A novel anti-inflammatory role for simvastatin in inflammatory arthritis.
3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) exert favorable effects on lipoprotein metabolism, but may also possess anti-inflammatory properties. Therefore, we explored the activities of simvastatin, a lipophilic statin, in a Th1-driven model of murine inflammatory arthritis. We report in this study that simvastatin markedly inhibited not only developing but also clinically evident collagen-induced arthritis in doses that were unable to significantly alter cholesterol concentrations in vivo. Ex vivo analysis demonstrated significant suppression of collagen-specific Th1 humoral and cellular immune responses. Moreover, simvastatin reduced anti-CD3/anti-CD28 proliferation and IFN-gamma release from mononuclear cells derived from peripheral blood and synovial fluid. Proinflammatory cytokine production in vitro by T cell contact-activated macrophages was suppressed by simvastatin, suggesting that such observations have direct clinical relevance. These data clearly illustrate the therapeutic potential of statin-sensitive pathways in inflammatory arthritis.
Leung
Bernard P
BP
Department of Immunology, Glasgow Royal Infirmary, University of Glasgow, Glasgow, United Kingdom.
Sattar
Naveed
N
Crilly
Anne
A
Prach
Morag
M
McCarey
David W
DW
Payne
Helen
H
Madhok
Rajan
R
Campbell
Carol
C
Gracie
J Alastair
JA
Liew
Foo Y
FY
McInnes
Iain B
IB
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003094:Collagen / Q000276:immunology; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018106:CD28 Antigens; D017252:CD3 Complex; D018984:Epitopes, T-Lymphocyte; D007106:Immune Sera; D007166:Immunosuppressive Agents; D003094:Collagen; D019821:Simvastatin