Peroxisome proliferator-activated receptor-gamma agonists inhibit experimental allergic encephalomyelitis by blocking IL-12 production, IL-12 signaling and Th1 differentiation.
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.
Natarajan
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Division of Neuroimmunology, Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN 37212, USA.
Bright
J J
JJ
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D007155:Immunologic Factors / Q000627:therapeutic use; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000494:pharmacology*; D053614:Janus Kinase 2; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000276:immunology; D004676:Myelin Basic Protein / Q000276:immunology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D013844:Thiazoles / Q000627:therapeutic use; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D004268:DNA-Binding Proteins; D007155:Immunologic Factors; D004676:Myelin Basic Protein; D011518:Proto-Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D018664:Interleukin-12; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D015230:Prostaglandin D2; C039671:ciglitazone