Abstract
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear receptor transcription factor that regulates adipocyte differentiation and glucose homeostasis. PPARgamma agonists are potent therapeutic agents for the treatment of type 2 diabetes and obesity. PPARgamma agonists also prevent inflammation in animal models, suggesting their use for the treatment of human inflammatory diseases. Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated inflammatory demyelinating disease model of multiple sclerosis (MS) and IL-12 plays a crucial role in the pathogenesis of EAE and MS. In this study we have examined the effect of PPARgamma agonists on the pathogenesis of EAE. In vivo treatment of SJL/J mice with PPARgamma agonists, 15-deoxydelta(12,14) prostaglandin J2 or Ciglitazone, decreased the duration and clinical severity of active immunization and adoptive transfer models of EAE. PPARgamma agonists inhibited EAE in association with a decrease in IL-12 production and differentiation of neural antigen-specific Th1 cells. In vitro treatment of activated T cells with PPARgamma agonists inhibited IL-12-induced activation of JAK-STAT signaling pathway and Th1 differentiation. These findings highlight the fact that PPARgamma agonists regulate central nervous system inflammation and demyelination by inhibiting IL-12 production, IL-12 signaling and Th1 differentiation in EAE.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Differentiation
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Cells, Cultured
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DNA-Binding Proteins / metabolism
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Dose-Response Relationship, Drug
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Encephalomyelitis, Autoimmune, Experimental / prevention & control*
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Immunologic Factors / therapeutic use
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Interleukin-12 / biosynthesis*
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Interleukin-12 / pharmacology*
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Janus Kinase 2
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Kinetics
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Lymphocyte Activation / drug effects
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Macrophages / drug effects
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Macrophages / immunology
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Mice
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Microglia / drug effects
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Microglia / immunology
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Myelin Basic Protein / immunology
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Prostaglandin D2 / analogs & derivatives*
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Prostaglandin D2 / therapeutic use
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins*
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Receptors, Cytoplasmic and Nuclear / agonists*
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Signal Transduction / drug effects
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Spinal Cord / drug effects
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Spinal Cord / pathology
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Th1 Cells / drug effects
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Th1 Cells / immunology*
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Thiazoles / therapeutic use
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Thiazolidinediones*
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Transcription Factors / agonists*
Substances
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15-deoxy-delta(12,14)-prostaglandin J2
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DNA-Binding Proteins
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Immunologic Factors
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Myelin Basic Protein
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Proto-Oncogene Proteins
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Receptors, Cytoplasmic and Nuclear
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Thiazoles
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Thiazolidinediones
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Transcription Factors
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Interleukin-12
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Protein-Tyrosine Kinases
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JAK2 protein, human
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Jak2 protein, mouse
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Janus Kinase 2
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Prostaglandin D2
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ciglitazone