Rebamipide prevents peripheral arthritis and intestinal inflammation by reciprocally regulating Th17/Treg cell imbalance in mice with curdlan-induced spondyloarthritis.

Hong-Ki Min,Seung Hoon Lee,Mi-La Cho,Jennifer Lee,Eun-Kyung Kim,Seon-Yeong Lee,Jae-Kyung Kim,Sung-Hwan Park,Seung-Ki Kwok

doi:10.1186/s12967-016-0942-5

Hong-Ki Min, Seung Hoon Lee + Show 7 more

Open Access

https://doi.org/10.1186/s12967-016-0942-5

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Abstract

BackgroundSpondyloarthritis (SpA) usually manifests as arthritis of the axial and peripheral joints but can also result in extra-articular manifestations such as inflammatory bowel disease. Proinflammatory cytokine interleukin-17 (IL-17) plays a crucial role in the pathogenesis of SpA. Rebamipide inhibits signal transducer and activator of transcription 3 that controls IL-17 production and Th17 cell differentiation. This study examined the effect of rebamipide on SpA development.MethodsSKG ZAP-70W163C mice were immunized with curdlan to induce SpA features. The mice were then intraperitoneally injected with rebamipide or vehicle 3 times a week for 14 weeks and their clinical scores were evaluated. Histological scores of the paw and spine and the length of the gut were measured at sacrifice. Immunohistochemical staining of IL-17 and tumor necrosis factor-α (TNF-α) was performed using tissue samples isolated from the axial joints, peripheral joints, and gut. Spleen tissue samples were isolated from both rebamipide- or vehicle-treated mice with SpA at 14 weeks after curdlan injection to determine the effect of rebamipide on Th17 and regulatory T (Treg) cell differentiation.ResultsRebamipide decreased the clinical and histological scores of the peripheral joints. The total length of the gut was preserved in rebamipide-treated mice. IL-17 and TNF-α expression in the spine, peripheral joints, and gut was lower in rebamipide-treated mice than in control mice. Th17 cell differentiation was suppressed whereas Treg cell differentiation was upregulated in the spleen of rebamipide-treated mice.ConclusionRebamipide exerted beneficial effects in mice with SpA by preventing peripheral arthritis and intestinal inflammation and by regulating Th17/Treg cell imbalance, suggesting that it can be used as a potential therapeutic agent for treating arthritis to SpA patients.

Highlights

Spondyloarthritis (SpA) usually manifests as arthritis of the axial and peripheral joints but can result in extra-articular manifestations such as inflammatory bowel disease
SpA can be classified into ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, arthritis associated with inflammatory bowel disease, and undifferentiated SpA based on its clinical manifestations [1]
Rebamipide prevents peripheral arthritis in mice with SpA We investigated whether rebamipide prevented peripheral arthritis in the mouse model of SpA

Summary

Introduction

Spondyloarthritis (SpA) usually manifests as arthritis of the axial and peripheral joints but can result in extra-articular manifestations such as inflammatory bowel disease. Proinflammatory cytokine interleukin-17 (IL-17) plays a crucial role in the pathogenesis of SpA. This study examined the effect of rebamipide on SpA development. The mice were intra‐ peritoneally injected with rebamipide or vehicle 3 times a week for 14 weeks and their clinical scores were evaluated. Spleen tissue samples were isolated from both rebamipide- or vehicle-treated mice with SpA at 14 weeks after curdlan injection to determine the effect of rebamipide on Th17 and regulatory T (Treg) cell differentiation. Spondyloarthritis (SpA) is a chronic immune-mediated inflammatory arthritis that usually accompanies sacroiliitis and spondylodiscitis. Recent studies have shown that interleukin-23 (IL-23) and IL-17 play a crucial role in the pathogenesis of SpA [2, 3]. Recent clinical trials on the treatment of AS and PsA with anti-IL-17 monoclonal antibodies (Abs) have provided promising results [9, 10]

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