Glucocorticoid-induced tumor necrosis factor receptor family-related protein exacerbates collagen-induced arthritis by enhancing the expansion of Th17 cells.
ABSTRACT Rheumatoid arthritis (RA), a chronic autoimmune form of inflammatory joint disease, progressively affects multiple joints with pathological changes in the synovia, cartilage, and bone. Numerous studies have suggested a critical role for glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) in the pathogenesis of autoimmune arthritis by modulating both innate and adaptive immune reactions, but the underlying mechanisms by which GITR activation promotes arthritic progression remain largely unclear. In this study, we found that collagen-induced arthritis mice treated with the ligand of GITR (GITRL) displayed an earlier onset of arthritis with a markedly increased severity of arthritic symptoms and joint damage, in which significantly increased Th17 cells in both spleen and draining lymph nodes were observed. Notably, results showed that a marked expansion of Th17 cells with increased RORγt mRNA expression was induced from naïve CD4(+) T cells when cultured with GITRL. Consistently, normal mice that were treated with GITRL were found to display a substantial expansion of splenic Th17 cells. Furthermore, we detected elevated serum levels of GITRL in patients with RA, which were positively correlated with an increase in interleukin-17 production. Taken together, the results from this study have revealed a new function of GITRL in exacerbating autoimmune arthritis via the enhancement of the expansion of Th17 cells.
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ABSTRACT: OBJECTIVE.: To determine a role of leptin in modulating Th17 cell response and joint inflammation in collagen-induced arthritis (CIA) mice. METHODS.: Leptin receptor expression on T cells was examined by PCR analysis, immunofluorescence microscopy and flow cytometry. Effects of leptin on Th17 cell differentiation and proliferation were evaluated by quantitative PCR, carboxyfluorescein diacetate succinimidyl ester proliferation assay and flow cytometry. Dynamic changes of leptin concentrations in joint tissue and synovial fluid of CIA mice were determined by immunohistochemistry and ELISA assay. Leptin was intraarticularly injected into the knee joint of CIA mice for assessing arthritis symptoms and joint pathology. Both Th1 and Th17 cell populations in spleen, draining lymph nodes and joint tissue were analyzed by flow cytometry and ELISPOT assay whereas IL-17 mRNA and protein levels in the joint tissue was measured by PCR analysis and ELISA assay. RESULTS.: In culture, leptin treatment significantly increased Th17 cell generation from naïve CD4(+) T cells. During CIA induction, markedly elevated levels of leptin were detected in the joint tissue and synovial fluid. Moreover, intraarticular injection of leptin in the knee joint of collagen-immunized mice resulted in an early onset of arthritis and substantially increased severity of clinical symptoms, accompanied with more pronounced synovium hyperplasia and joint damage. Further examination by immunofluorescence microscopy confirmed significantly increased Th17 cells in joint tissue and draining lymph nodes of leptin-treated CIA mice. CONCLUSION.: Together, our results have identified a new function of leptin in enhancing Th17 cell response and exacerbating joint inflammation in CIA mice.Arthritis & Rheumatism 07/2012; · 7.48 Impact Factor
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ABSTRACT: The aim of this paper is to investigate the correlation of glucocorticoid-induced tumor necrosis factor receptor- (TNFR-) related protein ligand (GITRL) with disease activity and organ involvement in patients with systemic lupus erythematosus (SLE). Serum GITRL levels were measured in 58 patients with SLE and 30 healthy controls matched for age and sex. Patients were assessed for clinical and laboratory variables. Correlations of serum GITRL levels with SLEDAI, laboratory values, and clinical manifestations were assessed. Serum GITRL levels were determined by ELISA. Serum GITRL levels were markedly increased in patients with SLE compared with healthy controls (mean 401.3 ng/mL and 36.59 ng/mL, resp.; P < 0.0001). SLE patients with active disease showed higher serum GITRL levels compared to those with inactive disease (mean 403.3 ng/mL and 136.3 ng/mL, resp; P = 0.0043) as well as normal controls (36.59 ng/mL; P < 0.0001). Serum GITRL levels were positively correlated with SLEDAI, titers of anti-dsDNA antibody, erythrocyte sedimentation rate (ESR), and IgM and negatively correlated with complement3 (C3). Serum GITRL levels were higher in SLE patients with renal involvement and vasculitis compared with patients without the above-mentioned manifestations.Clinical and Developmental Immunology 01/2012; 2012:265868. · 3.06 Impact Factor