Rheumatology International

, Volume 31, Issue 11, pp 1451–1458

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

  • Haobo Lin
  • Youjun Xiao
  • Guoqiang Chen
  • Di Fu
  • Yujin Ye
  • Liuqin Liang
  • Jinjin Fan
  • Xiuyan Yang
  • Lin Sun
  • Hanshi Xu
Original Article

DOI: 10.1007/s00296-010-1510-6

Cite this article as:
Lin, H., Xiao, Y., Chen, G. et al. Rheumatol Int (2011) 31: 1451. doi:10.1007/s00296-010-1510-6

Abstract

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.

Keywords

StatinRhoToll-like receptorInflammationRheumatoid arthritis

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Haobo Lin
    • 1
  • Youjun Xiao
    • 1
  • Guoqiang Chen
    • 2
  • Di Fu
    • 1
  • Yujin Ye
    • 1
  • Liuqin Liang
    • 1
  • Jinjin Fan
    • 3
  • Xiuyan Yang
    • 1
  • Lin Sun
    • 4
  • Hanshi Xu
    • 1
  1. 1.Department of Rheumatology, The First Affiliated HospitalSun Yat-sen UniversityGuangzhou, GuangdongPeople’s Republic of China
  2. 2.Department of RheumatologyFushan Hospital of Sun Yat-sen UniversityFushan, GuangdongPeople’s Republic of China
  3. 3.Department of Nephrology, The First Affiliated HospitalSun Yat-sen UniversityGuangzhou, GuangdongPeople’s Republic of China
  4. 4.Department of Pathology, School of MedicineNorthwestern UniversityChicagoUSA