HMG-CoA reductase inhibitor simvastatin suppresses Toll-like receptor 2 ligand-induced activation of nuclear factor kappa B by preventing RhoA activation in monocytes from rheumatoid arthritis patients

作者：Lin, Haobo; Xiao, Youjun; Chen, Guoqiang; Fu, Di; Ye, Yujin; Liang, Liuqin; Fan, Jinjin; Yang, Xiuyan; Sun, Lin; Xu, Hanshi^*

来源：Rheumatology International, 2011, 31(11): 1451-1458.

DOI：10.1007/s00296-010-1510-6

• Statin
• Rho
• Toll-like receptor
• Inflammation
• Rheumatoid arthritis

To investigate whether anti-inflammatory effects of HMG-CoA reductase inhibitor simvastatin (SMV) in rheumatoid arthritis (RA) is mediated by Toll-like receptor-2 (TLR-2) signal via inhibiting activation of RhoA, a small Rho GTPase that plays an important role in inflammatory responses. Peripheral blood monocytes from active RA patients were treated with Staphylococcus aureus peptidoglycan (PG), a ligand of TLR-2, in the presence or absence of SMV. RhoA activity was assessed by a pull-down assay. DNA-binding activity was measured by a sensitive multi-well colorimetric assay. Cytokine secretion was measured by ELISA. PG stimulation increased the level of active GTP-bound RhoA compared with unstimulated monocytes, and the effect of PG on RhoA activity was suppressed with anti-TLR-2 monoclonal antibody. RhoA inhibition either with a specific inhibitor or by siRNA transfection inhibited activation of NF-kappa B and secretion of TNF alpha and IL-1 beta in PG-induced RA monocytes. SMV mitigated PG-induced increase in RhoA activity and NF-kappa B activation as well as secretion of TNF alpha and IL-1 beta. The inhibitory effects of SMV were completely reversed by mevalonate and geranylgeranyl pyrophosphate. Our results indicate the modulation of RhoA on TLR-2-mediated inflammatory signaling in RA and provide a novel evidence for anti-inflammatory effects of statins through influencing TLR-2 signaling via RhoA in RA.

• 出版日期2011-11
• 单位西北大学; 中山大学