pathogenesis of certain skin disorders, in particular, psoriasis. The concept of the subsets of T cells responsible for psoriasis has been modified in the order of Th1, T cytotoxic 1, and again Thl, and Thl7 cells. IL-22 is the strongest cytokine in the keratinocyte-proliferative ability. Since IL-22 is produced by Th17 cells, they are crucial for the proliferation of keratinocytes. Furthermore, IL-22 with the help of IL-17 can induce the critical events of psoriasis, including signal transducer and activator of transcription 3 (STAT3) activation, cytokine/chemokine (IL-8 etc.) production, and antimicrobial peptide elaboration. For maintaining Th17 cells, IL-23 is required and is released from tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthetase (iNOS)-producing dendritic cells (TIP-DCs). TIP-DCs are activated via an autocrine mechanism by virtue of TNF-alpha. The above cytokine network in the pathogenesis of psoriasis has been proven by the therapeutic effectiveness of cytokine-blocking biologics. Antibodies against TNF-alpha or its soluble receptor have already been widely used in the treatment of psoriasis. The involvement of Th17 cells has also been shown in allergen-specific immune responses. The percentage of Th17 cells is increased in the peripheral blood of patients with atopic dermatitis (AD) and associated with the severity of AD. Drug eruption is another disease where Th17 cells are involved in the pathogenesis. The percentage of circulating Th17 cells are increased in drug-induced hypersensitivity syndrome, etc. Th17 cells and IL-22 are increased in patients with acute generalized exanthematous pustulosis. Since IL-17 and IL-22 cooperatively stimulate keratinocytes to produce IL-8, keratinocyte-derived IL-8 contributes to the accumulation ofneutrophils in the lesi

Topics: Antimicrobial Cationic Peptides; Autocrine Communication; Autoimmune Diseases; Dendritic Cells; Dermatitis, Atopic; Drug Eruptions; Humans; Interleukin-17; Interleukin-22; Interleukin-23; Interleukin-8; Interleukins; Keratinocytes; Nitric Oxide Synthase Type II; Psoriasis; Receptors, Interleukin; STAT3 Transcription Factor; Th17 Cells; Tumor Necrosis Factor-alpha

Systemically applied agents to modulate the Fas/FasL system, e.g., by stimulation of Fas on activated leukocytes or tumor cells failed as strategies in immune therapy due to severe toxic effects in the host. Recently, a novel strategy has been developed by using immobilized immune active biologicals in a medical device that may allow immune management without expensive systemic therapy. This review reports on the potential role of Fas/FasL in immune therapy and summarizes current experimental and clinical data with the leukocyte inhibition module (LIM), an immobilized anti-Fas antibody containing device yet used in extracorporeal blood circulation. This proof of principal may stimulate the development of other devices based on the regulation of Fas/FasL or other targets relevant for immune disorders.

Topics: Animals; Apoptosis; Autoimmune Diseases; Cardiopulmonary Bypass; Equipment and Supplies; Fas Ligand Protein; fas Receptor; Humans; Immunoglobulin M; Interleukin-8; Lymphoma, T-Cell; Membrane Glycoproteins; Virus Diseases

Autoimmune diseases afflict more than 3% of the U.S. population. Current therapy for mild to moderate cases is symptomatic, however advanced cases suffer high morbidity and mortality. Advanced patients have benefited from stem cell therapy in the form of bone marrow transplantation in conjunction with high-dose cytotoxic therapy. Broader application of stem cell therapy requires better understanding of how adult stem cells affect development and foster treatment of autoimmune pathologies, and of better ways to manipulate the host immune responses. While extensive research documents the role of hematopoietic stem cells (HSCs) in autoimmune disease, few studies have addressed if and how mesenchymal stem cells (MSCs) contribute to their etiopathology. Recent characterization of MSCs and their role in hematopoiesis and immune modulation suggest that their potential for cell therapy extends beyond their traditional accessory function in HSC engraftment. MSCs contribute significantly to tissue restructuring and immune functioning, in addition to facilitating durable, long-lasting stem cell engraftment. MSCs are relatively easy to obtain and expand in in vitro cultures, rendering them a prime candidate for genetic manipulations for stem cell therapy. They have the potential to differentiate into multiple lineages such as osteoblasts, adipose tissue, cartilage, tendon, and stromal cells. The role of MSCs for autoimmune disease therapy could thus be based both on immune function modulation and contribution to hematopoiesis. In this review, we examine the biology of MSCs, and their potential for cell therapy of autoimmune disease.

Topics: Adipose Tissue; Animals; Autoimmune Diseases; Cartilage; Cell Lineage; Chemokines, CXC; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Interleukin-8; Lupus Vulgaris; Mesenchymal Stem Cells; Models, Biological; Nervous System Diseases; Stem Cell Transplantation; Stem Cells; Stromal Cells

Topics: Autoimmune Diseases; Drugs, Investigational; Humans; Interleukin-8; Psoriasis; T-Lymphocytes

Psoriasis represents an inflammatory skin disorder which is characterized by a marked hyperproliferation of keratinocytes in association with vascular expansion, fibroblast activation, leukocyte infiltration, alterations of eicosanoid metabolism and of cytokine production. However, it is unclear at present whether these changes may be a cause or a result of the significantly increased keratinocyte turnover. More than one mechanism is involved in triggering active psoriasis, particularly a genetic predisposition and environmental factors affecting the immune system. Most of the therapeutic regimes used for the treatment of psoriasis are immunosuppressive. Therefore, it is tempting to speculate that a specific defect of the immune system represents an important pathogenic principle in psoriasis. There are several lines of evidence that changes in cytokine production by keratinocytes and immunocompetent cells in the skin of the patients (particularly of interleukin-6 and TGF-alpha) may play an important role in the propagation of the inflammatory response in psoriasis. Further studies are required to reveal the role of a local T-cell activation as a basic mechanism for initiation and maintenance of the psoriatic inflammatory response. Accordingly, parameters, such as the evaluation of cytokine production in vitro and in vivo, as well as the measurement of cellular activation products, may be useful tools for diagnosis and monitoring of psoriasis.

Topics: Autoimmune Diseases; Cytokines; Humans; Interferons; Interleukin-1; Interleukin-6; Interleukin-8; Lymphocyte Activation; Psoriasis; T-Lymphocytes; Tumor Necrosis Factor-alpha

The effectiveness of plasma exchange (PE) with continuous hemodiafiltration (CHDF) in the treatment of critically ill patients was evaluated based on changes in cytokine levels. Twenty-six patients with acute hepatic failure were treated with PE (PE group) or PE and CHDF (PE+CHDF group), and the levels of cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 were determined before and after treatment. Bilirubin levels were significantly lower after treatment in both the PE and PE+CHDF groups. There were no significant differences in TNF-alpha levels before and after treatment in the PE group, but the TNF-alpha level was significantly lower after treatment in the PE+CHDF group. There were no significant differences in the IL-6 levels before and after treatment in both the PE and PE+CHDF groups. There were no significant differences in IL-8 levels before and after treatment in the PE group, but the IL-8 level was significantly lower after treatment in the PE+CHDF group. PE with CHDF therapy was given to 5 patients with acutely aggravated autoimmune diseases, 2 patients with hemorrhagic shock and encephalopathy syndrome, and 3 patients with thrombotic microangiopathy. The results suggested that PE with CHDF therapy are useful in critically ill patients with suspected hypercytokinemia.

Topics: Adult; Aged; Autoimmune Diseases; Bilirubin; Blood Coagulation Disorders; Critical Illness; Cytokines; Female; Hemodiafiltration; Humans; Interleukin-6; Interleukin-8; Liver Failure, Acute; Male; Middle Aged; Plasma Exchange; Shock, Hemorrhagic; Tumor Necrosis Factor-alpha

In the pathophysiology of autoimmune-mediated uveitis, granulocytes have emerged as possible disease mediators and were shown to be pre-activated in equine recurrent uveitis (ERU), a spontaneous disease model. We therefore used granulocytes from ERU horses to identify early molecular mechanisms involved in this dysregulated innate immune response. Primary granulocytes from healthy and ERU horses were stimulated with IL8, and cellular response was analyzed with differential proteomics, which revealed significant differences in protein abundance of 170 proteins in ERU. Subsequent ingenuity pathway analysis identified three activated canonical pathways "PKA signaling", "PTEN signaling" and "leukocyte extravasation". Clustered to the leukocyte extravasation pathway, we found the membrane-type GPI-anchored protease MMP25, which was increased in IL8 stimulated ERU granulocytes. These findings point to MMP25 as a possible regulator of granulocyte extravasation in uveitis and a role of this molecule in the impaired integrity of the blood-retina-barrier. In conclusion, our analyses show a clearly divergent reaction profile of pre-activated granulocytes upon IL8 stimulation and provide basic information for further in-depth studies on early granulocyte activation in non-infectious ocular diseases. This may be of interest for the development of new approaches in uveitis diagnostics and therapy. Raw data are available via ProteomeXchange with identifier PXD013648.

Topics: Animals; Autoimmune Diseases; Granulocytes; Horse Diseases; Horses; Interleukin-8; Proteomics; Recurrence; Uveitis

Pemphigoid diseases refer to a group of severe autoimmune skin blistering diseases characterized by subepidermal blistering and loss of dermal-epidermal adhesion induced by autoantibody and immune cell infiltrate at the dermal-epidermal junction and upper dermis. Here, we explore the role of the immune cell-secreted serine protease, granzyme B, in pemphigoid disease pathogenesis using three independent murine models. In all models, granzyme B knockout or topical pharmacological inhibition significantly reduces total blistering area compared to controls. In vivo and in vitro studies show that granzyme B contributes to blistering by degrading key anchoring proteins in the dermal-epidermal junction that are necessary for dermal-epidermal adhesion. Further, granzyme B mediates IL-8/macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity. Clinically, granzyme B is elevated and abundant in human pemphigoid disease blister fluids and lesional skin. Collectively, granzyme B is a potential therapeutic target in pemphigoid diseases.

Topics: Animals; Autoantigens; Autoimmune Diseases; Blister; Chemokine CXCL2; Chemotactic Factors; Collagen Type XVII; Disease Models, Animal; Epidermolysis Bullosa; Granzymes; Humans; Inflammation; Integrin alpha6; Interleukin-8; Neutrophil Infiltration; Non-Fibrillar Collagens; Pemphigoid, Bullous; Severity of Illness Index

Interleukin-17A (IL-17A) produced by Th17 cells, contributes to the pathogenesis of various autoimmune diseases by stimulating the release of cytokines and chemokines and its regulation. Anti-IL-17A antibody which blocks the function of IL-17A has been proved to be an effective treatment of autoimmune disease. The aim of our study was to generate a potential humanized anti-IL-17A therapeutic monoclonal antibody (mAb) through a comprehensive panel of in vitro and in vivo biological activity studies, as well as physicochemical characterization. HZD37-5, a humanized monoclonal antibody specifically recognizing N78 loci of IL-17A, binds to human and rhesus monkeys, blocks IL-17 induced signal transduction and the release of IL-6, IL-8, CXCL-1 and G-GSF. In an in vivo efficacy mouse model, HZD37-5 significantly inhibited human IL-17A induced-keratinocyte chemoattractant (KC) secretion in a dose-dependent manner. The pharmacokinetics (PK) study result of HZD37-5 in rhesus monkeys indicated that HZD37-5 had favorable PK characteristics with limited distribution (78.0-78.8 ml/kg), slow elimination (5.00-6.45 ml/day/kg), long half-life (9.1-10.7 days) and high bioavailability (103%) following a single IV or SC dose at 1.5 mg/kg. These findings provided a comprehensive preclinical characterization of HZD37-5 and supported that it may be developed as a potential therapeutic for the treatment of autoimmune diseases, including psoriasis, psoriatic arthritis, axial spondyloarthritis, etc.

Topics: Animals; Antibodies, Monoclonal, Humanized; Autoimmune Diseases; Chemokine CXCL1; Chemotactic Factors; Dose-Response Relationship, Drug; Humans; Interleukin-17; Interleukin-6; Interleukin-8; Keratinocytes; Macaca mulatta; Mice; Rabbits; Signal Transduction

Myositis is a heterogeneous family of diseases that includes dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM), inclusion body myositis (IBM), polymyositis and overlap myositis. Additional subtypes of myositis can be defined by the presence of myositis-specific autoantibodies (MSAs). The purpose of this study was to define unique gene expression profiles in muscle biopsies from patients with MSA-positive DM, AS and IMNM as well as IBM.. RNA-seq was performed on muscle biopsies from 119 myositis patients with IBM or defined MSAs and 20 controls. Machine learning algorithms were trained on transcriptomic data and recursive feature elimination was used to determine which genes were most useful for classifying muscle biopsies into each type and MSA-defined subtype of myositis.. The support vector machine learning algorithm classified the muscle biopsies with >90% accuracy. Recursive feature elimination identified genes that are most useful to the machine learning algorithm and that are only overexpressed in one type of myositis. For example, CAMK1G (calcium/calmodulin-dependent protein kinase IG), EGR4 (early growth response protein 4) and CXCL8 (interleukin 8) are highly expressed in AS but not in DM or other types of myositis. Using the same computational approach, we also identified genes that are uniquely overexpressed in different MSA-defined subtypes. These included apolipoprotein A4 (APOA4), which is only expressed in anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) myopathy, and MADCAM1 (mucosal vascular addressin cell adhesion molecule 1), which is only expressed in anti-Mi2-positive DM.. Unique gene expression profiles in muscle biopsies from patients with MSA-defined subtypes of myositis and IBM suggest that different pathological mechanisms underly muscle damage in each of these diseases.

Topics: Adult; Animals; Apolipoproteins A; Autoimmune Diseases; Biopsy; Calcium-Calmodulin-Dependent Protein Kinase Type 1; Cell Adhesion Molecules; Cell Culture Techniques; Dermatomyositis; Early Growth Response Transcription Factors; Female; Humans; Hydroxymethylglutaryl CoA Reductases; Interleukin-8; Machine Learning; Male; Mice; Mucoproteins; Muscle, Skeletal; Muscular Diseases; Myositis; Myositis, Inclusion Body; Polymyositis; Transcriptome

Topics: Adult; Aged; Autoimmune Diseases; Black or African American; Breast Neoplasms; Case-Control Studies; DNA-Activated Protein Kinase; Female; Genetic Predisposition to Disease; Humans; Interleukin-2 Receptor beta Subunit; Interleukin-8; MAP Kinase Kinase Kinase 1; Middle Aged; Nuclear Proteins; Polymorphism, Single Nucleotide; Protein Interaction Maps; Receptors, Estrogen; Risk Factors; Toll-Like Receptor 6

Type 2 autoimmune pancreatitis (type 2 AIP) develops in isolation or sometimes in association with ulcerative colitis. Its diagnosis requires the histologic confirmation of granulocytic epithelial lesions (GELs) with no diagnostic biomarker currently available. This study aimed to elucidate the tissue expression of cytokines and their diagnostic value in this condition. In quantitative polymerase chain reaction for multiple cytokines using tissue-derived mRNA, the expression level of interleukin (IL)-8 was markedly higher in type 2 AIP than in type 1 AIP (P<0.001). In immunostaining, IL-8 expression was detected in the ductal/ductular epithelium (11/13; 85%) and infiltrating neutrophils or lymphocytes (12/12; 100%) in type 2 AIP, but was almost entirely negative in type 1 AIP (n=13; both, P<0.001). Although obstructive pancreatitis adjacent to pancreatic cancers (peritumoral pancreatitis) exhibited IL-8 expression in the epithelium (3/12; 25%) and inflammatory cells (10/12; 83%), expression levels were significantly lower than those in type 2 AIP (P<0.001 and 0.020, respectively). The presence of either GELs or IL-8-positive epithelium discriminated type 2 AIP from type 1 AIP or obstructive pancreatitis with 92% sensitivity and 92% to 100% specificity. Furthermore, CD3/IL-8-coexpressing lymphocytes were almost restricted to type 2 AIP. Interestingly, a similar pattern of IL-8 expression was also observed in colonic biopsies of ulcerative colitis. In conclusion, the overexpression of IL-8 may underlie the development of GELs in type 2 AIP, and IL-8 immunostaining or IL-8/CD3 double staining may become an ancillary method for its diagnosis. The similar expression pattern of IL-8 in ulcerative colitis also suggests a pathogenetic link between the 2 conditions.

Topics: Adolescent; Adult; Autoimmune Diseases; Colitis, Ulcerative; Female; Granulocytes; Humans; Interleukin-8; Male; Middle Aged; Pancreatitis; Young Adult

Chemokines induce leukocyte chemotaxis and contribute to chronic inflammation. To clarify the association between functional polymorphisms in genes encoding some chemokines and the pathogenesis of Autoimmune thyroid disease (AITD), we genotyped IL8 -251T/A, Regulated upon Activation, Normal T cell Expressed and presumably Secreted (RANTES) - 403G/A, -28C/G, MIG rs2276886G/A, IP10 -1596C/T, Monocyte Chemoattractant Protein1 (MCP1) - 2518G/A and IL16 -295T/C polymorphisms. We genotyped these polymorphisms using the PCR-RFLP method in 149 Graves' disease (GD) patients, including 59 patients with intractable GD and 53 patients with GD in remission, as well as 131 Hashimoto's disease (HD) patients, including 54 patients with severe HD, 46 patients with mild HD and 99 healthy controls. The IL8 -251TT genotype and MIG rs2276886 A allele were more frequent in patients with AITD (p = 0.0139 and p = 0.0005, respectively). The RANTES - 403AA and -28GG genotypes were less frequent in patients with AITD (p = 0.0164 and p = 0.0221, respectively). The MCP1 -2518GG genotype was more frequent in HD patients (p = 0.0323). The MIG rs2276886 AG genotype was less frequent in patients with intractable GD (p = 0.0051). Interestingly, the age of onset in GD patients with the RANTES - 28CC genotype was younger than in those with -28CG and GG genotypes (p = 0.0028). In this study, we first reported that the polymorphisms in IL8, RANTES and MIG genes are associated with the development of AITD, and that the MIG rs2276886 AG genotype is associated with the intractability of GD. The RANTES - 28CC genotype is associated with young onset of GD.

Topics: Adult; Aged; Alleles; Autoantibodies; Autoimmune Diseases; Biomarkers; Case-Control Studies; Chemokine CCL2; Chemokine CCL5; Chemokine CXCL9; Chemokines; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Graves Disease; Hashimoto Disease; Humans; Interleukin-16; Interleukin-8; Male; Middle Aged; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Receptors, Cytokine; Thyroid Diseases

To observe and compare the effects of Chinese herbal prescriptions for promoting blood circulation, clearing heat, removing toxicity, and dispersing stagnated liver-Qi on cytokines in mode rats with experimental autoimmune prostatitis (EAP) to provide an experimental basis for the use of Chinese herbal prescriptions in the treatment of chronic prostatitis.. One-hundred and ten male Wistar rats were randomly divided into 11 groups: blank group; model group; Huoxuehuayu (promoting blood circulation to remove blood stasis) high, middle, and low dose groups; Qingrejiedu (clearing heat and removing toxicity) high, middle, and low dose groups; and Shuganliqi (dispersing stagnated liver-Qi) high, middle, and low dose groups. Except the blank group, rats in all groups were injected subcutaneously in multiple points on days 0 and 30 with prostatic protein extractive solution (60 mg/ mL), and intraperitoneally injected with diphtheria-pertussis and tetanus vaccine (DPT vaccine) to establish the EAP model. Model rats were adminis- trated high, middle, and low doses of Chinese herb- al prescriptions and were sacrificed after 4 weeks. Pathological changes in the prostate gland were observed with HE staining and changes in serum interleukin-6 (IL-6), interleukin-8 (IL-8), and prostaglandin E2 (PGE2) levels were detected with enzyme-linked immunosorbent assay.. Compared with the blank group, serum PGE2, IL-6, and IL-8 levels in the model group were significantly higher (P < 0.05). Compared with the model group, serum PGE2, IL-6, and IL-8 levels in the Qingrejiedu low dose and middle dose groups were significantly lower (P < 0.05), with the lower dose having a more obvious effect. Serum PGE2, IL-6, and IL-8 levels in the Huoxuehuayu high dose group (P < 0.05), IL-6 and IL-8 levels in the Huoxue- huayu middle dose group (P < 0.05), and the IL-8 level in the Huoxuehuavu low dose group were significantly lower than those in the model group (p < 0.05). There were significant differences in PGE2 and IL-6 levels among the different dose groups of Shuganliqi drugs (P < 0.05). Compared with the model group, serum PGE2, IL-6, and IL-8 levels in the Shuganliqi high dose group (P < 0.05) and IL-8 level in the Shugangliqi low dose group were significantly lower (P < 0.05), while the Shuganliqi middle dose group did not change significantly.. Therefore, in TCM treatment of autoimmune prostatitis, different treatment methods should select different doses. For prescriptions that clear heat and remove toxicity, low doses should be used. For prescriptions that promote blood circulation to remove blood stasis and for prescriptions that disperse stagnated liver-Qi, high doses should be used.

Topics: Animals; Autoimmune Diseases; Drug Prescriptions; Drugs, Chinese Herbal; Humans; Interleukin-6; Interleukin-8; Male; Prostatitis; Rats; Rats, Wistar

Autoimmune inner ear disease (AIED) is a poorly understood disease marked by bilateral, rapidly progressive hearing loss triggered by unknown stimuli, which is corticosteroid responsive in 60 % of patients. Although the mechanism of the disease is not precisely understood, a complex interaction of cytokines is believed to contribute toward the inflammatory disease process and hearing loss. Previously, we showed the role of TNF-α in steroid-sensitive and IL-1β in steroid-resistant immune-mediated hearing loss. N-Acetylcysteine (NAC), a broad spectrum antioxidant, has been effective in other autoimmune disorders. Other studies have shown NAC to have a protective adjunct role in human idiopathic sudden hearing loss, where the addition of NAC resulted in better hearing recovery than with steroids alone, although the mechanism of this protection was not elucidated. In the present study, we observed PBMCs from AIED patients exhibited higher baseline TNF-α and MPO levels compared with normal healthy controls. NAC effectively abrogates LPS-mediated TNF-α release from PBMC of both AIED patients and controls. We demonstrated that in AIED patients, the TNF-α downstream signaling pathway appears aberrantly regulated, influencing both MPO and IL-8 expression. Given that NAC effectively abrogated LPS-mediated TNF-α release and exerted minimal effects on the downstream targets of this pathway, we feel NAC may be a rational adjunct therapy for this enigmatic disease, worthy of clinical exploration.

Topics: Acetylcysteine; Antioxidants; Autoimmune Diseases; Humans; Interleukin-8; Labyrinth Diseases; Leukocytes, Mononuclear; Molecular Targeted Therapy; Peroxidase; Tumor Necrosis Factor-alpha

It is widely accepted that perforin regulatory elements are hypomethylated in CD4+ T cells from patients with active lupus, but whether this is the case in autoimmune emphysema is not known.. Twenty rats were randomly divided into a normal control group and an emphysema group. Rat models of emphysema were established by intraperitoneal injection with xenogeneic endothelial cells. The levels of tumour necrosis factor-α, interleukin-8 and matrix metalloproteinase (MMP)-9 in bronchoalveolar lavage fluid (BALF) were measured, lung mean linear intercept and destructive index measured. Mean methylation of perforin gene promoter in CD4+ T cells and the expression of perforin were investigated. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling methods were used to examine the percentage of apoptotic cells in the alveolar septa.. The levels of MMP-9 in BALF were higher in emphysema group than in control group (P < 0.05). The mean linear intercept and destructive index were higher in emphysema group than in control group (P < 0.05). The mean perforin gene promotor methylation of emphysema group was significantly decreased as compared with control group, while the expression levels of perforin gene were relatively higher (P < 0.05). There were more terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling-positive cells in the alveolar septa in control group than in emphysema group.. Hypomethylation of perforin regulatory elements in CD4+ T cells may result in the lung septal cell apoptosis associated with the development of experimental autoimmune emphysema. MMP-9 may play an important role in the pathogenesis of this kind of disease.

Topics: Animals; Autoimmune Diseases; Bronchoalveolar Lavage Fluid; CD4-Positive T-Lymphocytes; Cell Culture Techniques; Disease Models, Animal; DNA Methylation; In Situ Nick-End Labeling; Interleukin-8; Male; Matrix Metalloproteinase 9; Pore Forming Cytotoxic Proteins; Pulmonary Emphysema; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Regulatory Elements, Transcriptional; Sequence Analysis, DNA; Spleen; Tumor Necrosis Factor-alpha

The T helper cell subsets Th1, Th2, Th17, and Treg play an important role in immune cell homeostasis, in host defense, and in immunological disorders. Recently, much attention has been paid to Th17 cells which seem to play an important role in the early phase of the adoptive immune response and autoimmune disease. When generating Th17 cells under in vitro conditions the amount of IL-17A producing cells hardly exceeds 20% while the nature of the remaining T cells is poorly characterized. As engagement of the aryl hydrocarbon receptor (AHR) has also been postulated to modulate the differentiation of T helper cells into Th17 cells with regard to the IL-17A expression we ask how far do Th17 polarizing conditions in combination with ligand induced AHR activation have an effect on the production of other T helper cell cytokines. We found that a high proportion of T helper cells cultured under Th17 polarizing conditions are IL-8 and IL-9 single producing cells and that AHR activation results in an upregulation of IL-8 and a downregulation of IL-9 production. Thus, we have identified IL-8 and IL-9 producing T helper cells which are subject to regulation by the engagement of the AHR.

Topics: Autoimmune Diseases; Basic Helix-Loop-Helix Transcription Factors; CD4-Positive T-Lymphocytes; Cell Culture Techniques; Cell Differentiation; Cytokines; Homeostasis; Humans; Interleukin-8; Interleukin-9; Ligands; Receptors, Aryl Hydrocarbon; Th17 Cells

To establish a rat model of autoimmune prostatitis using purified prostatic proteins (PPP).. Thirty-six male Wistar rats were randomized into three groups of equal number to receive intramuscular injection of normal saline (normal control group) and PPP at 15 mg/ml (low-concentration group) and 80 mg/ml (high-concentration group). At 4 weeks after modeling, the rats were sacrificed for HE staining of the prostate tissue and examination of the inflammatory factors IL-8 and IL-10 in the serum, immunoglobulins IgA and IgM, and regulatory T cells Th1/Th2.. Three rats died in the high-concentration PPP group but none in the low-concentration PPP and normal control groups. Gross observation of the prostate showed increased volume and hard texture of the prostate in the two PPP groups, but no significant change in the normal controls. Pathological examination exhibited morphological damage to the prostatic tissue and inflammatory cellular infiltration in the experimental rats. The serum level of IL-8 was significantly higher in the low- and high-concentration PPP groups ([129.07 +/- 11.48] and [147.58 +/- 17.70] pg/ml) than in the control ([94.12 +/- 7.04] pg/ml) (P < 0.05), while that of IL-10 was remarkably lower in the former two groups ([227.14 +/- 18.19] and [187.14 +/- 16.32] pg/ml) than in the latter ([252.48 +/- 21.72] pg/ml, P < 0.05). The serum level of IgA was markedly elevated in the low- and high-concentration PPP groups as compared with that in the control ([0.25 +/- 0.37] and [0.31 +/- 0.42] vs [0.19 +/- 0.14] mg/ml, P < 0.05), and so was that of IgM ([0.23 +/- 0.41] and [0.34 +/- 0.58 ] vs [0.17 +/- 0.33] mg/ml, P < 0.05). No significant changes were observed in the levels of regulatory T cells Th1/Th2.. Both low and high concentrations of purified prostatic proteins can be used for the construction of autoimmune prostatitis models in rats, while low concentration is preferable for its advantages of lower mortality of the rats and inducement of more consistent manifestations of autoimmune prostatitis.

Topics: Animals; Autoimmune Diseases; Disease Models, Animal; Humans; Interleukin-10; Interleukin-8; Male; Prostatic Secretory Proteins; Prostatitis; Rats; Rats, Wistar

To evaluate the therapeutic effect of Compound Xuanju Capsule (CXC) on autoimmune prostatitis in rat models.. Sixty healthy male Wistar rats were randomly divided into five groups of equal number: blank control, low-concentration purified prostate protein (low-conc PPP), low-conc PPP + CXC treatment, high-concentration PPP (hi-con PPP), and hi-conc PPP + CXC treatment. Autoimmune prostatitis models were established by intragastric administration of PPP solution at 15 mg/ml (low concentration) and 80 mg/ml, respectively. At 30 days after modeling, the rats in the blank control and low-conc and hi-conc PPP model groups were treated with normal saline, and those in the other two groups with CXC at a daily dose of 0.068 g/ml. At 30, 45, and 60 days, all the animals were sacrificed for observation of pathological changes in the prostate tissue and determination of the levels of IL-8, IL-10, and TNF-alpha in the serum.. Compared with the PPP models, the hi-conc PPP + CXC group showed significantly reduced levels of IL-8 and TNF-alpha in the serum at 45 days ([148.54 +/- 17.23] and [62.14 +/- 5.59] pg/ml vs [100.77 +/- 11.08] and [32.63 +/- 2.91] pg/ml, P < 0.05) and at 60 days ([143.69 +/- 17.28] and [59.38 +/- 5.50] pg/mlvs [95.77 +/-10.53] and [29.63 +/- 2.66] pg/ml, P < 0.05), and so did the low-cone PPP + CXC group at 45 days ([128.47 +/- 12.21] and [40.43 +/- 3.64] pg/ml vs [111.76 +/- 10.07] and [35.44 +/- 3.17] pg/ml, P < 0.05) and at 60 days ([131.07 +/- 10.93] and [43.34 +/- 3.91] pg/ml vs [97.46 +/- 8.75] and [30.44 +/- 2.75] pg/ml, P < 0.05). The serum level of IL-10 was remarkably elevated in the hi-cone PPP + CXC group as compared with that of the PPP models at 45 and 60 days ([189.14 +/- 16.78] and [184.14 +/- 15.89] pg/ml vs [230.48 +/- 29.96] and [248.48 +/- 31.03] pg/ml, P < 0.05), and so was it in low-cone PPP + CXC group ([223.14 +/- 17.87] and [224.14 +/- 17.93] pg/ml vs [231.42 +/- 23.18] and [249.42 +/- 24.97] pg/ml, P < 0.05). Pathological examination revealed morphological damages to the prostate tissue and infiltration of inflammatory cells in the model rats, but no obvious changes in the normal controls. At 15 days of treatment, the rats in the PPP + CXC group showed enlarged prostate glandular cavity, mild proliferation of epithelial cells, no obvious infiltration of inflammatory cells in the interstitial tissue, and a few visible fibrous tissues under the light microscope.. Compound Xuanju Capsule is efficacious on autoimmune prostatis in rats by reducing inflammatory changes in the prostate tissue and improving the expression of inflammatory factors.

Topics: Animals; Autoimmune Diseases; Capsules; Interleukin-10; Interleukin-8; Male; Prostatic Hyperplasia; Prostatic Secretory Proteins; Prostatitis; Random Allocation; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

The regenerating gene (Reg) was isolated originally as a gene specifically over-expressed in regenerating pancreatic islets and constitute a growth factor family. Reg gene product (Reg) is important in the pathophysiology of various human inflammatory diseases. Recently, the possible involvement of human REG in the regeneration of salivary ductal epithelial cells of patients with primary Sjögren's syndrome (SS) was reported. However, the expression of the REG family genes in minor salivary glands (MSG) and the occurrence of anti-REG Iα autoantibodies in SS patients were obscured. In this study, we examined the expression of REG family genes in the MSG of SS and screened anti-REG Iα autoantibodies in SS. The mRNA levels of REG family genes in MSG were quantified using real-time reverse transcription-polymerase chain reaction (RT-PCR) and REG Iα expression in the MSG was analysed by immunohistochemistry. The mRNA level of REG Iα in the MSG of SS patients was significantly higher than that of control. REG Iα protein was expressed highly in SS ductal epithelial cells. Anti-REG Iα autoantibodies in the sera were found in 11% of SS. All the MSG in the anti-REG Iα autoantibody-positive group showed REG Iα expression, whereas only 40% showed REG Iα expression in the anti-REG Iα autoantibody-negative group. The anti-REG Iα autoantibody-positive group showed significantly lower saliva secretion and a higher ratio of grade 4 (by Rubin-Holt) in sialography. These data suggest strongly that autoimmunity to REG Iα might play a role in the degeneration of MSG ductal epithelial cells in primary SS.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Autoantibodies; Autoimmune Diseases; Child; Female; Humans; Interleukin-6; Interleukin-8; Lithostathine; Male; Middle Aged; Salivary Glands, Minor; Sjogren's Syndrome; Young Adult

The aim of this study is to understand intracellular regulatory mechanisms in peripheral blood mononuclear cells (PBMCs), which are either common to many autoimmune diseases or specific to some of them. We incorporated large-scale data such as protein-protein interactions, gene expression and demographical information of hundreds of patients and healthy subjects, related to six autoimmune diseases with available large-scale gene expression measurements: multiple sclerosis (MS), systemic lupus erythematosus (SLE), juvenile rheumatoid arthritis (JRA), Crohn's disease (CD), ulcerative colitis (UC) and type 1 diabetes (T1D). These data were analyzed concurrently by statistical and systems biology approaches tailored for this purpose. We found that chemokines such as CXCL1-3, 5, 6 and the interleukin (IL) IL8 tend to be differentially expressed in PBMCs of patients with the analyzed autoimmune diseases. In addition, the anti-apoptotic gene BCL3, interferon-γ (IFNG), and the vitamin D receptor (VDR) gene physically interact with significantly many genes that tend to be differentially expressed in PBMCs of patients with the analyzed autoimmune diseases. In general, similar cellular processes tend to be differentially expressed in PBMC in the analyzed autoimmune diseases. Specifically, the cellular processes related to cell proliferation (for example, epidermal growth factor, platelet-derived growth factor, nuclear factor-κB, Wnt/β-catenin signaling, stress-activated protein kinase c-Jun NH2-terminal kinase), inflammatory response (for example, interleukins IL2 and IL6, the cytokine granulocyte-macrophage colony-stimulating factor and the B-cell receptor), general signaling cascades (for example, mitogen-activated protein kinase, extracellular signal-regulated kinase, p38 and TRK) and apoptosis are activated in most of the analyzed autoimmune diseases. However, our results suggest that in each of the analyzed diseases, apoptosis and chemotaxis are activated via different subsignaling pathways. Analyses of the expression levels of dozens of genes and the protein-protein interactions among them demonstrated that CD and UC have relatively similar gene expression signatures, whereas the gene expression signatures of T1D and JRA relatively differ from the signatures of the other autoimmune diseases. These diseases are the only ones activated via the Fcɛ pathway. The relevant genes and pathways reported in this study are discussed at length, and may be helpful in the d

Topics: Apoptosis; Arthritis, Juvenile; Autoimmune Diseases; B-Cell Lymphoma 3 Protein; Cell Proliferation; Chemokine CXCL1; Chemokine CXCL5; Chemokine CXCL6; Chemokines, CXC; Colitis, Ulcerative; Crohn Disease; Diabetes Mellitus, Type 1; Gene Expression; Humans; Inflammation; Interferon-gamma; Interleukin-8; Leukocytes, Mononuclear; Lupus Erythematosus, Systemic; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Multiple Sclerosis; Protein Interaction Maps; Proto-Oncogene Proteins; Receptors, Calcitriol; Receptors, IgE; Signal Transduction; Transcription Factors; Transcriptome

Primary autoimmune neutropenia (AIN) is more common in newborns, and usually benign or self-limiting, so most cases require no specific therapy. In adults, however, for little tendency toward spontaneous remission, they require certain treatments and careful managements. Here we report a successful management of primary AIN patient by estimating the granulopoiesis according to CRP levels without administration of G-CSF or increase of prednisolone when peripheral neutrophil counts dropped down. Transient elevation of CRP associated with severe drop down in neutrophil count, and subsequent dramatic neutrophil increase was occasionally observed during the follow up with minimal dose of prednisolone. Coexistence of decreased neutrophil counts and elevated CRP levels was accompanied by increase of serum levels of IL-6 and IL-8. Although this is the report of only one patient, these elevated CRP levels combined with severe drop down and subsequently spontaneous rapid recovery in neutrophil count, were repetitively observed, suggesting the preceding CRP elevation before neutrophil recovery. We propose the important part of CRP as a predictor of granulopoiesis in patients with neutropenia.

Topics: Autoimmune Diseases; Biomarkers; C-Reactive Protein; Cell Count; Female; Humans; Interleukin-6; Interleukin-8; Middle Aged; Neutropenia; Neutrophils; Prognosis

A short, 4-step route to the scaffold of frondosin A and B is reported. The [1-methoxycarbonyl-5-(2',5'-dimethoxyphenyl)pentadienyl]Fe(CO)(3)(+) cation was prepared in two steps from (methyl 6-oxo-2,4-hexadienoate)Fe(CO)(3). Reaction of this cation with isopropenyl Grignard or cyclohexenyllithium reagents affords (2-alkenyl-5-aryl-1-methoxycarbonyl-3-pentene-1,5-diyl)Fe(CO)(3) along with other addition products. Oxidative decomplexation of these (pentenediyl)iron complexes, utilizing CuCl(2), affords 6-aryl-3-methoxycarbonyl-1,4-cycloheptadienes via the presumed intermediacy of a cis-divinylcyclopropane.

Topics: Alkadienes; Animals; Aquatic Organisms; Autoimmune Diseases; Bridged Bicyclo Compounds; Cations; Chemistry, Pharmaceutical; Ferric Compounds; Humans; Interleukin-8; Iron; Magnetic Resonance Spectroscopy; Models, Molecular; Neoplasms; Oxidation-Reduction; Porifera; Receptors, Interleukin-8

The association between vitamin D deficiency and asthma epidemic has been recognized. Tumor necrosis factor (TNF)-alpha and chemokines play important roles in pathogenesis of asthma. However, whether vitamin D has immunoregulatory function on TNF-alpha and chemokines expression in human monocytes is still unknown. The human monocytic cell line, THP-1 cells and human primary monocytes were pretreated with various concentration of 1alpha,25-(OH)(2)D(3) for 2 h before stimulation with lipopolysaccharide (LPS). Supernatants were collected 24 or 48 h after LPS stimulation. The levels of TNF-alpha, interferon-inducible protein 10 (IP-10)/CXCL10 (the Th1-related chemokine), macrophage-derived chemokine (MDC)/ CCL22 (the Th2-related chemokine), and interleukin 8 (IL-8)/CXCL8 (the neutrophil chemoattractant) were measured by ELISA. 1alpha,25-(OH)(2)D(3) could significantly suppress TNF-alpha and IP-10 expression in LPS-stimulated THP-1 and human primary monocytes. However, 1alpha,25-(OH)(2)D(3), especially in higher concentration, could significantly enhance MDC expression. 1alpha,25-(OH)(2)D(3) had no significant effects on IL-8 expression. We found 1alpha,25-(OH)(2)D(3) could significantly suppress TNF-alpha and Th1-related chemokine IP-10, which both play important roles in pathogenesis of severe refractory asthma and autoimmune diseases. However, 1alpha,25-(OH)(2)D(3) enhanced Th2-related chemokine MDC, which may result in Th2 inflammatory cell recruitment and thus adversely affect asthmatic patients. Although vitamin D has potential utility in the treatment of asthma and autoimmune diseases, excessive use of vitamin D may not be suitable in patients with Th2 allergic diseases.

Topics: Asthma; Autoimmune Diseases; Calcitriol; Cell Line; Cells, Cultured; Chemokine CCL22; Chemokine CXCL10; Chemokines; Cholecalciferol; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Humans; Interleukin-8; Lipopolysaccharides; Monocytes; Osmolar Concentration; Time Factors; Tumor Necrosis Factor-alpha; Up-Regulation; Vitamin D Deficiency

Biological functions of proteins are influenced by posttranslational modifications such as on/off switching by phosphorylation and modulation by glycosylation. Proteolytic processing regulates cytokine and chemokine activities. In this study, we report that natural posttranslational citrullination or deimination alters the biological activities of the neutrophil chemoattractant and angiogenic cytokine CXCL8/interleukin-8 (IL-8). Citrullination of arginine in position 5 was discovered on 14% of natural leukocyte-derived CXCL8(1-77), generating CXCL8(1-77)Cit(5). Peptidylarginine deiminase (PAD) is known to citrullinate structural proteins, and it may initiate autoimmune diseases. PAD efficiently and site-specifically citrullinated CXCL5, CXCL8, CCL17, CCL26, but not IL-1beta. In comparison with CXCL8(1-77), CXCL8(1-77)Cit(5) had reduced affinity for glycosaminoglycans and induced less CXCR2-dependent calcium signaling and extracellular signal-regulated kinase 1/2 phosphorylation. In contrast to CXCL8(1-77), CXCL8(1-77)Cit(5) was resistant to thrombin- or plasmin-dependent potentiation into CXCL8(6-77). Upon intraperitoneal injection, CXCL8(6-77) was a more potent inducer of neutrophil extravasation compared with CXCL8(1-77). Despite its retained chemotactic activity in vitro, CXCL8(1-77)Cit(5) was unable to attract neutrophils to the peritoneum. Finally, in the rabbit cornea angiogenesis assay, the equally potent CXCL8(1-77) and CXCL8(1-77)Cit(5) were less efficient angiogenic molecules than CXCL8(6-77). This study shows that PAD citrullinates the chemokine CXCL8, and thus may dampen neutrophil extravasation during acute or chronic inflammation.

Topics: Animals; Arginine; Autoimmune Diseases; Citrulline; Cornea; Glycosylation; Humans; Hydrolases; Inflammation; Interleukin-8; Neovascularization, Physiologic; Phosphorylation; Protein Processing, Post-Translational; Protein-Arginine Deiminases; Rabbits

To explore the acting mechanism of Danpu Capsule (DPC) in treating chronic prostatitis by observing its effect on inflammatory factors in autoimmune prostatitis rat model.. The rat model was established by abdominal subcutaneous multiple points injection of rat's prostate tissue antigen. Thirty modeled rats were randamly divided into 3 groups, the DPC group, the Qianlietai Tablet (QLT) group and the model group. They were treated via gastrogavage respectively with DPC, Qianlietai Tablet and normal saline respectively. Besides, a control group was set up with 10 healthy rats. All animals were sacrificed 56 days after treatment. Pathologic change of prostatic tissue was observed by light microscopy, and the levels of interleukin 8 (IL-8), interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-alpha) and prostaglandin E2 (PGE2) in blood serum and prostatic tissue were detected by enzyme linked immunosorbent assay (ELISA).. Compared with the normal group, the serum and prostatic levels of IL-8, IL-10 and TNF-alpha, as well as the prostatic level of PGE2 in the model group were higher (P <0.05 or P <0.01). In the DPC group, the serum and prostatic levels of IL-8 was 3.07 +/- 0.61 ng/L and 7.32 +/- 2.44 ng/L respectively, which was lower than those in the model group (4.73 +/- 1.95 ng/L and 10.14 +/- 3.64 ng/L, respectively); that of TNF-alpha in the DPC group (85.34 +/- 19.20 ng/L and 87.01 +/- 15.4 ng/L) was also lower in the model group (111.48 +/- 31.57 ng/L and 119.88 +/- 14.13 ng/L); similar difference between the two groups was also shown in prostatic level of IL-10 (34.05 +/- 7.56 ng/L vs 47.20 +/- 15.97 ng/L), and so was PGE2 (603.97 +/- 114.62 ng/L vs 712.58 +/- 117.10 ng/L), all with statistical significance (P <0.05 or P <0. 01).. DPC could reduce the prostatic inflammatory response of model rats, and regulate the local immune condition.

Topics: Animals; Autoimmune Diseases; Capsules; Disease Models, Animal; Drugs, Chinese Herbal; Humans; Inflammation Mediators; Interferon-gamma; Interleukin-10; Interleukin-8; Male; NF-kappa B; Prostatitis; Random Allocation; Rats; Rats, Wistar

Auto-antibodies against heat shock proteins (HSPs) are frequently found in the sera of patients with rheumatic and other autoimmune diseases. However, it is unclear whether these auto-antibodies play a role in the pathophysiology and etiology of these diseases. We found that a murine anti-HSP60 mAb enhanced the production of IL-8 and tumor necrosis factor-alpha induced by human HSP60 in the human monocytic cell lines THP-1 and U937, and human peripheral blood monocytes. Similar enhancement was observed with the combination of human HSP70 protein and a murine anti-HSP70 mAb. The enhancing effects were also observed for F(ab')2 fragment, but not for monovalent Fab fragment. This suggests that the enhancement is due to cross-linking of HSP by the anti-HSP antibodies. The induction of IL-8 was dramatically suppressed by the transfection of a dominant-negative mutant of Toll-like receptor 4. We also found that sera from patients with rheumatic autoimmune diseases, which contained higher anti-HSP60 auto-antibody titers than sera from healthy donors, significantly enhanced the IL-8 production induced by human HSP60 in THP-1 cells. We propose that auto-antibodies against HSPs have the potential to play a pathogenic role in rheumatic autoimmune diseases by enhancing inflammatory reactions.

Topics: Animals; Autoantibodies; Autoimmune Diseases; Cell Line; Cytokines; Enzyme-Linked Immunosorbent Assay; Heat-Shock Proteins; Humans; Interleukin-8; Mice; Monocytes; Toll-Like Receptors; Transfection; Tumor Necrosis Factor-alpha

Leukocyte infiltration during acute and chronic inflammation is regulated by exogenous and endogenous factors, including cytokines, chemokines and proteases. Stimulation of fibroblasts and human microvascular endothelial cells with the inflammatory cytokines interleukin-1beta (IL-1beta) or tumour necrosis factor alpha (TNF-alpha) combined with either interferon-alpha (IFN-alpha), IFN-beta or IFN-gamma resulted in a synergistic induction of the CXC chemokine CXCL10, but not of the neutrophil chemoattractant CXCL8. In contrast, simultaneous stimulation with different IFN types did not result in a synergistic CXCL10 protein induction. Purification of natural CXCL10 from the conditioned medium of fibroblasts led to the isolation of CD26/dipeptidyl peptidase IV-processed CXCL10 missing two NH2-terminal residues. In contrast to intact CXCL10, NH2-terminally truncated CXCL10(3-77) did not induce extracellular signal-regulated kinase 1/2 or Akt/protein kinase B phosphorylation in CXC chemokine receptor 3-transfected cells. Together with the expression of CXCL10, the expression of membrane-bound CD26/dipeptidyl peptidase IV was also upregulated in fibroblasts by IFN-gamma, by IFN-gamma plus IL-1beta or by IFN-gamma plus TNF-alpha. This provides a negative feedback for CXCL10-dependent chemotaxis of activated T cells and natural killer cells. Since TNF-alpha and IL-1beta are implicated in arthritis, synovial concentrations of CXCL8 and CXCL10 were compared in patients suffering from crystal arthritis, ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis. All three groups of autoimmune arthritis patients (ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis) had significantly increased synovial CXCL10 levels compared with crystal arthritis patients. In contrast, compared with crystal arthritis, only rheumatoid arthritis patients, and not ankylosing spondylitis or psoriatic arthritis patients, had significantly higher synovial CXCL8 concentrations. Synovial concentrations of the neutrophil chemoattractant CXCL8 may therefore be useful to discriminate between autoimmune arthritis types.

Topics: Autoimmune Diseases; Biomarkers; Cells, Cultured; Chemokine CXCL10; Chemokines, CXC; Cytokines; Dermis; Dipeptidyl Peptidase 4; Drug Combinations; Endothelial Cells; Fibroblasts; Humans; Infant, Newborn; Inflammation Mediators; Interleukin-8; Joint Diseases; Ligands; Peptide Fragments; Protein Isoforms; Receptors, Chemokine; Receptors, CXCR3; Rheumatic Diseases; Signal Transduction

The expression of BP180 has previously been demonstrated to be influenced by both calcium (Ca(2+)) concentration and binding of anti-BP180-antibodies in cultured keratinocytes of the skin squamous cell carcinoma line DJM-1. Here, BP180 expression was studied in cultured normal human epidermal keratinocytes by confocal laser scanning microscopy. We exploited an experimental system, in which BP180 was previously shown to mediate, upon incubation with anti-BP180 antibodies, a specific signal-transducing event that leads to the release of inflammatory mediators, such as IL-8 from cultured normal human epidermal keratinocytes (NHEK). We found that without addition of BP180-specific IgG, BP180 is predominantly expressed on the cell surface irrespective of the Ca(2+) concentration. In contrast, cell surface BP180 was greatly reduced in NHEK kept in high Ca(2+) medium after incubation with BP180-specific IgG for 12 h compared to low Ca(2+) medium. This effect was seen with antibodies to both N- and C-terminal fragments of the BP180 ectodomain, respectively. In addition, a slightly higher BP180 expression was found in NHEK cultured in low compared to high Ca(2+) medium by Western blotting. Interestingly, in contrast to NHEK kept under low Ca(2+ )conditions, in NHEK grown in high Ca(2+) medium, no elevated levels of IL-8 were released after treatment of cells with anti-BP180 IgG compared to normal IgG. Our data indicate that the Ca(2+)-modulated expression of BP180 is functionally relevant. This finding sheds further light on the complex pathomechanism in blister formation of BP180-related autoimmune blistering skin diseases.

Topics: Animals; Autoantigens; Autoimmune Diseases; Blister; Calcium; Carrier Proteins; Cells, Cultured; Collagen Type XVII; Cytoskeletal Proteins; Dystonin; Gene Expression Regulation; Humans; Interleukin-8; Keratinocytes; Nerve Tissue Proteins; Non-Fibrillar Collagens; Rabbits

Patients with T-cell large granular lymphocytic leukemia (T-LGLL) have a high incidence of autoimmune disorders. The pathogenesis of associated T-LGLL and autoimmune abnormalities is not clear. In this study we have investigated the role of cytokines in the development of immune complications in LGLL.. We studied clinical and laboratory features of 15 patients diagnosed with T-LGLL. The patients had various autoimmune disturbances: persistent neutropenia, immune thrombocytopenia, pure red-cell aplasia, Hashimoto's thyroiditis, sicca syndrome, systemic lupus erythemathosus, systemic scleroderma. The T-LGLL cells obtained from these patients were activated by phytohemagglutinin and incubated for 3 days. Using ELISA technique we analysed the release of sIL-2R, IL-4, IL-6, IL-8, IL-10, IL-12 and TNF-alpha in the supernatant.. Cytokine analysis of supernatants obtained from the LGLL T cells stimulated with PHA revealed increased sIL-2R production in 40% (six patients), TNF-alpha - in 47% (seven patients), IL-6 - in 67% (10 patients), IL-10 - in 47% (seven) and IL-8 - in 60% (nine) of patients. Levels of IL-4 and IL-12 were not elevated compared to controls. No correlation was found between LGL count, CD4 versus CD8 expansion, or in the clinical findings of the patients and cytokine release in vitro.. Our findings showing the potential of LGLL cells for cytokine release in vitro suggests that these cells may play a major role in the immune disturbances observed in large granular lymphocytic leukemia accompanied by autoimmunity features.

Topics: Adult; Aged; Autoimmune Diseases; Case-Control Studies; Cell Culture Techniques; Culture Media, Conditioned; Cytokines; Female; Humans; Interleukin-10; Interleukin-2; Interleukin-6; Interleukin-8; Leukemia, T-Cell; Lymphocyte Activation; Male; Middle Aged; Phytohemagglutinins; T-Lymphocytes; Tumor Necrosis Factor-alpha

A series of nicotinamide N-oxides was synthesized and shown to be novel, potent, and selective antagonists of the CXCR2 receptor. Furthermore, these compounds showed significant functional activity against GRO-alpha-driven human neutrophil chemotaxis. Compounds of this class may be useful for the treatment of inflammatory, auto-immune, and allergic disorders.

Topics: Autoimmune Diseases; Binding Sites; Chemokine CXCL1; Chemokines, CXC; Chemotactic Factors; Chemotaxis; Growth Substances; Humans; Hypersensitivity; Inflammation; Inhibitory Concentration 50; Intercellular Signaling Peptides and Proteins; Interleukin-8; Neutrophils; Niacinamide; Protein Binding; Receptors, Interleukin-8B; Structure-Activity Relationship

In autoimmune bullous skin diseases, accumulation of neutrophils and/or eosinophils in the affected skin represents a characteristic feature. So far, however, the induction of this granulocyte infiltration has not been elucidated.. Regarding their biological effects, the chemokines interleukin 8 (IL-8) and RANTES (regulated upon activation normal T lymphocyte expressed and secreted) could play a role in this granulocyte accumulation.. Immunohistochemical examination of lesional skin from patients with bullous pemphigoid, pemphigus, dermatitis herpetiformis and linear IgA disease was performed using a set of different antibodies against IL-8 and RANTES. Additionally, blister fluids were screened for soluble RANTES peptide using an ELISA.. No difference in chemokine expression was found in lesions of autoimmune bullous diseases compared to normal skin.. In contrast to chronic inflammatory diseases like psoriasis and eczema, where keratinocyte IL-8 immunoreactivity was found to differ from normal skin, keratinocyte immunoreactivity is not altered in autoimmune bullous diseases.

Topics: Autoimmune Diseases; Blister; Chemokine CCL5; Dermatitis Herpetiformis; Enzyme-Linked Immunosorbent Assay; Humans; Immunoglobulin A; Immunohistochemistry; Interleukin-8; Pemphigoid, Bullous; Pemphigus; Skin; Skin Diseases, Vesiculobullous

Topics: Adolescent; Adult; Aged; Antibodies; Antibodies, Antinuclear; Autoantibodies; Autoimmune Diseases; Child; Female; Humans; Interleukin-8; Lupus Erythematosus, Systemic; Male; Middle Aged

Eighty-seven patients with heparin-associated thrombocytopenia (HAT) showed either a positive heparin platelet aggregometry test result and/or the presence of antibodies to heparin-platelet factor 4 (H-PF4) complexes by enzyme-linked immunosorbent assay (ELISA). Fifteen of these patients lacked antibodies to H-PF4, and plasma from these patients was analyzed for the presence of antibodies to PF4-related chemokines, Neutrophil-activating peptide-2 (NAP-2) and interleukin-8 (IL-8). Of these 15 patients, 6 showed antibodies to IL-8 and 3 to the platelet basic protein (PBP)-derived protein, NAP-2. Antibodies to IL-8 and NAP-2 were not observed in control patients (n = 38), patients with HAT and H-PF4 autoantibodies (n = 72), patients with autoimmune diseases (n = 21), or patients with non-HAT thrombocytopenia (n = 30). Five of these nine patients with anti-IL-8 or anti-NAP-2 developed thrombosis during heparin treatment, which is not statistically different from the patients with H-PF4 antibodies. The existence of autoantibodies to IL-8 and NAP-2 in HAT patients highlights the significance of chemokines in the pathogenesis of HAT. The contribution of heparin in vitro was minimal in patients with anti-IL-8 and anti-NAP-2 antibodies, suggesting a biologic difference from the majority of patients with HAT and anti-PF4 antibodies. It may be that antibodies to IL-8 and NAP-2 have weaker affinity for heparin and that the ELISA system may not reflect in vivo heparin-chemokine complex formation. Alternatively, antichemokine autoantibodies may predate heparin exposure, and the role of heparin in initiating HAT may be to mobilize the chemokines and to target them to platelets, neutrophils, or endothelial cells. Subsequent chemokine-binding autoantibodies then lead to cell activation resulting in thrombocytopenia and thrombosis.

Topics: Adult; Aged; Antibody Specificity; Autoantibodies; Autoimmune Diseases; beta-Thromboglobulin; Female; Heparin; Humans; Immunoglobulin G; Immunoglobulin M; Interleukin-8; Male; Middle Aged; Peptides; Platelet Aggregation; Platelet Factor 4; Purpura, Thrombocytopenic, Idiopathic

Proteinase 3 is the major target antigen of antineutrophil cytoplasmic autoantibodies (ANCA) in Wegener's granulomatosis and is contained in the azurophilic granules of polymorphonuclear neutrophils, the dominant cell type in vascular lesions during the early stages of systemic vasculitis. This study questioned whether neutrophil lysosomal enzymes, once released at the site of inflammation, are able to potentiate the influx of additional neutrophils by enhancing the production of the chemotactic cytokine interleukin-8 (IL-8) by endothelial cells. Therefore, human umbilical vein endothelial cells in culture were incubated with varying concentrations of highly purified proteinase 3, human neutrophil elastase, and cathepsin G for different time periods. The supernatants were subsequently assessed for IL-8 antigen by using a sandwich ELISA. The presence of both proteinase 3 and elastase resulted in an increased production of IL-8, up to 15.6- and 4.2-fold, respectively, in a dose- and time-dependent fashion. Cathepsin G did not influence IL-8 production. Although the addition of an alpha 1-proteinase inhibitor completely abrogated elastase-mediated IL-8 production, it did not significantly influence the effect of proteinase 3. Both proteinase 3-and elastase-mediated production of IL-8 was inhibited by cycloheximide, indicating de novo synthesis. This was supported by the finding of increased IL-8 mRNA levels in proteinase 3-treated human umbilical vein endothelial cells by using Northern blot analysis. Taken together, the neutrophil lysosomal enzymes proteinase 3 and human neutrophil elastase may contribute to a self-perpetuating process of neutrophil recruitment in acute inflammation by increasing de novo synthesis of IL-8 by endothelial cells. The studies presented here also show that proteinase 3 mediates its effect independently of its enzymatic activity, indicating a hitherto unknown mode of action on endothelial cells.

Topics: alpha 1-Antitrypsin; Autoantigens; Autoimmune Diseases; Cathepsin G; Cathepsins; Cells, Cultured; Chemotaxis, Leukocyte; Cycloheximide; Endothelium, Vascular; Gene Expression Regulation; Granulomatosis with Polyangiitis; Humans; Interleukin-8; Lysosomes; Myeloblastin; Neutrophils; Protein Synthesis Inhibitors; RNA, Messenger; Serine Endopeptidases; Stimulation, Chemical; Umbilical Veins

Circulating levels of the proinflammatory cytokines interleukin-6 (IL-6), IL-8, and tumor necrosis factor-alpha (TNF-alpha) were measured in 13 children with autoimmune hepatitis (AIH) (seven with type 1 and six with type 2). In untreated children with type 1 AIH, TNF-alpha, IL-6, and IL-8 levels were elevated when compared to those of healthy controls (p < 0.005, p < 0.02, p = 0.06, respectively), whereas in children with type 2 AIH, cytokine levels were normal in all except one sample. A significant decrease in circulating IL-6, IL-8, and TNF-alpha was observed when patients were evaluated during a subsequent remission. We found no significant correlation of cytokine levels with alanine aminotransferase (ALT) activity, total serum gamma-globulins, or prothrombin activity. In patients with cirrhosis, serum IL-8 and IL-6 levels were higher (significantly in the case of IL-8) than those of patients without cirrhosis. In conclusion, activation of the in vivo production of the proinflammatory cytokines IL-6, IL-8, and TNF-alpha appears to be associated with type 1 but not with type 2 AIH.

Topics: Adolescent; Alanine Transaminase; Autoimmune Diseases; Child; Child, Preschool; Hepatitis; Humans; Infant; Interleukin-6; Interleukin-8; Tumor Necrosis Factor-alpha

Acute alcoholic hepatitis is characterized by a unique degree of liver neutrophil infiltration, often accompanied by marked peripheral neutrophilia in the absence of demonstrable bacterial or fungal infection. In this study we assayed plasma and tissue levels of a potent neutrophil activator and chemotaxin, interleukin-8, in patients with a spectrum of alcoholic liver diseases and in normal and diseased control subjects. Levels of circulating interleukin-8 were undetectable in normal subjects but highly elevated in patients with alcoholic hepatitis, particularly in those who died (geometric mean = 600 ng/L; confidence interval = 323 to 1,120 vs. geometric mean = 184 ng/L; confidence interval = 114 to 309 in survivors). Levels correlated with biochemical indicators of severe disease (bilirubin: R = 0.38; international prothrombin ratio: R = 0.28; white blood cell count: R = 0.35; creatinine: R = 0.34) and with tumor necrosis factor-alpha (R = 0.43) and soluble tumor necrosis factor receptors (p55; R = 0.59). In contrast, moderate elevations in the levels of circulating interleukin-8 were seen in alcoholic cirrhosis (geometric mean = 93 ng/L; confidence interval = 40 to 213) and in alcoholic patients undergoing alcohol withdrawal (geometric mean = 137 ng/L; confidence interval = 72 to 259). Levels in nonalcoholic inflammatory liver disease were comparatively low (geometric mean = 17 ng/L; confidence interval = 10 to 29).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Autoimmune Diseases; Female; Hepatic Encephalopathy; Hepatitis; Hepatitis, Alcoholic; Humans; Immunohistochemistry; Interleukin-8; Liver; Liver Cirrhosis, Alcoholic; Liver Diseases, Alcoholic; Male; Neutrophils; Prospective Studies; Tumor Necrosis Factor-alpha