Przemysław J. Kotyla


3­‍‑Hydroxy‑3­‍‑Methyl­‍‑Glutharyl­‍‑Coenzyme A reductase inhibitors, known as statins, form a group of chemical compounds that are characterized by the ability to inhibit cholesterol synthesis. Statins have proved their efficacy as potent drugs in the primary and secondary prevention of cardiovascular events. It has also been shown that the therapeutic effects of statins go beyond reduction of cholesterol level. These properties, which are separate from the influence on cholesterol synthesis, are sometimes called the pleiotropic effect. This effect comprises immunomodulation, an anti­‍‑inflammatory effect, and endothelial function recovery.


statins; immunomodulatory activity; pleiotropic effect

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Goldstein J.L., Brown M.S.: Regulation of the mevalonate pathway. Nature. 1990, 343 (6257), 425–430.

Downs J.R., Clearfield M., Tyroler H.A., Whitney E.J., Kruyer W., Langendorfer A. et al.: Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS): additional perspectives on tolerability of long‑term treatment with lovastatin. Am J Cardiol. 2001, 87 (9), 1074–1079.

Tsiara S., Elisaf M., Mikhailidis D.P.: Early vascular benefits of statin therapy. Curr Med Res Opin. 2003, 19 (6), 540–556.

Watts G.F., Burke V.: Lipid‑lowering trials in the primary and secondary prevention of coronary heart disease: new evidence, implications and outstanding issues. Curr Opin Lipidol. 1996, 7 (6), 341–355.

Superko H.R., Krauss R.M.: Coronary artery disease regression. Convincing evidence for the benefit of aggressive lipoprotein management. Circulation. 1994, 90 (2), 1056–1069.

Takemoto M., Liao J.K.: Pleiotropic effects of 3‑hydroxy‑3‑methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol. 2001, 21 (11), 1712–1719.

Buhaescu I., Izzedine H.: Mevalonate pathway: a review of clinical and therapeutical implications. Clin Biochem. 2007, 40 (9–10), 575–584.

Takai Y., Sasaki T., Matozaki T.: Small GTP‑binding proteins. Physiol Rev. 2001, 81 (1), 153–208.

Corsini A., Mazzotti M., Raiteri M., Soma M.R., Gabbiani G., Fumagalli R. et al.: Relationship between mevalonate pathway and arterial myocyte proliferation: in vitro studies with inhibitors of HMG‑CoA reductase. Atherosclerosis. 1993, 101 (1), 117–125.

Negre‑Aminou P., van E.M., van Leeuwen R.E., Collard J.G., Cohen L.H.: Differential effect of simvastatin on various signal transduction intermediates in cultured human smooth muscle cells. Biochem Pharmacol. 2001, 61 (8), 991–998.

Griendling K.K., Minieri C.A., Ollerenshaw J.D., Alexander R.W.: Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994, 74 (6), 1141–1148.

Chapel H., Haeney M., Siraj M., Snowden N.: Immunologia kliniczna. Wyd. Czelej, Lublin 2011.

Goldman F., Hohl R.J., Crabtree J., Lewis‑Tibesar K., Koretzky G.: Lovastatin inhibits T‑cell antigen receptor signaling independent of its effects on ras. Blood. 1996, 88 (12), 4611–4619.

Grip O., Janciauskiene S., Lindgren S.: Pravastatin down‑regulates inflammatory mediators in human monocytes in vitro. Eur J Pharmacol. 2000, 410 (1), 83–92.

Rosenson R.S., Tangney C.C., Casey L.C.: Inhibition of proinflammatory cytokine production by pravastatin. Lancet. 1999, 353 (9157), 983–984.

Dunn S.E., Youssef S., Goldstein M.J., Prod’homme T., Weber M.S., Zamvil S.S. et al.: Isoprenoids determine Th1/Th2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin. J Exp Med. 2006, 203 (2), 401–412.

Youssef S., Stuve O., Patarroyo J.C., Ruiz P.J., Radosevich J.L., Hur E.M. et al.: The HMG‑CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature. 2002, 420 (6911), 78–84.

Murphy K.M., Reiner S.L.: The lineage decisions of helper T cells. Nat Rev Immunol. 2002, 2 (12), 933–944.

Robinson D.S., O’Garra A.: Further checkpoints in Th1 development. Immunity. 2002, 16 (6), 755–758.

Leung B.P., Sattar N., Crilly A., Prach M., McCarey D.W., Payne H. et al.: A novel anti‑inflammatory role for simvastatin in inflammatory arthritis. J Immunol. 2003, 170 (3), 1524–1530.

Chow S.C.: Immunomodulation by statins: mechanisms and potential impact on autoimmune diseases. Arch Immunol Ther Exp (Warsz). 2009, 57 (4), 243–251.

Lawman S., Mauri C., Jury E.C., Cook H.T., Ehrenstein M.R.: Atorvastatin inhibits autoreactive B cell activation and delays lupus development in New Zealand black/white F1 mice. J Immunol. 2004, 173 (12), 7641–7646.

Gahmberg C.G., Tolvanen M., Kotovuori P.: Leukocyte adhesion – structure and function of human leukocyte beta2‑integrins and their cellular ligands. Eur J Biochem. 1997, 245 (2), 215–232.

Yusuf‑Makagiansar H., Anderson M.E., Yakovleva T.V., Murray J.S., Siahaan T.J.: Inhibition of LFA‑1/ICAM‑1 and VLA‑4/VCAM‑1 as a therapeutic approach to inflammation and autoimmune diseases. Med Res Rev. 2002, 22 (2), 146–167.

Nishibori M., Takahashi H.K., Mori S.: The regulation of ICAM‑1 and LFA‑1 interaction by autacoids and statins: a novel strategy for controlling inflammation and immune responses. J Pharmacol Sci. 2003, 92 (1), 7–12.

Zimmerman T., Blanco F.J.: Inhibitors targeting the LFA‑1/ICAM‑1 cell‑adhesion interaction: design and mechanism of action. Curr Pharm Des. 2008, 14 (22), 2128–2139.

Prasad R., Giri S., Nath N., Singh I., Singh A.K.: Inhibition of phosphoinositide 3 kinase‑Akt (protein kinase B)‑nuclear factor‑kappa B pathway by lovastatin limits endothelial‑monocyte cell interaction. J Neurochem. 2005, 94 (1), 204–214.

Thewissen M., Somers V., Hellings N., Fraussen J., Damoiseaux J., Stinissen P.: CD4+CD28null T cells in autoimmune disease: pathogenic features and decreased susceptibility to immunoregulation. J Immunol. 2007, 179 (10), 6514–6523.

Fasth A.E., Snir O., Johansson A.A., Nordmark B., Rahbar A., Klint E. et al.: Skewed distribution of proinflammatory CD4+CD28null T cells in rheumatoid arthritis. Arthritis Res Ther. 2007, 9 (5), R87.

Link A., Selejan S., Hewera L., Walter F., Nickenig G., Bohm M.: Rosuvastatin induces apoptosis in CD4(+)CD28 (null) T cells in patients with acute coronary syndromes. Clin Res Cardiol. 2011, 100 (2), 147–158.

Pawlik A., Ostanek L., Brzosko I., Brzosko M., Masiuk M., Machaliński B. et al.: Therapy with infliximab decreases the CD4+CD28‑ T cell compartment in peripheral blood in patients with rheumatoid arthritis. Rheumatol Int. 2004, 24 (6), 351–354.

Hori S., Nomura T., Sakaguchi S.: Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003, 299 (5609), 1057–1061.

Tang T.T., Song Y., Ding Y.J., Liao Y.H., Yuan J., Zhou Z.H. et al.: Atorvastatin up‑regulates regulatory T‑cell and improves clinical disease activity in patients with rheumatoid arthritis. J Lipid Res. 2011, 52 (2), 1023–1032.

Zhang X., Markovic‑Plese S.: Statins’ immunomodulatory potential against Th17 cell‑mediated autoimmune response. Immunol Res. 2008, 41 (3), 165–174.

Hot A., Miossec P.: Effects of interleukin (IL)‑17A and IL‑17F in human rheumatoid arthritis synoviocytes. Ann Rheum Dis. 2011, 70 (5), 727–723.

Reith W., LeibundGut‑Landmann S., Waldburger J.M.: Regulation of MHC class II gene expression by the class II transactivator. Nat Rev Immunol. 2005, 5 (10), 793–806.

Lee S.J., Qin H., Benveniste E.N.: The IFN‑gamma‑induced transcriptional program of the CIITA gene is inhibited by statins. Eur J Immunol. 2008, 38 (8), 2325–2336.

Wagner A.H., Gebauer M., Guldenzoph B., Hecker M.: 3‑hydroxy‑3‑methylglutaryl coenzyme A reductase‑independent inhibition of CD40 expression by atorvastatin in human endothelial cells. Arterioscler Thromb Vasc Biol. 2002, 22 (11), 1784–1789.

Wagner A.H., Gebauer M., Pollok‑Kopp B., Hecker M.: Cytokine‑inducible CD40 expression in human endothelial cells is mediated by interferon regulatory factor‑1. Blood. 2002, 99 (2), 520–525.

Yilmaz A., Reiss C., Tantawi O., Weng A., Stumpf C., Raaz D. et al.: HMG‑CoA reductase inhibitors suppress maturation of human dendritic cells: new implications for atherosclerosis. Atherosclerosis. 2004, 172 (1), 85–93.


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