Lee Jung-Eun, Im Dong-Soon
Department of Biomedical & Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02446, Republic of Korea.
Department of Biomedical & Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02446, Republic of Korea; Department of Fundamental Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02446, Republic of Korea.
Int Immunopharmacol. 2025 May 16;155:114660. doi: 10.1016/j.intimp.2025.114660. Epub 2025 Apr 13.
Lower levels of oleoylethanolamide (OEA) have been observed in the synovial fluids of patients with rheumatoid arthritis and osteoarthritis compared to healthy controls. OEA is known as an anti-inflammatory lipid and acts as an endogenous ligand for GPR119. This study investigated the functional roles of GPR119 using a murine collagen-induced arthritis (CIA) model. The effects of OEA and AR231453, a selective synthetic GPR119 agonist, were tested on the CIA model in Gpr119 wild-type (WT) and deficient DBA-1 J mice. In the CIA model, administration of OEA or AR231453 reduced arthritis scores, foot thickness, loss of proteoglycan, and bone erosion in Gpr119 WT mice, but not in Gpr119-deficient mice. Treatment with OEA or AR231453 significantly suppressed the CIA-induced increase in pro-inflammatory cytokine expression in the feet and IgG levels in the serum, and rebalanced Th1/Th17 and Treg cells in the spleens of Gpr119 WT mice, but not in Gpr119-deficient mice. Additionally, OEA and AR231453 suppressed mRNA expression levels of inflammatory cytokines in human SW982 synovial cells. Both compounds also suppressed Th1/17 cell differentiation and enhanced Treg differentiation in splenocytes from Gpr119 WT mice, but not in Gpr119 knockout mice. These findings suggest that GPR119 activation may serve as a therapeutic strategy for rheumatoid arthritis by regulating Th1/Th17/Treg cell differentiation and rebalancing Th1/Th17 and Treg cells.
与健康对照组相比，类风湿性关节炎和骨关节炎患者滑液中的油酰乙醇胺（OEA）水平较低。OEA是一种抗炎脂质，作为GPR119的内源性配体发挥作用。本研究使用小鼠胶原诱导性关节炎（CIA）模型研究了GPR119的功能作用。在Gpr119野生型（WT）和缺陷型DBA-1 J小鼠的CIA模型中测试了OEA和选择性合成GPR119激动剂AR231453的作用。在CIA模型中，给予OEA或AR231453可降低Gpr119 WT小鼠的关节炎评分、足厚度、蛋白聚糖损失和骨侵蚀，但对Gpr119缺陷型小鼠无效。用OEA或AR231453治疗可显著抑制CIA诱导的足部促炎细胞因子表达增加和血清IgG水平，并使Gpr119 WT小鼠脾脏中的Th1/Th17和Treg细胞重新平衡，但对Gpr119缺陷型小鼠无效。此外，OEA和AR231453抑制了人SW982滑膜细胞中炎性细胞因子的mRNA表达水平。这两种化合物还抑制了Gpr119 WT小鼠脾细胞中Th1/17细胞分化并增强了Treg分化，但对Gpr119基因敲除小鼠无效。这些发现表明，激活GPR119可能通过调节Th1/Th17/Treg细胞分化和重新平衡Th1/Th17和Treg细胞，作为类风湿性关节炎的一种治疗策略。
