title: 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.
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.
authors.affiliation: Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Road 2, Guangzhou, Guangdong 510080, People's Republic of China.
authors.forename: Haobo
authors.initials: H
authors.lastname: Lin
authors.forename: Youjun
authors.initials: Y
authors.lastname: Xiao
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Chen
authors.forename: Di
authors.initials: D
authors.lastname: Fu
authors.forename: Yujin
authors.initials: Y
authors.lastname: Ye
authors.forename: Liuqin
authors.initials: L
authors.lastname: Liang
authors.forename: Jinjin
authors.initials: J
authors.lastname: Fan
authors.forename: Xiuyan
authors.initials: X
authors.lastname: Yang
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
authors.forename: Hanshi
authors.initials: H
authors.lastname: Xu
mesh_terms: 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
chemical_list: 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
references.citation: Autoimmunity. 1998;28(4):197-208
references.pmid: 9892501
references.citation: EMBO J. 2000 Jun 1;19(11):2393-8
references.pmid: 10835338
references.citation: Arthritis Rheum. 1995 Dec;38(12):1762-70
references.pmid: 8849348
references.citation: Circulation. 2004 Jun 1;109(21 Suppl 1):II18-26
references.pmid: 15173059
references.citation: J Immunol. 1999 Aug 1;163(3):1577-83
references.pmid: 10415062
references.citation: Arthritis Rheum. 2006 Feb;54(2):579-86
references.pmid: 16447234
references.citation: Arthritis Rheum. 2001 Aug;44(8):1897-907
references.pmid: 11508443
references.citation: Cancer Lett. 2001 Apr 10;165(1):1-10
references.pmid: 11248412
references.citation: Lancet. 2004 Jun 19;363(9426):2015-21
references.pmid: 15207950
references.citation: J Rheumatol. 2005 Nov;32(11):2095-101
references.pmid: 16265685
references.citation: Rheumatology (Oxford). 2007 Jun;46(6):920-6
references.pmid: 17314215
references.citation: J Immunol. 2003 Feb 1;170(3):1524-30
references.pmid: 12538717
references.citation: Genes Dev. 1997 Sep 15;11(18):2295-322
references.pmid: 9308960
references.citation: Kidney Int. 2003 Jan;63(1):12-23
references.pmid: 12472764
references.citation: Lupus. 2003;12(8):607-11
references.pmid: 12945719
references.citation: J Immunol. 2003 Jul 1;171(1):96-105
references.pmid: 12816987
references.citation: Arthritis Rheum. 2004 May;50(5):1457-67
references.pmid: 15146415
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13859-64
references.pmid: 9811891
references.citation: J Immunol. 2004 Jul 1;173(1):507-14
references.pmid: 15210811
references.citation: J Am Soc Nephrol. 2004 Jul;15(7):1711-20
references.pmid: 15213258
references.citation: Arthritis Rheum. 1997 Jan;40(1):5-18
references.pmid: 9008595
references.citation: Cell Signal. 2001 Feb;13(2):85-94
references.pmid: 11257452
references.citation: J Immunol. 2009 Mar 15;182(6):3522-9
references.pmid: 19265130
references.citation: J Immunol. 2003 Jan 1;170(1):19-23
references.pmid: 12496377
references.citation: Arthritis Res Ther. 2005;7(3):R476-84
references.pmid: 15899034
references.citation: Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8301-5
references.pmid: 12048257
references.citation: Arthritis Rheum. 2006 Nov;54(11):3441-51
references.pmid: 17075836
references.citation: Ann Rheum Dis. 2003 Nov;62 Suppl 2:ii86-9
references.pmid: 14532158
references.citation: Cell Immunol. 2005 Feb;233(2):90-6
references.pmid: 15963480
references.citation: Arthritis Rheum. 1988 Mar;31(3):315-24
references.pmid: 3358796
references.citation: Am J Physiol Renal Physiol. 2006 Nov;291(5):F995-1004
references.pmid: 16774905
references.citation: Front Biosci. 2005 Sep 01;10:2478-88
references.pmid: 15970510
references.citation: Cell. 2004 Jan 23;116(2):167-79
references.pmid: 14744429
references.citation: Science. 1995 Apr 14;268(5208):221-5
references.pmid: 7716512
references.citation: Nature. 1990 Feb 1;343(6257):425-30
references.pmid: 1967820
references.citation: Eur J Pharmacol. 2005 Jun 15;516(3):282-9
references.pmid: 15970284
references.citation: Annu Rev Immunol. 2000;18:621-63
references.pmid: 10837071
references.citation: Curr Opin Rheumatol. 2007 May;19(3):289-95
references.pmid: 17414958
references.citation: Inflamm Allergy Drug Targets. 2007 Mar;6(1):3-16
references.pmid: 17352684
references.citation: Genes Dev. 1997 Feb 15;11(4):463-75
references.pmid: 9042860
references.citation: Arterioscler Thromb Vasc Biol. 2005 Jul;25(7):1439-45
references.pmid: 15860745
references.citation: Arthritis Rheum. 2007 Jul;56(7):2192-201
references.pmid: 17599732
references.citation: Nucleic Acids Res. 2001 Feb 15;29(4):E21
references.pmid: 11160941