Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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


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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others


  1. Kobashigawa, J. A. et al. Effect of pravastatin on outcomes after cardiac transplantation. N. Engl. J. Med. 333, 621–627 (1995)

    Article  CAS  Google Scholar 

  2. Pahan, K., Sheikh, F. G., Namboodiri, A. M. & Singh, I. 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 (1997)

    Article  CAS  Google Scholar 

  3. Wong, B. et al. Statins suppress THP-1 cell migration and secretion of matrix metalloproteinase 9 by inhibiting geranylgeranylation. J. Leukoc. Biol. 69, 959–962 (2001)

    CAS  Google Scholar 

  4. Zamvil, S. S. & Steinman, L. The T lymphocyte in experimental allergic encephalomyelitis. Annu. Rev. Immunol. 8, 579–621 (1990)

    Article  CAS  Google Scholar 

  5. Slavin, A. J. et al. Requirement for endocytic antigen processing and influence of invariant chain and H-2M deficiencies in CNS autoimmunity. J. Clin. Invest. 108, 1133–1139 (2001)

    Article  CAS  Google Scholar 

  6. Romano, M. et al. Inhibition of monocyte chemotactic protein-1 synthesis by statins. Lab. Invest. 80, 1095–1100 (2000)

    Article  CAS  Google Scholar 

  7. Steinman, L., Rosenbaum, J. T., Sriram, S. & McDevitt, H. O. In vivo effects of antibodies to immune response gene products: prevention of experimental allergic encephalomyelitis. Proc. Natl Acad. Sci. USA 78, 7111–7114 (1981)

    Article  ADS  CAS  Google Scholar 

  8. Bottazo, G. F., Pujol-Borrell, R., Hanufusa, T. & Feldmann, M. Role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity. Lancet 2, 1115–1119 (1983)

    Article  Google Scholar 

  9. Kwak, B., Mulhaupt, F., Myit, S. & Mach, F. Statins as a newly recognized type of immunomodulator. Nature Med. 6, 1399–1402 (2000)

    Article  CAS  Google Scholar 

  10. Mach, B., Steimle, V., Martinez-Soria, E. & Reith, W. Regulation of MHC class II genes: lessons from a disease. Annu. Rev. Immunol. 14, 301–331 (1996)

    Article  CAS  Google Scholar 

  11. Muhlethaler-Mottet, A., Otten, L. A., Steimle, V. & Mach, B. 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. 16, 2851–2860 (1997)

    Article  CAS  Google Scholar 

  12. Maeda, A. & Sobel, R. A. Matrix metalloproteinases in the normal human central nervous system, microglial nodules, and multiple sclerosis lesions. J. Neuropathol. Exp. Neurol. 55, 300–309 (1996)

    Article  CAS  Google Scholar 

  13. Rudick, R. A. Contemporary immunomodulatory therapy for multiple sclerosis. J. Neuroophthalmol. 21, 284–291 (2001)

    Article  CAS  Google Scholar 

  14. Staffa, J. A., Chang, J. & Green, L. Cerivastatin and reports of fatal rhabdomyolysis. N. Engl. Med. 346, 539–540 (2002)

    Article  Google Scholar 

  15. Bernini, F., Poli, A. & Paoletti, R. Safety of HMG-CoA reductase inhibitors: focus on atorvastatin. Cardiovasc. Drugs Ther. 15, 211–218 (2001)

    Article  CAS  Google Scholar 

  16. Cilla, D. D. Jr, Whitfield, L. R., Gibson, D. M., Sedman, A. J. & Posvar, E. L. Multiple-dose pharmacokinetics, pharmacodynamics, and safety and atorvastatin, an inhibitor of HMG-CoA reductase, in healthy subjects. Clin. Pharmacol. Ther. 60, 687–695 (1996)

    Article  CAS  Google Scholar 

  17. Dostal, L. A., Whitfield, I. R. & Anderson, J. A. Fertility and general reproduction studies in rats with the HMG-CoA reductase inhibitor, atorvastatin. Fundam. Appl. Toxicol. 32, 285–292 (1996)

    Article  CAS  Google Scholar 

  18. Hardardottir, F., Baron, J. L. & Janeway, C. A. Jr. T cells with two functional antigen-specific receptors. Proc. Natl Acad. Sci. USA 92, 354–358 (1995)

    Article  ADS  CAS  Google Scholar 

  19. Piskurich, J. F., Linhoff, M. W., Wang, Y. & Ting, J. P. Y. Two distinct gamma interferon-inducible promoters of the major histocompatibility complex class II transactivator gene are differentially regulated by STAT1, interferon regulatory factor 1, and transforming growth factor beta. Mol. Cell. Biol. 19, 431–440 (1999)

    Article  CAS  Google Scholar 

  20. Waldburger, J. M., Suter, T., Fontana, A., Acha-Orbea, H. & Reith, W. Selective abrogation of major histocompatibility complex class II expression on extrahematopoietic cells in mice lacking promoter IV of the class II transactivator gene. J. Exp. Med. 194, 393–406 (2001)

    Article  CAS  Google Scholar 

  21. Soos, J. M. et al. Malignant glioma cells use MHC class II transactivator (CIITA) promoters III and IV to direct IFN-gamma-inducible CIITA expression and can function as nonprofessional antigen presenting cells in endocytic processing and CD4+ T-cell activation. Glia 36, 391–405 (2001)

    Article  CAS  Google Scholar 

  22. Darnell, J. E. Jr. STATs and gene regulation. Science 277, 1630–1635 (1997)

    Article  ADS  CAS  Google Scholar 

  23. Weitz-Schmidt, G. et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nature Med. 7, 687–692 (2001)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  25. Cuthbert, J. A. & Lipsky, P. E. Sterol metabolism and lymphocyte responsiveness: inhibition of endogenous sterol synthesis prevents mitogen-induced human T cell proliferation. J. Immunol. 126, 2093–2099 (1981)

    CAS  PubMed  Google Scholar 

  26. Steinman, L. Multiple sclerosis: a two-stage disease. Nature Immunol. 2, 762–764 (2001)

    Article  CAS  Google Scholar 

  27. Stanislaus, R., Pahan, K., Singh, A. K. & Singh, I. Amelioration of experimental allergic encephalomyelitis in Lewis rats by lovastatin. Neurosci. Lett. 269, 71–74 (1999)

    Article  CAS  Google Scholar 

  28. Walker, W. S., Gatewood, J., Olivas, E., Askew, D. & Havenith, C. E. Mouse microglial cell lines differing in constitutive and interferon-gamma-inducible antigen-presenting activities for naive and memory CD4+ and CD8+ T cells. J. Neuroimmunol. 63, 163–174 (1995)

    Article  CAS  Google Scholar 

  29. Aloisi, F. et al. Relative efficiency of microglia, astrocytes, dendritic cells and B cells in naive CD4+ T cell priming and Th1/Th2 cell restimulation. Eur. J. Immunol. 29, 2705–2714 (1999)

    Article  CAS  Google Scholar 

  30. Soos, J. M. et al. Astrocytes express elements of the class II endocytic pathway and process central nervous system autoantigen for presentation for encephalitogenic T cells. J. Immunol. 161, 5959–5966 (1998)

    CAS  PubMed  Google Scholar 

Download references


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.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Scott S. Zamvil.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing