An herbal formula attenuates collagen-induced arthritis via inhibition of JAK2-STAT3 signaling and regulation of Th17 cells in mice.
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ABSTRACT:
SUBMITTER: Wu X
PROVIDER: S-EPMC5546477 | biostudies-other | 2017 Jul
REPOSITORIES: biostudies-other
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Project description:Signal transducer and activator of transcription 3 (STAT3) orchestrates the differentiation of several cell types, including interleukin-17 (IL-17)-releasing Th17 cells. Dysregulation of Th17 cells results in chronic inflammatory responses. Ssu72 is a C-terminal domain phosphatase required for transcriptional regulation. However, the mechanism by which Ssu72 affects STAT3 activation and Th17 cell differentiation is unclear. Here, we found that Ssu72 overexpression suppresses STAT3 activation and Th17 cell responses in vitro. A systemic infusion of Ssu72 attenuates experimental autoimmune arthritis by reducing STAT3 activity and the differentiation of Th17 cells. It also reduces joint destruction, serum immunoglobulin concentrations and osteoclastogenesis but increases the number of marginal zone B cells and B10 cells. These effects are associated with reduced p-STAT3 levels and the suppression of Th17 cell formation in vivo. Based on these data, Ssu72 is related to STAT3 activation and the inflammatory response; and Ssu72 overexpression in T-cell-mediated immunity has potential utility for the treatment of autoimmune arthritis.
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Project description:BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease. Soufeng sanjie formula (SF), which is composed of scolopendra (dried body of Scolopendra subspinipes mutilans L. Koch), scorpion (dried body of Buthus martensii Karsch), astragali radix (dried root of Astragalus membranaceus (Fisch.) Bge), and black soybean seed coats (seed coats of Glycine max (L.) Merr), is a traditional Chinese prescription for treating RA. However, the mechanism of SF in treating RA remains unclear. This study was aim to investigate the anti-arthritic effects of SF in a collagen-induced arthritis (CIA) mouse model and explore the mechanism by which SF alleviates arthritis in CIA mice.MethodsFor in vivo studies, female DBA/1J mice were used to establish the CIA model, and either SF (183 or 550 mg/kg/day) or methotrexate (MTX, 920 mg/kg, twice/week) was orally administered to the mice from the day of arthritis onset. After administration for 30 days, degree of ankle joint destruction and serum levels of IgG and inflammatory cytokines were determined. The balance of Th17/Treg cells in the spleen and lymph nodes was analyzed using flow cytometry. Moreover, the expression levels of retinoic acid receptor-related orphan nuclear receptor (ROR) γt and phosphorylated STAT3 (pSTAT3, Tyr705) in the spleen were detected by immunohistochemistry. Furthermore, the effect of SF on Th17 cells differentiation in vitro was investigated in CD4+ T cells under Th17 polarization conditions.ResultsSF decreased the arthritis score, ameliorated paw swelling, and reduced cartilage loss in the joint of CIA mice. In addition, SF decreased the levels of bovine collagen-specific IgG in sera of CIA mice. SF decreased the levels of inflammatory cytokines (TNF-α, IL-6, and IL-17A) and increased the level of IL-10 both in the sera and the joint of CIA mice. Moreover, SF treatment rebalanced the Th17/Treg ratio in the spleen and lymph nodes of CIA mice. SF also reduced the expression levels of ROR γt and pSTAT3 (Tyr705) in the spleen of CIA mice. In vitro, SF treatment reduced Th17 cell generation and IL-17A production and inhibited the expression of RORγt, IRF4, IL-17A, and pSTAT3 (Tyr705) under Th17 polarization conditions.ConclusionsOur results suggest that SF exhibits anti-arthritic effects and restores Th17/Treg homeostasis in CIA mice by inhibiting Th17 cell differentiation.
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Project description:Wenjinghuoluo (WJHL) prescription, the typical rheumatoid arthritis (RA) treatment compound in traditional Chinese medicine, shows favorable efficacy. The precise mechanism of WJHL on RA therapy is yet to be elucidated. This study aimed to determine the metabolic biomarkers in the early onset of RA and evaluate the regulation effect of WJHL on metabolite levels. Multivariate statistical analysis identified 93 biomarkers by precise MS/MS. These biomarkers played an important role in the regulation of key metabolic pathways associated with collagen-induced arthritis (CIA). A total of 68 biomarkers were related to the treatment of CIA by WJHL therapy. In addition, pathway analysis results showed six and three significant related pathways according to corresponding differential metabolites before and after WJHL therapy. Finally, disease and function prediction of ingenuity pathway analysis indicated that lipid metabolism, small molecule biochemistry, and carbohydrate metabolism were associated functions of WJHL therapy on CIA. Furthermore, top analysis-ready molecules of up-regulated thiamine and down-regulated arachidonic acid maybe the most related metabolites of WJHL therapy on CIA. The present work indicates that a metabolomics platform provides a new insight into understanding the mechanisms of action of natural medicines, such as WJHL.
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