辛伐他汀对类风湿关节炎成纤维样滑膜细胞分泌趋化因子的影响及其机制

Inhibitory effect of simvastatin on TNF-α-induced chemokines secretion in rheumatoid arthritis fibroblast like synoviocytes via inhibition of RhoA activation

目的:研究降脂药辛伐他汀(SMV)对类风湿关节炎(RA)成纤维样滑膜细胞(FLS)分泌趋化因子的影响及其机制研究。方法:FLS分离自活动性RA患者滑膜组织;小分子GTP酶RhoA活性检测采用pull-down方法;趋化因子水平采用ELISA检测;细胞活性检测采用MTT法。结果:辛伐他汀(1μmol/L)显著抑制肿瘤坏死因子α(TNF-α)诱导的白细胞介素-8(IL-8)和单核细胞趋化蛋白(MCP-1)分泌,对RhoA活化也有显著的抑制作用;辛伐他汀的上述抑制作用可被甲羟戊酸(MEVA)和焦磷酸香叶基香叶酯(GGPP)逆转。RhoA抑制剂C3转移酶对TNF-α诱导的IL-8、MCP-1等趋化因子分泌亦有显著的抑制作用。结论:辛伐他汀通过调节RhoA活性对TNF-α诱导的趋化因子分泌发挥抑制作用,提示抑制趋化因子分泌可能是辛伐他汀有效治疗RA的机制之一。

AIM：To investigate the effect of simvastatin（SMV） on tumor necrosis factor α（TNF-α）-induced chemokine secretion in rheumatoid arthritis fibroblast-like synoviocytes（RA FLS）.METHODS： RhoA activity was determined by pull-down assay.Chemokine secretion was measured by ELISA.MTT test was used to detect cell viability.RESULTS： Simvastatin attenuated TNF-α-induced interleukin-8（IL-8） and monocyte chemotactic protein-1（MCP-1） secretion as well as RhoA activation in RA FLS.The inhibitory effects of SMV were completely reversed by mevalonate（MEVA） and geranylgeranyl pyrophosphate（GGPP）.Suppression of RhoA activation with a specific inhibitor depressed the secretion of IL-8 and MCP-1 in TNF-α-induced RA FLS.CONCLUSION： Simvastatin inhibits TNF-α-induced secretion of IL-8 and MCP-1 in RA FLS through inhibition of RhoA activation,indicating a novel strategy for anti-inflammatory effects of statins on treatment of RA.