PPARgamma antagonists exacerbate neural antigen-specific Th1 response and experimental allergic encephalomyelitis.
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.
Raikwar
Himanshu P
HP
Department of Neurology, Vanderbilt University Medical Center, 1222 VSRH, 2201 Children's way, Nashville, TN 37212, USA.
Muthian
Gladson
G
Rajasingh
Johnson
J
Johnson
Caroline
C
Bright
John J
JJ
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
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