A Novel Anti-Inflammatory Role for Simvastatin in Inflammatory Arthritis

Abstract

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-γ 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.

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

“…In one study, simvastatin proved effective in ameliorating CIA, an animal model of RA (138). This study had a prophylactic and a therapeutic arm (statin treatment before and after induction of disease).…”

Atorvastatin does not decrease or delay diabetes onset in two different mouse models of type 1 diabetes

“…These properties have recently been studied in two different murine models of autoimmunity: one of experimental autoimmune encephalomyelitis [3] and one of collagen-induced arthritis [4]. Atorvastatin and simvastatin significantly suppressed autoimmunity in these respective animal models by inhibiting pathological pro-inflammatory responses.…”

“…Atorvastatin and simvastatin significantly suppressed autoimmunity in these respective animal models by inhibiting pathological pro-inflammatory responses. In both cases, evidence was found of a shift from a T helper type 1 (Th1) to a Th2 cell response [3,4]. There is also evidence that atorvastatin can mediate a modest, but clinically apparent, anti-inflammatory effect in patients with rheumatoid arthritis [5].…”

“…Some authors argue that achievement of pleiotropic effects in mice may require a dose of up to 40 mg·kg −1 ·day −1 [4]. These doses are much higher than those used in man, but could be necessary in murine studies as a result of the rapid upregulation of HMG-CoA reductase in response to the treatment [4].…”

“…Some authors argue that achievement of pleiotropic effects in mice may require a dose of up to 40 mg·kg −1 ·day −1 [4]. These doses are much higher than those used in man, but could be necessary in murine studies as a result of the rapid upregulation of HMG-CoA reductase in response to the treatment [4]. However, it has been reported that the minimum dose required to induce an immunomodulatory effect in murine experimental autoimmune encephalomyelitis is 0.1 mg/kg, which is clearly below the dose administered in our mice [3].…”