Statins as novel immunomodulators: From cell to potential clinical benefit

Summary

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 cyto-kine interferon gamma (IFN-γ). Recently, it has been demonstrated that statins repress the induction of MHC-II by IFN-γ 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.

This publication was partially financed by Serono Foundation for the Advancement of Medical Science.

Part of this paper was originally presented at the 2^nd International Workshop on New Therapeutic Targets in Vascular Biology from February 6-9, 2003 in Geneva, Switzerland.

Keywords

Atherosclerosis - cytokines - immunity (auto-) - inflammatory mediators - lipid mediators

• References

• 1 Lopez AD, Murray CC. The global burden of disease, 1990-2020. Nat Med 1998; 4: 1241-3.
• 2 Libby P. Inflammation in atherosclerosis. Nature 2002; 420: 868-74.
• 3 Glass CK, Witztum JL. Atherosclerosis: the road ahead. Cell 2001; 104: 503-16.
• 4 Lusis AJ. Atherosclerosis. Nature 2000; 407: 233-41.
• 5 Libby P. Changing concepts of atherogenesis. J Intern Med 2000; 247: 349-58.
• 6 Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation 2000; 101: 207-13.
• 7 Plana JC, Jones PH. The use of statins in acute coronary syndromes: the mechanisms behind the outcomes. Curr Atheroscler Rep 2001; 3: 355-64.
• 8 Gotto Jr AM. Statin therapy: where are we? Where do we go next?. Am J Cardiol 2001; 87: 13B-18B.
• 9 Gotto Jr. AM, Grundy SM. Lowering LDL cholesterol: questions from recent meta-analyses and subset analyses of clinical trial. Data Issues from the Interdisciplinary Council on Reducing the Risk for Coronary Heart Disease, ninth Council meeting. Circulation 1999; 99: E1-7.
• 10 Corsini A. et al. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther 1999; 84: 413-28.
• 11 Bellosta S, Ferri N, Bernini F. et al. Non-lipid-related effects of statins. Ann Med 2000; 32: 164-76.
• 12 Farmer JA. Pleiotropic effects of statins. Curr Atheroscler Rep 2000; 2: 208-17.
• 13 Kwak BR, Mach F. Statins inhibit leukocyte recruitment: new evidence for their anti-inflammatory properties. Arterioscler Thromb Vasc Biol 2001; 21: 1256-8.
• 14 Gotto Jr, AM Jr., Farmer JA. Pleiotropic effects of statins: do they matter?. Curr Opin Lipidol 2001; 12: 391-4.
• 15 Casey PJ. Protein lipidation in cell signaling. Science 1995; 268: 221-5.
• 16 Maltese WA, Sheridan KM, Repko EM. et al. Post-translational modification of low molecular mass GTP-binding proteins by isoprenoid. J Biol Chem 1990; 265: 2148-55.
• 17 Veillard NR, Mach F. Statin: the new aspirin ?. Cell Mol Life Sci 2002; 59: 1771-86.
• 18 Kobashigawa JA. et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995; 333: 621-7.
• 19 Wenke K. et al. Simvastatin reduces graft vessel disease and mortality after heart transplantation: a four-year randomized trial. Circulation 1997; 96: 1398-1402.
• 20 Steimle V, Otten LA, Zufferey M. et al. Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). Cell 1993; 75: 135-46.
• 21 Steimle V, Siegrist CA, Mottet A. et al. Regulation of MHC class II expression by interferon-gamma mediated by the transactivator gene CIITA. Science 1994; 265: 106-9.
• 22 Muhlethaler-Mottet A, Otten LA, Steimle V. et al. Expression of MHC class II molecules in different cellular and functional compartments is controlled by differential usage of multiple promoters of the transactivator CIITA. EMBO J 1997; 16: 2851-60.
• 23 Kwak B, Mulhaupt F, Myit S. et al. Statins as a newly recognized type of immunomodula-tor. Nat Med 2000; 6: 1399-402.
• 24 Kwak B, Mulhaupt F, Veillard N. et al. The HMG-CoA reductase inhibitor simvastatin inhibits IFN-gamma induced MHC class II expression in human vascular endothelial cells. Swiss Med Wkly 2001; 131: 41-6.
• 25 Palinski W.. Immunomodulation: A new role for statins ? Nat Med 200. 6: 1311-12.
• 26 Sadeghi MM, Tiglio A, Sadigh K. et al. Inhibition of interferon-gamma-mediated of microvascular endothelial cell major histo-compatibility complex class II gene activation by HMG-CoA reductase inhibitors. Transplantation 2001; 71: 1262-8.
• 27 Youssef S, Stüve O, Patarroyo JC. et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 2002; 420: 78-84.
• 28 Leung BP, Satta N, Crilly A. et al. A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol 2003; 170: 1524-30.
• 29 Mulhaupt F, Kwak B, Veillard N. et al. Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in atheroma-associated cells. Possible implications for atherogenesis and transplantation. Circulation 2001; 104 II 212
• 30 Wagner AH, Gebauer M, Güldenzoph B. et al. 3-hydroxy-3-methylglutaryl coenzyme A reductase-independent inhibition of CD40 expression by atorvastatin in human endothelial cells. Arterioscler Thromb Vasc Biol 2002; 22: 1784-9.
• 31 Schönbeck U, Gerdes N, Varo N. et al. Oxidized low-density lipoprotein augments and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors limit CD40 and CD40L expression in human vascular cells. Circulation 2002; 106: 2888-93.
• 32 Leung BP, Satta N, Crilly A. et al. A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol 2003; 170: 1524-30.