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Simvastatin Inhibits IL-17 Secretion by Targeting Multiple IL-17-Regulatory Cytokines and by Inhibiting the Expression of IL-17 Transcription Factor RORC in CD4⁺ Lymphocytes

Xin Zhang^*, Jianping Jin, Xueyan Peng, Vinod S. Ramgolam^* and Silva Markovic-Plese^1,*,

^* Department of Neurology, Center for Bioinformatics, and Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599; and Department of Neurology, Yale University School of Medicine, New Haven, CT 06510

Statins, extensively used as cholesterol-lowering agents, have recently been identified as immunomodulatory agents. This study investigated the statins’ mechanisms that target the autoimmune response in humans, and evaluated their therapeutic potential in multiple sclerosis. Our results demonstrated statin-mediated increases in suppressor of cytokine secretion (SOCS) 3 and suppressor of cytokine secretion 7, which negatively regulate the STAT/JAK signal transduction pathway and IL-6 and IL-23 gene expression in monocytes. Simvastatin also induced IFN-, IL-4, and IL-27 production in monocytes, which together inhibited IL-17 transcription and secretion in CD4⁺ T cells. IL-17-producing CD4⁺ cells, referred to as Th17 cells, have recently been found to play a central role in the development of autoimmune diseases. Furthermore, simvastatin directly inhibited the expression of retinoic acid-related orphan nuclear hormone receptor C, a transcription factor that controls IL-17 production in CD4⁺ T cells. This effect was reversed by mevalonic acid, a downstream metabolite of 3-hydroxy-3-methylglutaryl CoA reductase, confirming that simvastatin’s specific effect is through the inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase. These results provide evidence for the novel immunomodulatory mechanisms of statins, which selectively target the regulation of cytokine transcription involved in the development of the human autoimmune response. Based on the described immunomodulatory mechanisms, good safety profile and oral bioavailability, statins represent a promising therapeutic approach for multiple sclerosis and other chronic inflammatory diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Silva Markovic-Plese, 6109 Neuroscience Research Building, 103 Mason Farm Road, Chapel Hill, NC 27599. E-mail address: markovics{at}neurology.unc.edu

² Abbreviations used in this paper: MS, multiple sclerosis; RR, relapsing remitting; GA, glatiramer acetate; EAE, experimental autoimmune encephalomyelitis; SOCS, suppressor of cytokine secretion; HC, healthy control; qRT-PCR, quantitative real time PCR; DC, dendritic cell; RORC, retinoic acid-related orphan nuclear hormone receptor C; HMG, 3-hydroxy-3-methylglutaryl.

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