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A directly GP130‐targeting small molecule ameliorates collagen‐induced arthritis (CIA) by inhibiting IL‐6/GP130 signalling and Th17 differentiation
Author(s) -
Park YeonHwa,
Kim Hee Jung,
Heo TaeHwe
Publication year - 2020
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.13215
Subject(s) - immunology , arthritis , rheumatoid arthritis , inflammation , interleukin 17 , cancer research , medicine , chemistry
Rheumatoid arthritis is a chronic inflammatory disease associated with joint inflammation and destruction driven by T helper 17 (Th17) cells. Interleukin‐6 (IL‐6) is secreted by many cell types, including macrophages and synovial fibroblasts. It induces the differentiation and function of Th17 cells that can increase lymphocytic infiltration in the joint. LMT‐28 can suppress IL‐6 signalling through direct binding to glycoprotein‐130 and alleviate inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. The purpose of this study was to assess whether LMT‐28 could potently inhibit Th17 differentiation and to determine the mechanism involved in the attenuating effect of LMT‐28 on rheumatoid arthritis through the IL‐6 signalling pathway. LMT‐28 reduced the arthritis score and showed protective effects against bone and cartilage destruction in collagen‐induced arthritis (CIA) mice. In mice with CIA, LMT‐28 markedly decreased serum levels of IL‐6, TNF and IL‐1β compared to vehicle control. Moreover, LMT‐28 attenuated Th17 cell activation in lymph nodes of CIA mice. We demonstrated that LMT‐28 suppressed differentiation of Th17 in mouse splenocytes and human peripheral blood mononuclear cells (PBMCs). Additionally, LMT‐28 inhibited phosphorylation of GP130, STAT3 and ERK induced by Hyper‐IL‐6 in human fibroblast‐like synoviocytes (FLS). Collectively, these results suggest that LMT‐28 can inhibit differentiated/activated‐Th17 cells in rheumatoid arthritis by blocking activation of the STAT3 pathway. LMT‐28 can attenuate rheumatoid arthritis by inhibiting differentiation/activation of Th17 cells and suppressing the proliferation and signalling activation of the IL‐6/solubleIL‐6 receptor complex stimulated FLS.