Statins as novel immunomodulators: from cell to potential clinical benefit

In the last decades, substantial progress has been made in understanding the relationship between lipid disorders and prevention of cardiac ischemic disease. Statins competitively inhibit 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme crucial to cholesterol biosynthesis. Statins have long been thought to exert their benefits by reducing cholesterol synthesis, but the fact that mevalonate is the precursor of isoprenoids that regulate diverse cellular functions has led investigators to examine pleiotropic effects for these agents. Statins have never been shown to be involved in the immune response, although two clinical trials have suggested that in heart transplant patients, statin therapy has beneficial effects on the incidence of cardiac rejection, coronary vasculopathy, and survival. Major Histocompatibility Complex class II (MHC-II) molecules, which affect the immune response and organ rejection after transplantation, may be induced by the pro-inflammatory cytokine interferon gamma (IFN-gamma). Recently, it has been demonstrated that statins repress the induction of MHC-II by IFN-gamma in vitro, and thus may suggest a potential role for statins as immunosuppressive agents in vivo. Indeed, two recent in vivo studies performed on different animal models provide further evidence that statin-treatment positively influence immunological disorders.