Abstract
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.
Publication types
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
CD40 Antigens / biosynthesis
-
Cell Division / genetics
-
Cell Division / immunology
-
Demyelinating Diseases / genetics
-
Demyelinating Diseases / immunology
-
Demyelinating Diseases / pathology
-
Encephalomyelitis, Autoimmune, Experimental / genetics*
-
Encephalomyelitis, Autoimmune, Experimental / immunology
-
Encephalomyelitis, Autoimmune, Experimental / pathology
-
Female
-
Genetic Carrier Screening*
-
Glycoproteins / administration & dosage
-
Glycoproteins / immunology*
-
Histocompatibility Antigens Class II / biosynthesis
-
Injections, Intramuscular
-
Interferon-gamma / biosynthesis
-
Interleukin-12 / biosynthesis
-
Lymphocyte Activation / genetics
-
Lymphocyte Activation / immunology
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Myelin-Oligodendrocyte Glycoprotein
-
Nerve Tissue Proteins / administration & dosage
-
Nerve Tissue Proteins / immunology*
-
Peptide Fragments / administration & dosage
-
Peptide Fragments / immunology*
-
Peroxisomes / metabolism*
-
Receptors, Cytoplasmic and Nuclear / deficiency*
-
Receptors, Cytoplasmic and Nuclear / genetics*
-
Receptors, Cytoplasmic and Nuclear / physiology
-
Severity of Illness Index
-
Spleen / cytology
-
Spleen / immunology
-
Spleen / metabolism
-
Th1 Cells / immunology*
-
Th1 Cells / metabolism
-
Th1 Cells / pathology
-
Transcription Factors / deficiency*
-
Transcription Factors / genetics*
-
Transcription Factors / physiology
-
Up-Regulation / genetics
-
Up-Regulation / immunology
Substances
-
CD40 Antigens
-
Glycoproteins
-
Histocompatibility Antigens Class II
-
Myelin-Oligodendrocyte Glycoprotein
-
Nerve Tissue Proteins
-
Peptide Fragments
-
Receptors, Cytoplasmic and Nuclear
-
Transcription Factors
-
myelin oligodendrocyte glycoprotein (35-55)
-
Interleukin-12
-
Interferon-gamma