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-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.The 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)3 reductase inhibitors (statins) have been unequivocally shown to reduce cardiovascular morbidity and mortality (1, 2). Although such clinical benefits are mediated in part through lipid modulation, recent studies demonstrate broader properties for statins, particularly in modifying inflammatory pathways ongoing within the atherosclerotic lesion (3). The molecular mechanisms subserving such immunomodulatory activities remain unclear. HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonic acid (MVA) during cholesterol synthesis. Downstream metabolites, including geranylgeranyl pyrophosphate and farnesyl pyrophosphate regulate prenylation within several critical signaling pathways (4). Statins inhibit IFN-γ-inducible macrophage MHC class II expression via class II transactivator suppression (5) and activate peroxisome proliferator-activated receptor-α via inhibition of Rho-dependent pathways (6). Moreover, some statins (e.g., lovastatin, simvastatin) may modulate T cell costimulation through direct effects on LFA-1/ICAM-1 interactions, dependent upon recognition of a novel statin binding site on β2integrins (7). These properties indicate that statins might modulate functional maturation of T lymphocytes.Following Ag exposure, T lymphocytes mature to different functional phenotypes distinguished on the pattern of cytokine production. Th1 responses, characterized by IFN-γ release, are critical to the development and course of several important autoimmune diseases, including rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease (8), and have a postulated role in vascular wall inflammation (9, 10). However, definitive proof that statins can modify Th1/Th2 responses with immunopathologic consequence in vivo has until now been lacking.We have used inflammatory arthritis as a model in which to test the above hypothesis. Elevated levels of proinflammatory cytokine production characterize RA synovial inflammation (11). Moreover, successful therapeutic targeting of cytokines in RA, particularly TNF-α, has demonstrated their critical pathogenetic importance. Th1 responses predominate within RA synovial T cell subsets and contribute significantly to dysregulated cytokine production (12, 13, 14). Synovial Th1 cells may drive macrophage cytokine release through secretion of IFN-γ or IL-17 (15), or may act through direct cognate cell-cell membrane interactions, involving several ligand pairs including LFA-1/ICAM-1 (16, 17). In this study, we document for the first time a novel anti-arthritic effect of statins. We show that simvastatin can effectively suppress murine collagen-induced arthritis (CIA), either prophylactically, or if administered after clinically evident onset of disease, via specific suppression of the pathologic Th1 and proinflammatory responses. The clinical relevance of these observations is illustrated by parallel studies in RA-derived human cells in which simvastatin suppressed cytokine release by PBMCs and by macrophages following cell contact-dependent interaction with activated T lymphocytes.