Acknowledgements We thank S. Birren and M. Chao for providing some of the p75 mutant mice and constructs; K. Gerhold for technical assistance; K.-F. Lee for discussion; and M. Greenberg, V. Koprivica and K.-F. Lee for critical reading of the manuscript. This study was supported by the Alfred Sloan Foundation, the Burrough Wellcome Fund, the EJLB Foundation, the International Spinal Research Trust, the John Merck Fund, the Klingenstein Fund, the Whitehall Foundation, the National Institute of Drug Abuse, and the National Institute of Neurological Disorders and Stroke (to Z.H.). K.C.W. is a recipient of a Howard Hughes Predoctoral Fellowship. R.S. is supported by a postdoctoral fellowship from the Lefler Foundation. Competing interests statement The authors declare that they have no competing financial interests. Correspondence and requests for materials should be addressed to Z.H. (e-mail: zhigang.he@tch.harvard.edu). .............................................................. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease Sawsan Youssef*, Olaf Stu ¨ve†, Juan C. Patarroyo†, Pedro J. Ruiz*‡, Jennifer L. Radosevich*, Eun Mi Hur*, Manuel Bravo†, Dennis J. Mitchell*, Raymond A. Sobel§, Lawrence Steinman* & Scott S. Zamvil† * Department of Neurology and Neurological Sciences, Beckman Center for Molecular Medicine; and § Department of Pathology (Neuropathology), Stanford University, Stanford, California 94305, USA † Department of Neurology, University of California San Francisco, 521 Parnassus Avenue, San Francisco, California 94143, USA ‡ Present address: Department of Medicine, California Pacific Medical Center, 2333 Buchanan Street, San Francisco, California 94115, USA ............................................................................................................................................................................. 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 inflamma- tory diseases 1–3 . Atorvastatin (Lipitor) was tested in chronic and relapsing experimental autoimmune encephalomyelitis, a CD4 1 Th1-mediated central nervous system (CNS) demyelinating dis- ease model of multiple sclerosis 4,5 . Here we show that oral atorvastatin prevented or reversed chronic and relapsing paraly- sis. Atorvastatin induced STAT6 phosphorylation and secretion of Th2 cytokines (interleukin (IL)-4, IL-5 and IL-10) and trans- forming growth factor (TGF)-b. Conversely, STAT4 phosphoryl- ation was inhibited and secretion of Th1 cytokines (IL-2, IL-12, interferon (IFN)-g and tumour necrosis factor (TNF)-a) 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-g-inducible transcription at multiple MHC class II transactivator (CIITA) promoters and suppressed class II upregulation. Atorvastatin suppressed IFN-g-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 acti- vation. 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. In 1995, it was reported that pravastatin treatment of cardiac transplant recipients was associated with a reduction in haemo- dynamically significant rejection episodes and increased survival, independent of its cholesterol-lowering effects 1 . Subsequent studies demonstrated that certain statins could inhibit production of specific pro-inflammatory molecules 2,3,6 . Lovastatin inhibited pro- duction of TNF-a and inducible nitric oxide synthetase (iNOS) by microglia and astrocytes 2 . MHC class II expression is central to immune regulation in T-cell-mediated autoimmune disease 5,7,8 . Statins prevented IFN-g-inducible MHC class II expression on non-professional APC 9 , suggesting that statins might inhibit anti- gen presentation to pro-inflammatory Th1 cells. In that study, it was observed that statins inhibited IFN-g-inducible expression of the MHC class II transactivator (CIITA), the master regulator for MHC class II expression 10 . In endothelial cells, IFN-g-inducible CIITA transcription was inhibited at CIITA promoter (p) IV 11 , which Figure 1 Atorvastatin treatment inhibits or reverses chronic and relapsing EAE. a, Oral atorvastatin ameliorated MOG p35–55-induced EAE in C57BL/6 mice when administered at EAE onset (within one day of initial symptoms), or b, after acute EAE was established. c, Oral atorvastatin prevented exacerbations of relapsing EAE induced by immunization of SJL/J mice with PLP p139–151. d, Relapsing EAE in SJL/J mice was reversed when atorvastatin treatment began at the onset of the first relapse. e, Limited EAE development in MBP Ac1–11-specific TCR transgenic mice after atorvastatin treatment was discontinued. f, PLP p139–151-induced EAE in SJL/J mice was significantly reduced by 0.1 mg kg 21 , but not 0.01 mg kg 2 1 atorvastatin. Number of mice per group in each experiment: a (7), b (14), c (10), d (10), e (7) and f (7). In a–d mice were scored and randomized immediately before first treatment. Open circle, 1 mg kg 2 1 atorvastatin; filled circle, 10 mg kg 21 atorvastatin; shaded circle, vehicle only (PBS). Solid bars beneath each panel indicate atorvastatin treatment. *P value , 0.001, comparison of either atorvastatin-treated group with vehicle-only (PBS)-treated group. letters to nature NATURE | VOL 420 | 7 NOVEMBER 2002 | www.nature.com/nature 78 © 2002 Nature Publishing Group