Peroxisome proliferator-activated receptor-gamma-deficient heterozygous mice develop an exacerbated neural antigen-induced Th1 response and experimental allergic encephalomyelitis.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear receptor transcription factor that regulates cell growth, differentiation, and homeostasis. PPARgamma agonists are potent therapeutic agents for type 2 diabetes, obesity, and inflammation. Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated inflammatory demyelinating autoimmune disease model of multiple sclerosis. We have shown recently that PPARgamma agonists inhibit EAE by blocking IL-12 production, IL-12 signaling, and neural Ag-induced Th1 differentiation. In this study, we show that the PPARgamma-deficient heterozygous mice develop an exacerbated EAE with prolonged clinical symptoms than the wild-type littermates, following immunization with myelin oligodendrocyte glycoprotein (MOG) p35-55 peptide. The exacerbation of EAE in PPARgamma(+/-) mice associates with an increased expansion of CD4(+) and CD8(+) T cells and expression of CD40 and MHC class II molecules in response to MOGp35-55 Ag. The PPARgamma(+/-) mice also showed an increase in T cell proliferation and Th1 response to MOGp35-55 Ag than the wild-type littermates. These findings suggest that PPARgamma be a critical physiological regulator of CNS inflammation and demyelination in EAE and perhaps multiple sclerosis and other Th1 cell-mediated autoimmune diseases.
Natarajan
Chandramohan
C
Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA. brightj@ctrvax.vanderbilt.edu
Muthian
Gladson
G
Barak
Yaavov
Y
Evans
Ronald M
RM
Bright
John J
JJ
D000818:Animals; D019013:CD40 Antigens / Q000096:biosynthesis; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D003711:Demyelinating Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D005260:Female; D006580:Genetic Carrier Screening; D006023:Glycoproteins / Q000008:administration & dosage / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D007273:Injections, Intramuscular; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000276:immunology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology*; D020675:Peroxisomes / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D012720:Severity of Illness Index; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D019013:CD40 Antigens; D006023:Glycoproteins; D000949:Histocompatibility Antigens Class II; D063308:Myelin-Oligodendrocyte Glycoprotein; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C445081:myelin oligodendrocyte glycoprotein (35-55); D018664:Interleukin-12; D007371:Interferon-gamma