title: PPARgamma antagonists exacerbate neural antigen-specific Th1 response and experimental allergic encephalomyelitis.
abstract: Peroxisome proliferator-activated receptor-gamma is a nuclear receptor transcription factor that regulates cell growth, differentiation and homeostasis. PPARgamma agonists have been used in the treatment of obesity, diabetes, cancer and inflammation. We and others have shown recently that PPARgamma agonists ameliorate experimental allergic encephalomyelitis (EAE), a Th1 cell-mediated autoimmune disease model of multiple sclerosis (MS). We have further shown that PPARgamma agonists inhibit EAE through blocking IL-12 signaling leading to Th1 differentiation and the PPARgamma-deficient heterozygous mice (PPARgamma(+/-)) develop an exacerbated EAE. In this study, we show that in vivo treatment (i.p.) with 100 mug PPARgamma antagonists, Bisphenol A diglycidyl ether (BADGE) or 2-Chloro-5-nitro-N-(4-pyridyl)benzamide (T0070907), on every other day from day 0 to 30, increased the severity and duration of EAE in C57BL/6 wild-type and PPARgamma(+/-) mice. The exacerbation of EAE by PPARgamma antagonists associates with an augmented neural antigen-induced T cell proliferation, IFNgamma production or Th1 differentiation. These results further suggest that PPARgamma is a critical physiological regulator of CNS inflammation and demyelination in EAE.
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, 1222 VSRH, 2201 Children's way, Nashville, TN 37212, USA.
authors.forename: Himanshu P
authors.initials: HP
authors.lastname: Raikwar
authors.forename: Gladson
authors.initials: G
authors.lastname: Muthian
authors.forename: Johnson
authors.initials: J
authors.lastname: Rajasingh
authors.forename: Caroline
authors.initials: C
authors.lastname: Johnson
authors.forename: John J
authors.initials: JJ
authors.lastname: Bright
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage*; D001559:Benzhydryl Compounds; D049109:Cell Proliferation / Q000187:drug effects; D003711:Demyelinating Diseases / Q000209:etiology / Q000235:genetics / Q000473:pathology; D004306:Dose-Response Relationship, Immunologic; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004852:Epoxy Compounds / Q000008:administration & dosage*; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000172:deficiency; D010446:Peptide Fragments / Q000276:immunology; D011725:Pyridines / Q000008:administration & dosage*; D018417:Th1 Cells / Q000187:drug effects*; D013936:Thymidine / Q000493:pharmacokinetics; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics; D000098826:Bisphenol A Compounds
chemical_list: D001549:Benzamides; D001559:Benzhydryl Compounds; D004852:Epoxy Compounds; D006023:Glycoproteins; D007371:Interferon-gamma; D063308:Myelin-Oligodendrocyte Glycoprotein; D047495:PPAR gamma; D010446:Peptide Fragments; D011725:Pyridines; D013936:Thymidine; D014316:Tritium; C458508:T 0070907; C445081:myelin oligodendrocyte glycoprotein (35-55); C019273:bisphenol A diglycidyl ether; D000098826:Bisphenol A Compounds