Immunomodulatory effects of HMG-CoA reductase inhibitors

Hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are competitive inhibitors of the rate-limiting enzyme in cholesterol synthesis. Several clinical trials have shown a marked reduc- tion in cholesterol levels associated with decreased cardiovascular mortality in patients treated with statins. However, more recent observations have suggested that the clinical benefits of statins may be, at least in part, independent of the effect of statins on cholesterol synthesis. These so-called pleiotropic or cholesterol-independent effects of statins could be the result of reduction in the formation of intermediaries in the mevalonate pathway as statins, by inhibiting L-mevalonic acid synthesis, also prevent the production of isoprenoids in the cholesterol biosynthetic pathway. Isoprenoids serve as important lipid attachments for the posttranslational modification of a variety of proteins such as small GTP-binding proteins of the Ras superfamily implicated in intracellular signaling. The list of different pleitropic effects of statins is still growing and includes, among others, direct effects of statins on modulating endothelial function, decreasing oxidative stress and, more recently, anti-inflammatory and immunomodulatory actions of statins. For instance, statins decrease T cell activation, the recruitment of inflammatory cells into atherosclerotic lesions, and inhibit IFN-γ expression of MHC II on antigen-presenting cells. This review article summarizes the anti-inflammatory and immunomodulatory effects of statins and thus provides a new rationale to use statins as a new class of immunosuppressive agents.