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.
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-κB and secretion of TNFα and IL-1β in PG-induced RA monocytes. SMV mitigated PG-induced increase in RhoA activity and NF-κB activation as well as secretion of TNFα and IL-1β. 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.
Lin
Haobo
H
Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Road 2, Guangzhou, Guangdong 510080, People's Republic of China.
Xiao
Youjun
Y
Chen
Guoqiang
G
Fu
Di
D
Ye
Yujin
Y
Liang
Liuqin
L
Fan
Jinjin
J
Yang
Xiuyan
X
Sun
Lin
L
Xu
Hanshi
H
D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D010457:Peptidoglycan / Q000378:metabolism / Q000494:pharmacology; D011241:Prednisone / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000235:genetics; D019821:Simvastatin / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D014162:Transfection; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018501:Antirheumatic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D010457:Peptidoglycan; D034741:RNA, Small Interfering; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D019821:Simvastatin; D020742:rhoA GTP-Binding Protein; D011241:Prednisone
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