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

Author

Listed:
  • Sawsan Youssef

    (Stanford University)

  • Olaf Stüve

    (University of California San Francisco)

  • Juan C. Patarroyo

    (University of California San Francisco)

  • Pedro J. Ruiz

    (Stanford University
    California Pacific Medical Center)

  • 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)

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.

Suggested Citation

  • 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 & Scott S. Zamvil, 2002. "The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease," Nature, Nature, vol. 420(6911), pages 78-84, November.
  • Handle: RePEc:nat:nature:v:420:y:2002:i:6911:d:10.1038_nature01158
    DOI: 10.1038/nature01158
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    Cited by:

    1. Jaime Gonzalez Cardona & Matthew D Smith & Jingya Wang & Leslie Kirby & Jason T Schott & Todd Davidson & Jodi L Karnell & Katharine A Whartenby & Peter A Calabresi, 2019. "Quetiapine has an additive effect to triiodothyronine in inducing differentiation of oligodendrocyte precursor cells through induction of cholesterol biosynthesis," PLOS ONE, Public Library of Science, vol. 14(9), pages 1-19, September.
    2. Chien-Cheng Chien & Po-Huang Chen & Chi-Hsiang Chung & Chien-An Sun & Wu-Chien Chien & Ke-Hung Chien, 2021. "Association between Statins and Retinal Vascular Occlusion: A Population-Based Cohort Study," IJERPH, MDPI, vol. 18(18), pages 1-11, September.
    3. Nick Bansback & Roberta Ara & Sue Ward & Aslam Anis & Hyon Choi, 2009. "Statin Therapy in Rheumatoid Arthritis," PharmacoEconomics, Springer, vol. 27(1), pages 25-37, January.
    4. Friedemann Paul & Sonia Waiczies & Jens Wuerfel & Judith Bellmann-Strobl & Jan Dörr & Helmar Waiczies & Mareile Haertle & Klaus D Wernecke & Hans-Dieter Volk & Orhan Aktas & Frauke Zipp, 2008. "Oral High-Dose Atorvastatin Treatment in Relapsing-Remitting Multiple Sclerosis," PLOS ONE, Public Library of Science, vol. 3(4), pages 1-9, April.

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