A directly GP130‐targeting small molecule ameliorates collagen‐induced arthritis (CIA) by inhibiting IL‐6/GP130 signalling and Th17 differentiation

Abstract

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.

CD3+CD4+gp130+ T Cells Are Associated With Worse Disease Activity in Systemic Lupus Erythematosus Patients

“…Another small molecule inhibitor LMT-28 (a derivative of oxazolidinone) was recently demonstrated to suppress IL-6 signaling by directly binding gp130, resulting in alleviation of inflammatory diseases such as RA and inflammatory bowel disease (69). LMT-28 could also suppress the differentiation of pro-inflammatory Th17 cells in human PBMCs by blocking gp130 and its subsequent STAT3 signaling cascade, and it was proposed as a gp130-specific inhibitor for treatment of RA (70). The availability of gp130-specific inhibitors represents promising avenues for future investigations to therapeutically target gp130 in SLE patients.…”

Two Main Cellular Components in Rheumatoid Arthritis: Communication Between T Cells and Fibroblast-Like Synoviocytes in the Joint Synovium

“…Single-use or combination treatment with LMT-28 (a derivative of oxazolidinone) and metformin significantly ameliorates arthritic signs in rats with CIA by suppressing Th17 differentiation and IL-6 signaling in FLS (66,67). A combination of LMT-28 and tetrahydropapaverine (THP, benzylisoquinoline alkaloid) could attenuate RA through the suppression of Th17 differentiation in T cells and proinflammatory cytokine-induced inflammation in FLS (68).…”

A GP130-Targeting Small Molecule, LMT-28, Reduces LPS-Induced Bone Resorption around Implants in Diabetic Models by Inhibiting IL-6/GP130/JAK2/STAT3 Signaling

“…According to previous studies, LMT-28, a derivative of oxazolidinone, has been shown to significantly inhibit IL-6 activity through direct binding to GP130 and is nontoxic with oral availability [11]. LMT-28 alleviated collageninduced arthritis and ameliorated the progression of pancreatitis in a mice model, and these two inflammatory diseases are related to an increase in IL-6 level [12]. This suggests that LMT-28 can be used to treat bone resorption in periimplantitis, which is also a type of inflammation with increased IL-6 level.…”

“…To evaluate the effects of LMT-28 on bone resorption in peri-implantitis, an appropriate animal model is needed that can simulate human diseases, diabetes mellitus, dentition defects, and peri-implantitis. In this study, we chose Sprague-Dawley (SD) rats, which are an ideal model for implant placement and induction of peri-implantitis [12][13][14]. Because osteoblasts express a large amount of IL-6 and RANKL in LPS-induced bone resorption, we chose osteoblasts as the cells to study in vitro [15].…”