PPARgamma antagonists reverse the inhibition of neural antigen-specific Th1 response and experimental allergic encephalomyelitis by Ciglitazone and 15-deoxy-Delta12,14-prostaglandin J2.
Peroxisome proliferator-activated receptor-gamma is a nuclear receptor transcription factor that regulates cell growth, differentiation and homeostasis. PPARgamma agonists have been used to treat obesity, diabetes, cancer and inflammation and recent studies have shown the protective effects of PPARgamma agonists on experimental allergic encephalomyelitis (EAE), a Th1 cell-mediated autoimmune disease model of multiple sclerosis (MS). Our studies have further demonstrated that the PPARgamma agonists, 15d-PGJ2 and Ciglitazone, inhibit EAE through blocking IL-12 signaling leading to Th1 differentiation and the PPARgamma deficient heterozygous mice (PPARgamma+/-) or those treated with PPARgamma antagonists develop an exacerbated EAE in association with an augmented Th1 response. In this study, we show that the PPARgamma antagonists, Bisphenol A diglycidyl ether (BADGE) and 2-chloro-5-nitro-N-(4-pyridyl)benzamide (T0070907), reverse the inhibition of EAE by the PPARgamma agonists, Ciglitazone and 15-Deoxy-Delta(12,14)-Prostaglandin J2, in C57BL/6 wild-type and PPARgamma+/- mice. The reversal of EAE by BADGE and T0070907 was associated with restoration of neural antigen-induced T cell proliferation, IFNgamma production and Th1 differentiation inhibited by Ciglitazone and 15d-PGJ2. These results suggest that Ciglitazone and 15d-PGJ2 ameliorate EAE through PPARgamma-dependent mechanisms and further confirm a physiological role for PPARgamma in the regulation of CNS inflammation and demyelination in EAE.
Raikwar
Himanshu P
HP
Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
Muthian
Gladson
G
Rajasingh
Johnson
J
Johnson
Caroline N
CN
Bright
John J
JJ
D000818:Animals; D000941:Antigens / Q000276:immunology; D001549:Benzamides / Q000494:pharmacology; D001559:Benzhydryl Compounds; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D003711:Demyelinating Diseases / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000517:prevention & control; D004797:Enzyme-Linked Immunosorbent Assay; D004852:Epoxy Compounds / Q000494:pharmacology; D005260:Female; D007155:Immunologic Factors / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology*; D063308:Myelin-Oligodendrocyte Glycoprotein; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology; D045162:Thiazolidinediones / Q000494:pharmacology*; D000098826:Bisphenol A Compounds
D000941:Antigens; D001549:Benzamides; D001559:Benzhydryl Compounds; D004852:Epoxy Compounds; D007155:Immunologic Factors; D007371:Interferon-gamma; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D047495:PPAR gamma; D015230:Prostaglandin D2; D011725:Pyridines; D045162:Thiazolidinediones; C097240:15-deoxy-delta(12,14)-prostaglandin J2; C571327:Mog protein, mouse; C458508:T 0070907; C019273:bisphenol A diglycidyl ether; D000098826:Bisphenol A Compounds; C039671:ciglitazone