We have explored in vitro and in vivo the immunomodulatory activities of simvastatin, an HMG Co-A reductase (HMGR) inhibitor, in the context of inflammatory arthritis.
Lymphocyte/monocyte populations were purified from peripheral blood (PB) and synovial fluid/tissues (SF/ST) from rheumatoid arthritis (RA) patients or normal controls as appropriate. Fibroblast-like synoviocytes (FLS) were obtained by serial culture from RAST and utilised from passage 3. T cells were mitogen or cytokine (IL-15) activated then fixed in PFA prior to co-culture with macrophages. Collagen-induced arthritis (CIA) developed in male DBA/1 mice on d26 following priming (d0)/ip challenge (d21) with type II collagen in CFA.
In vitro, simvastatin significantly suppressed macrophage TNFα release following cell contact with cytokine or mitogen activated T cells whether derived from normal or RAPB or from RA SF. Constitutive release of IL-6 by RAFLS was dose dependently suppressed by simvastatin (P < 0.05). In vivo, simvastatin administration (up to 40 mg/kg ip, n = 12/group) from d21 reduced plasma cholesterol by 20% and prevented the development of CIA in a dose dependent manner in comparison with injection of drug vehicle alone (P < 0.01). Ex vivo analysis indicated significant suppression of collagen-specific humoral and cellular immune responses. Moreover, administration of simvastatin (40 mg/kg) significantly suppressed established arthritis (n = 20/group) compared with drug vehicle (P < 0.01).
Simvastatin modulated the release of cell-contact induced proinflammatory cytokines in vitro from cells of RAPB and synovial origin. Both developing and importantly, established CIA were significantly suppressed by administration of simvastatin in vivo. These data demonstrate for the first time the anti-inflammatory, therapeutic potential of HMGR inhibitors in inflammatory arthritis.