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The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease

Nature volume 420, pages 78–84 (2002)Cite this article

Abstract

Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which are approved for cholesterol reduction, may also be beneficial in the treatment of inflammatory diseases1,2,3. Atorvastatin (Lipitor) was tested in chronic and relapsing experimental autoimmune encephalomyelitis, a CD4+ Th1-mediated central nervous system (CNS) demyelinating disease model of multiple sclerosis4,5. Here we show that oral atorvastatin prevented or reversed chronic and relapsing paralysis. Atorvastatin induced STAT6 phosphorylation and secretion of Th2 cytokines (interleukin (IL)-4, IL-5 and IL-10) and transforming growth factor (TGF)-β. Conversely, STAT4 phosphorylation was inhibited and secretion of Th1 cytokines (IL-2, IL-12, interferon (IFN)-γ and tumour necrosis factor (TNF)-α) was suppressed. Atorvastatin promoted differentiation of Th0 cells into Th2 cells. In adoptive transfer, these Th2 cells protected recipient mice from EAE induction. Atorvastatin reduced CNS infiltration and major histocompatibility complex (MHC) class II expression. Treatment of microglia inhibited IFN-γ-inducible transcription at multiple MHC class II transactivator (CIITA) promoters and suppressed class II upregulation. Atorvastatin suppressed IFN-γ-inducible expression of CD40, CD80 and CD86 co-stimulatory molecules. l-Mevalonate, the product of HMG-CoA reductase, reversed atorvastatin's effects on antigen-presenting cells (APC) and T cells. Atorvastatin treatment of either APC or T cells suppressed antigen-specific T-cell activation. Thus, atorvastatin has pleiotropic immunomodulatory effects involving both APC and T-cell compartments. Statins may be beneficial for multiple sclerosis and other Th1-mediated autoimmune diseases.

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Figure 1: Atorvastatin treatment inhibits or reverses chronic and relapsing EAE.
Figure 2: Atorvastatin treatment suppresses in vivo and in vitro MHC class II expression on microglia.
Figure 3: Atorvastatin inhibits T-cell proliferation and promotes a Th2 response.
Figure 4: Atorvastatin has immunomodulatory effects on both APC and T cells.
Figure 5: Adoptive transfer of atorvastatin-treated T cells prevents induction of EAE in recipient mice.

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Acknowledgements

We thank J. Bluestone, C. G. Fathman, A. J. Slavin, P. A. Nelson, E. Waubant and W. H. Robinson for discussions, R. Laskey for providing us with purified atorvastatin, and M. J. Eaton and N. A. van Venrooij for technical assistance. Support for this work was provided to S.S.Z. by the Alexander M. and June L. Maisin Foundation, the National Institutes of Health (NIH), the National Multiple Sclerosis Society (NMSS) and the Nancy Davis Foundation. S.S.Z. is a 2002 recipient of an Atorvastatin Research Award form Pfizer Inc., and a research grant from the Wadsworth Foundation. Support was provided to L.S. by the NIH and to R.A.S. by the NMSS. S.Y. is a fellow of the Katherine McCormick Foundation. O.S. is supported by a postdoctoral fellowship from the NMSS.

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Author notes

  1. Pedro J. Ruiz

    Present address: Department of Medicine, California Pacific Medical Center, 2333 Buchanan Street, San Francisco, California, 94115, USA

Authors and Affiliations

  1. Department of Neurology and Neurological Sciences, Beckman Center for Molecular Medicine, Stanford University, Stanford, California, 94305, USA

    Sawsan Youssef, Pedro J. Ruiz, Jennifer L. Radosevich, Eun Mi Hur, Dennis J. Mitchell & Lawrence Steinman

  2. Department of Pathology (Neuropathology), Stanford University, Stanford, California, 94305, USA

    Raymond A. Sobel

  3. Department of Neurology, University of California San Francisco, 521 Parnassus Avenue, San Francisco, California, 94143, USA

    Olaf Stüve, Juan C. Patarroyo, Manuel Bravo & Scott S. Zamvil

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Correspondence to Scott S. Zamvil.

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Youssef, S., Stüve, O., Patarroyo, J. et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420, 78–84 (2002). https://doi.org/10.1038/nature01158

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