The protective effects of NE 52‐QQ57 against interleukin‐33‐induced inflammatory response in activated synovial mast cells

Abstract Cytokines‐mediated immunity is essential for the pathological development of rheumatoid arthritis (RA). Inhibition of signaling has suggested a potential remedial approach to RA. G protein‐coupled receptor 4 (GPR4) has been proven to possess a broad range of physiological functions, but its function in synovial mast cells and RA is less reported. In this study, the protective effects of NE 52‐QQ57, a GPR4 antagonist, against interleukin (IL)‐33‐challenged inflammatory response in activated synovial mast cells were investigated. We report that IL‐33 amplified GPR4 expression in HMC‐1 mast cells. The GPR4 antagonist NE 52‐QQ57 alleviated IL‐33‐caused secretions of IL‐17, interferon‐γ, and tumor necrosis factor‐α in HMC‐1 mast cells. Furthermore, we note that NE 52‐QQ57 reduced IL‐33‐induced expressions of matrix metalloproteinase‐2 (MMP‐2) and MMP‐9. Also, NE 52‐QQ57 inhibited cyclooxygenase 2 and prostaglandin E2 expression in IL‐33‐challenged cells. Also, NE 52‐QQ57 ameliorated IL‐33‐induced oxidative stress by reducing mitochondrial reactive oxygen species and 4‐hydroxynonenal. Mechanistically, NE 52‐QQ57 mitigated IL‐33‐induced activation of the p38/nuclear factor‐κB signaling pathway. We conclude that targeting GPR4 might be a promising strategy for RA treatment.