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

Sawsan Youssef, Olaf Stüve, Juan C. Patarroyo, Pedro J. Ruiz, Jennifer L. Radosevich, Eun Mi Hur, Manuel Bravo, Dennis J. Mitchell, Raymond A. Sobel, Lawrence Steinman and Scott S. Zamvil ()
Additional contact information
Sawsan Youssef: Stanford University
Olaf Stüve: University of California San Francisco
Juan C. Patarroyo: University of California San Francisco
Pedro J. Ruiz: Stanford University
Jennifer L. Radosevich: Stanford University
Eun Mi Hur: Stanford University
Manuel Bravo: University of California San Francisco
Dennis J. Mitchell: Stanford University
Raymond A. Sobel: Stanford University
Lawrence Steinman: Stanford University
Scott S. Zamvil: University of California San Francisco

Nature, 2002, vol. 420, issue 6911, 78-84

Abstract: 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.

Date: 2002
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DOI: 10.1038/nature01158

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