Statin therapy and autoimmune disease: from protein prenylation to immunomodulation

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Abstract
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, reduce the conversion of HMG-CoA to L-mevalonate and therefore the downstream biosynthesis of cholesterol. There is increasing awareness that many of the beneficial effects of statins are mediated not through the depletion of cholesterol but through modulation of the immune system. A key cholesterol-independent effect of statins is the inhibition the biosynthesis of isoprenoids that are essential for the post-translational modification and function of various important signalling proteins, including those of the small GTPase family. Many of these prenylated proteins are involved in orchestrating immune responses. Statins attenuate antigen presentation to CD4+ T cells by inhibiting interferon-γ-induced MHC class II and co-stimulatory molecule expression and by interfering with antigen uptake and processing. T-cell proliferation is also impaired by statin-mediated inhibition of cytoskeletal remodelling. By altering transcriptional control of T-cell differentiation statins induce a bias towards T helper 2 (TH2)-cell differentiation and away from TH1-cell differentiation. Leukocyte trafficking is impaired as statins alter the expression of cell-adhesion molecules, chemokines, chemokine receptors and matrix metalloproteinases and inhibit adhesion-molecule signalling required for transvascular migration. Through their effect on cytoskeletal reorganization, statins also reduce leukocyte motility. In most cases, the treatment of animal models of autoimmune disease with statins elicits an improvement in clinical outcome that can be attributed to the effects highlighted above. In the few preliminary clinical trials reported so far, there is an indication that statins confer some clinical benefit. Despite several concerns, the high degree of patient tolerance and their simplicity of delivery make statins an attractive addition to currently available strategies for treating autoimmune disease.