A directly GP130-targeting small molecule ameliorates collagen-induced arthrites by inhibiting IL-6/GP130 signalling and Th17 differentiation

Abstract Rheumatoid arthritis is a chronic inflammatory disease that is characterized by joint destruction and inflammation by T helper 17 (Th17) cells. Interleukin-6 (IL-6) is secreted in cells such as macrophage or synovial fibroblast and induces the differentiation and function of Th17 cells that increase lymphocytic infiltration in the joint. LMT-28 suppresses IL-6 signaling through direct binding to glycoprotein-130, and alleviates inflammatory disease (such as rheumatoid arthritis, inflammatory bowel disease) in previous study. The purpose of this study is to assess whether LMT-28 would potently inhibit Th17 differentiation, and the mechanism of LMT-28 that attenuates rheumatoid arthritis through IL-6 signaling 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 the serum levels of IL-6, TNF, and IL-1β compared with each vehicle treated group. 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 PBMCs. Additionally, LMT-28 inhibited the phosphorylation of GP130, STAT3, and ERK induced by Hyper IL-6 in human fibroblast-like synoviocytes(FLS). Collectively, these results suggested that LMT-28 inhibits differentiated/activated-Th17 cells in rheumatoid arthritis by blocking activation of the STAT3 pathway.