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Immunomodulation by statins: mechanisms and potential impact on autoimmune diseases

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Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

Statins are inhibitors of the enzyme 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) and they are the most effective agents for lowering cholesterol in clinical practice for the treatment of cardiovascular diseases. However, it has become clear that statins also have pleiotropic immunomodulatory effects in addition to their lipid-lowering properties. As a result, much attention has been focused on their potential as therapeutic agents for the treatment of inflammatory autoimmune diseases. In this review the effect of statins on the expression and function of a variety of immune-relevant molecules will be discussed alongside the underlying mechanisms that contribute to the immunomodulatory effects of statins.

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Abbreviations

HMG-CoA:

hydroxy-3-methyl-glutaryl coenzyme A

LDL:

low-density lipoprotein

CAD:

coronary artery disease

MHC:

major histocompatibility complex

IL-2:

interleukin 2

ICAM1:

intercellular adhesion molecule 1

TH :

T helper

EAE:

experimental autoimmune encephalomyelitis

SLE:

systemic lupus erythematous

MK:

mevalonate kinase

References

  • Aktas O, Waiczies S, Smorodchenko A et al (2003) Treatment of relapsing paralysis in experimental encephalomyelitis by targeting TH1 cells through atorvastatin. J Exp Med 197: 725–733

    Article  PubMed  CAS  Google Scholar 

  • Ault A (1997) FDA warns of potential protease-inhibitor link to hyperglycaemia. Lancet 349: 1819

    Article  PubMed  CAS  Google Scholar 

  • Azuma RW, Suzuki J, Ogawa M et al (2004) HMG-CoA reductase inhibitor attenuates experimental autoimmune myocarditis through inhibition of T cell activation. Cardiovasc Res 64: 412–420

    Article  PubMed  CAS  Google Scholar 

  • Baetta R, Camera M, Comparato C et al (2002) Fluvastatin reduces tissue factor expression and macrophage accumulation in carotid lesions of cholesterol-fed rabbits in the absence of lipid lowering. Arterioscler Thromb Vasc Biol 22: 692–698

    Article  PubMed  CAS  Google Scholar 

  • Barsante MM, Roffe E, Yokoro CM et al (2005) Anti-inflammatory and analgesic effects of atorvastatin in a rat model of adjuvant-induced arthritis. Eur J Pharmacol 516: 282–289

    Article  PubMed  CAS  Google Scholar 

  • Bolego C, Poli A, Cignarella A et al (2002) Novel statins: pharmacological and clinical results. Cardiovasc Drugs Ther 16: 251–257

    Article  PubMed  CAS  Google Scholar 

  • Clotet B, Negredo E (2003) HIV protease inhibitors and dyslipidemia. AIDS Rev 5: 19–24

    PubMed  Google Scholar 

  • Clotet B, van der Valk M, Negredo E et al (2003) Impact of nevirapine on lipid metabolism. J Acquir Immune Defic Syndr 34(suppl 1): S79–84

    PubMed  CAS  Google Scholar 

  • Corsini A, Bellosta S, Baetta R et al (1999) New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther 84: 413–428

    Article  PubMed  CAS  Google Scholar 

  • Coward WR, Chow SC (2006) Effect of atorvastatin on TH1 and TH2 cytokine secreting cells during T cell activation and differentiation. Atherosclerosis 186: 302–309

    Article  PubMed  CAS  Google Scholar 

  • Coward WR, Marei A, Yang A et al (2006) Statin-induced proinflammatory response in mitogen-activated peripheral blood mononuclear cells through the activation of caspase-1 and IL-18 secretion in monocytes. J Immunol 176: 5284–5292

    PubMed  CAS  Google Scholar 

  • Derk CT, Jimenez SA (2006) Statins and the vasculopathy of systemic sclerosis: potential therapeutic agents?. Autoimmun Rev 5: 25–32

    Article  PubMed  CAS  Google Scholar 

  • Downs JR, Clearfield M, Weis S et al (1998) Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 279: 1615–1622

    Article  PubMed  CAS  Google Scholar 

  • Drenth JP, Cuisset L, Grateau G et al (1999) Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. Nat Genet 22: 178–181

    CAS  Google Scholar 

  • Gegg ME, Harry R, Hankey D et al (2005) Suppression of autoimmune retinal disease by lovastatin does not require TH2 cytokine induction. J Immunol 174: 2327–2335

    PubMed  CAS  Google Scholar 

  • Graham KL, Lee LY, Higgins JP et al (2008) Failure of oral atorvastatin to modulate a murine model of systemic lupus erythematosus. Arthritis Rheum 58: 2098–2104

    Article  PubMed  CAS  Google Scholar 

  • Grakoui A, Bromley SK, Sumen C et al (1999) The immunological synapse: a molecular machine controlling T cell activation. Science 285: 221–227

    Article  PubMed  CAS  Google Scholar 

  • Greenwood J, Steinman L, Zamvil SS (2006) Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol 6: 358–370

    Article  PubMed  CAS  Google Scholar 

  • Greenwood J, Walters CE, Pryce G et al (2003) Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. FASEB J 17: 905–907

    PubMed  CAS  Google Scholar 

  • Grip O, Janciauskiene S, Lindgren S (2000) Pravastatin down–regulates inflammatory mediators in human monocytes in vitro. Eur J Pharmacol 410: 83–92

    Article  PubMed  CAS  Google Scholar 

  • Gurevich VS, Shovman O, Slutzky L et al (2005) Statins and autoimmune diseases. Autoimmun Rev 4: 123–129

    Article  PubMed  CAS  Google Scholar 

  • Hanson J, Bossingham D (1998) Lupus-like syndrome associated with simvastatin. Lancet 352: 1070

    Article  PubMed  CAS  Google Scholar 

  • Hillyard DZ, Jardine AG, McDonald KJ et al (2004) Fluvastatin inhibits raft dependent Fc-gamma receptor signalling in human monocytes. Atherosclerosis 172: 219–228

    Article  PubMed  CAS  Google Scholar 

  • Houten SM, Kuis W, Duran M et al (1999) Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat Genet 22: 175–177

    Article  PubMed  CAS  Google Scholar 

  • Houten SM, Romeijn GJ, Koster J et al (1999) Identification and characterization of three novel missense mutations in mevalonate kinase cDNA causing mevalonic aciduria, a disorder of isoprene biosynthesis. Hum Mol Genet 8: 1523–1528

    Article  PubMed  CAS  Google Scholar 

  • Hsyu PH, Schultz-Smith MD, Lillibridge JH et al (2001) Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin. Antimicrob Agents Chemother 45: 3445–3450

    Article  PubMed  CAS  Google Scholar 

  • Jacobson TA (2004) Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors. Am J Cardiol 94: 1140–1146

    Article  PubMed  CAS  Google Scholar 

  • Jakobisiak M, Golab J (2003) Potential antitumor effects of statins. Int J Oncol 23: 1055–1069

    PubMed  CAS  Google Scholar 

  • Kohno H, Sakai T, Saito S et al (2007) Treatment of experimental autoimmune uveoretinitis with atorvastatin and lovastatin. Exp Eye Res 84: 569–576

    Article  PubMed  CAS  Google Scholar 

  • Kuipers HF, Biesta PJ, Groothuis TA et al (2005) Statins affect cell-surface expression of major histocompatibility complex class II molecules by disrupting cholesterol-containing microdomains. Hum Immunol 66: 653–665

    Article  PubMed  CAS  Google Scholar 

  • Kuipers HF, Rappert AA, Mommaas AM et al (2006) Simvastatin affects cell motility and actin cytoskeleton distribution of microglia. Glia 53: 115–123

    Article  PubMed  Google Scholar 

  • Kwak B, Mulhaupt F, Myit S et al (2000) Statins as a newly recognized type of immunomodulator. Nat Med 6: 1399–1402

    Article  PubMed  CAS  Google Scholar 

  • Kwak B, Mulhaupt F, Veillard N et al (2001) The HMG-CoA reductase inhibitor simvastatin inhibits IFN-gamma induced MHC class II expression in human vascular endothelial cells. Swiss Med Wkly 131: 41–46

    PubMed  CAS  Google Scholar 

  • Lawman S, Mauri C, Jury EC et al (2004) Atorvastatin inhibits autoreactive B cell activation and delays lupus development in New Zealand black/white F1 mice. J Immunol 173: 7641–7646

    PubMed  CAS  Google Scholar 

  • Leung BP, Sattar N, Crilly A et al (2003) A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol 170: 1524–1530

    PubMed  CAS  Google Scholar 

  • Liao JK (2002) Isoprenoids as mediators of the biological effects of statins. J Clin Invest 110: 285–288

    PubMed  CAS  Google Scholar 

  • Liu W, Li WM, Gao C et al (2005) Effects of atorvastatin on the TH1/TH2 polarization of ongoing experimental autoimmune myocarditis in Lewis rats. J Autoimmun 25: 258–263

    Article  PubMed  Google Scholar 

  • Lozanoska-Ochser B, Barone F, Pitzalis C et al (2006) Atorvastatin fails to prevent the development of autoimmune diabetes despite inhibition of pathogenic beta-cell-specific CD8 T-cells. Diabetes 55: 1004–1010

    Article  PubMed  CAS  Google Scholar 

  • Maron DJ, Fazio S, Linton MF (2000) Current perspectives on statins. Circulation 101: 207–213

    PubMed  CAS  Google Scholar 

  • Matsumoto M, Einhaus D, Gold ES et al (2004) Simvastatin augments lipopolysaccharide-induced proinflammatory responses in macrophages by differential regulation of the c-Fos and c-Jun transcription factors. J Immunol 172: 7377–7384

    PubMed  CAS  Google Scholar 

  • McKay A, Leung BP, McInnes IB et al (2004) A novel anti–inflammatory role of simvastatin in a murine model of allergic asthma. J Immunol 172: 2903–2908

    PubMed  CAS  Google Scholar 

  • Mestas J, Hughes CC (2004) Of mice and not men: differences between mouse and human immunology. J Immunol 172: 2731–2738

    PubMed  CAS  Google Scholar 

  • Monick MM, Powers LS, Butler NS et al (2003) Inhibition of Rho family GTPases results in increased TNF-alpha production after lipopolysaccharide exposure. J Immunol 171: 2625–2630

    PubMed  CAS  Google Scholar 

  • Montero MT, Hernandez O, Suarez Y et al (2000) Hydroxymethylglutaryl-coenzyme A reductase inhibition stimulates caspase-1 activity and TH1-cytokine release in peripheral blood mononuclear cells. Atherosclerosis 153: 303–313

    Article  PubMed  CAS  Google Scholar 

  • Moreno PR, Falk E, Palacios IF et al (1994) Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture. Circulation 90: 775–778

    CAS  Google Scholar 

  • Murillas J, Martin T, Ramos A et al (1999) Atorvastatin for protease inhibitor-related hyperlipidaemia. AIDS 13: 1424–1425

    Article  PubMed  CAS  Google Scholar 

  • Murphy KM, Reiner SL (2002) The lineage decisions of helper T cells. Nat Rev Immunol 2: 933–944

    Article  PubMed  CAS  Google Scholar 

  • Neuhaus O, Strasser-Fuchs S, Fazekas F et al (2002) Statins as immunomodulators: comparison with interferon-beta 1-beta in MS. Neurology 59: 990–997

    Article  PubMed  CAS  Google Scholar 

  • Noel B, Panizzon RG (2004) Lupus-like syndrome associated with statin therapy. Dermatology 208: 276–277

    Article  PubMed  Google Scholar 

  • Pahan K, Sheikh FG, Namboodiri AM et al (1997) Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages. J Clin Invest 100: 2671–2679

    Article  PubMed  CAS  Google Scholar 

  • Paintlia AS, Paintlia MK, Singh AK et al (2004) Regulation of gene expression associated with acute experimental autoimmune encephalomyelitis by Lovastatin. J Neurosci Res 77: 63–81

    Article  PubMed  CAS  Google Scholar 

  • Palinski W (2001) New evidence for beneficial effects of statins unrelated to lipid lowering. Arterioscler Thromb Vasc Biol 21: 3–5

    PubMed  CAS  Google Scholar 

  • Palinski W, Tsimikas S (2002) Immunomodulatory effects of statins: mechanisms and potential impact on arteriosclerosis. J Am Soc Nephrol 13: 1673–1681

    Article  PubMed  CAS  Google Scholar 

  • Palmer G, Chobaz V, Talabot-Ayer D et al (2004) Assessment of the efficacy of different statins in murine collagen-induced arthritis. Arthritis Rheum 50: 4051–4059

    Article  PubMed  CAS  Google Scholar 

  • Pfeffer MA, Sacks FM, Moye LA et al (1999) Influence of baseline lipids on effectiveness of pravastatin in the CARE Trial. Cholesterol And Recurrent Events. J Am Coll Cardiol 33: 125–130

    Article  CAS  Google Scholar 

  • Posvar EL, Radulovic LL, Cilla DD Jr et al (1996) Tolerance and pharmacokinetics of single-dose atorvastatin, a potent inhibitor of HMG-CoA reductase, in healthy subjects. J Clin Pharmacol 36: 728–731

    PubMed  CAS  Google Scholar 

  • Reape TJ, Groot PH (1999) Chemokines and atherosclerosis. Atherosclerosis 147: 213–225

    Article  PubMed  CAS  Google Scholar 

  • Robinson DS, O’Garra A (2002) Further checkpoints in TH1 development. Immunity 16: 755–758

    Article  PubMed  CAS  Google Scholar 

  • Rosenson RS, Tangney CC, Casey LC (1999) Inhibition of proinflammatory cytokine production by pravastatin. Lancet 353: 983–984

    Article  PubMed  CAS  Google Scholar 

  • Reith W, Mach B (2001) The bare lymphocyte syndrome and the regulation of MHC expression. Annu Rev Immunol 19: 331–373

    Article  PubMed  CAS  Google Scholar 

  • Rydgren T, Vaarala O, Sandler S (2007) Simvastatin protects against multiple low-dose streptozotocin-induced type 1 diabetes in CD-1 mice and recurrence of disease in nonobese diabetic mice. J Pharmacol Exp Ther 323: 180–185

    Article  PubMed  CAS  Google Scholar 

  • Sacks FM, Pfeffer MA, Moye LA et al (1996) The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 335: 1001–1009

    CAS  Google Scholar 

  • Sadeghi MM, Collinge M, Pardi R et al (2000) Simvastatin modulates cytokine-mediated endothelial cell adhesion molecule induction: involvement of an inhibitory G protein. J Immunol 165: 2712–2718

    PubMed  CAS  Google Scholar 

  • Sattler MB, Diem R, Merkler D et al (2005) Simvastatin treatment does not protect retinal ganglion cells from degeneration in a rat model of autoimmune optic neuritis. Exp Neurol 193: 163–171

    Article  PubMed  Google Scholar 

  • Schonbeck U, Libby P (2004) Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as antiinflammatory agents. Circulation 109: 1118–1126

    Article  Google Scholar 

  • Shepherd J, Cobbe SM, Ford I et al (1995) Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 333: 1301–1307

    CAS  Google Scholar 

  • Shovman O, Levy Y, Gilburd B et al (2002) Antiinflammatory and immunomodulatory properties of statins. Immunol Res 25: 271–285

    Article  PubMed  CAS  Google Scholar 

  • Stanislaus R, Gilg AG, Singh AK et al (2002) Immunomodulation of experimental autoimmune encephalomyelitis in the Lewis rats by Lovastatin. Neurosci Lett 333: 167–170

    Article  PubMed  CAS  Google Scholar 

  • Stanislaus R, Pahan K, Singh AK et al (1999) Amelioration of experimental allergic encephalomyelitis in Lewis rats by lovastatin. Neurosci Lett 269: 71–74

    Article  PubMed  CAS  Google Scholar 

  • Steimle V, Siegrist CA, Mottet A et al (1994) Regulation of MHC class II expression by interferon-gamma mediated by the transactivator gene CIITA. Science 265: 106–109

    Article  PubMed  CAS  Google Scholar 

  • Steinman L, Rosenbaum JT, Sriram S et al (1981) In vivo effects of antibodies to immune response gene products: prevention of experimental allergic encephalitis. Proc Natl Acad Sci USA 78: 7111–7114

    Article  PubMed  CAS  Google Scholar 

  • Sun D, Fernandes G (2003) Lovastatin inhibits bone marrowderived dendritic cell maturation and upregulates proinflammatory cytokine production. Cell Immunol 223: 52–62

    Article  PubMed  CAS  Google Scholar 

  • Takai Y, Sasaki T, Matozaki T (2001) Small GTP-binding proteins. Physiol Rev 81: 153–208

    PubMed  CAS  Google Scholar 

  • Thomas PB, Albini T, Giri RK et al (2005) The effects of atorvastatin in experimental autoimmune uveitis. Br J Ophthalmol 89: 275–279

    Article  PubMed  CAS  Google Scholar 

  • Tobert JA (2003) Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nat Rev Drug Discov 2: 517–526

    Article  PubMed  CAS  Google Scholar 

  • van Der Merwe PA, Davis SJ (2002) Immunology. The immunological synapse – a multitasking system. Science 295: 1479–1480

    Google Scholar 

  • Vladutiu AO, Steinman L (1987) Inhibition of experimental autoimmune thyroiditis in mice by anti-I-A antibodies. Cell Immunol 109: 169–180

    Article  PubMed  CAS  Google Scholar 

  • Vollmer T, Key L, Durkalski V et al (2004) Oral simvastatintreatment in relapsing-remitting multiple sclerosis. Lancet 363: 1607–1608

    Article  PubMed  CAS  Google Scholar 

  • Waldor MK, Sriram S, McDevitt HO et al (1983) In vivo therapy with monoclonal anti-I-A antibody suppresses immune responses to acetylcholine receptor. Proc Natl Acad Sci USA 80: 2713–2717

    Article  PubMed  CAS  Google Scholar 

  • Weitz-Schmidt G, Welzenbach K, Brinkmann V et al (2001) Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 7: 687–692

    Article  PubMed  CAS  Google Scholar 

  • Yilmaz A, Reiss C, Tantawi O et al (2004) HMG-CoA reductase inhibitors suppress maturation of human dendritic cells: new implications for atherosclerosis. Atherosclerosis 172: 85–93

    Article  PubMed  CAS  Google Scholar 

  • Youssef S, Stuve O, Patarroyo JC et al (2002) The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420: 78–84

    Article  PubMed  CAS  Google Scholar 

  • Zhang FL, Casey PJ (1996) Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem 65: 241–269

    Article  PubMed  CAS  Google Scholar 

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  1. School of Science, Monash University Sunway Campus, Jalan Lagoon Selatan, 46150, Bandar Sunway, Selangor Darul Ehsan, Malaysia

    Sek C. Chow (Prof.)

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Chow, S.C. Immunomodulation by statins: mechanisms and potential impact on autoimmune diseases. Arch. Immunol. Ther. Exp. 57, 243–251 (2009). https://doi.org/10.1007/s00005-009-0038-5

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  • DOI: https://doi.org/10.1007/s00005-009-0038-5

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