Abstract
Peroxisome proliferator-activated receptors (PPARs; PPAR-alpha, PPAR-delta, and PPAR-gamma) comprise a family of nuclear receptors that sense fatty acid levels and translate this information into altered gene transcription. Previously, it was reported that treatment of mice with a synthetic ligand activator of PPAR-delta, GW0742, ameliorates experimental autoimmune encephalomyelitis (EAE), indicating a possible role for this nuclear receptor in the control of central nervous system (CNS) autoimmune inflammation. We show that mice deficient in PPAR-delta (PPAR-delta(-/-)) develop a severe inflammatory response during EAE characterized by a striking accumulation of IFN-gamma(+)IL-17A(-) and IFN-gamma(+)IL-17A(+) CD4(+) cells in the spinal cord. The preferential expansion of these T helper subsets in the CNS of PPAR-delta(-/-) mice occurred as a result of a constellation of immune system aberrations that included higher CD4(+) cell proliferation, cytokine production, and T-bet expression and enhanced expression of IL-12 family cytokines by myeloid cells. We also show that the effect of PPAR-delta in inhibiting the production of IFN-gamma and IL-12 family cytokines is ligand dependent and is observed in both mouse and human immune cells. Collectively, these findings suggest that PPAR-delta serves as an important molecular brake for the control of autoimmune inflammation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain / immunology
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Brain / pathology
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / transplantation
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Cell Proliferation
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Encephalomyelitis, Autoimmune, Experimental / metabolism
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Encephalomyelitis, Autoimmune, Experimental / pathology*
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Female
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Gene Expression / immunology
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Glycoproteins / immunology
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Homeodomain Proteins / genetics
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Humans
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Interferon-gamma / genetics
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Interferon-gamma / metabolism
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Interleukin-12 / genetics
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Interleukin-12 / metabolism
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Interleukin-17 / genetics
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Interleukin-17 / metabolism
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / immunology
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Leukocytes, Mononuclear / metabolism
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Lipopolysaccharides / pharmacology
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Lymphocyte Activation / immunology
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Macrophages, Peritoneal / drug effects
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Macrophages, Peritoneal / immunology
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Macrophages, Peritoneal / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myelin-Oligodendrocyte Glycoprotein
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Myeloid Cells / drug effects
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Myeloid Cells / immunology
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Myeloid Cells / metabolism
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Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
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PPAR delta / antagonists & inhibitors
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PPAR delta / metabolism*
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Peptide Fragments / immunology
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Spinal Cord / immunology
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Spinal Cord / pathology
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T-Box Domain Proteins / genetics
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T-Lymphocytes, Helper-Inducer / drug effects
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T-Lymphocytes, Helper-Inducer / immunology
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T-Lymphocytes, Helper-Inducer / pathology*
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T-Lymphocytes, Helper-Inducer / transplantation
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Thiazoles / pharmacology
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Glycoproteins
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Homeodomain Proteins
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Interleukin-17
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Lipopolysaccharides
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Myelin-Oligodendrocyte Glycoprotein
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Nuclear Receptor Subfamily 1, Group F, Member 3
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PPAR delta
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Peptide Fragments
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T-Box Domain Proteins
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T-box transcription factor TBX21
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Thiazoles
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Tumor Necrosis Factor-alpha
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myelin oligodendrocyte glycoprotein (35-55)
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RAG-1 protein
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Interleukin-12
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(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid
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Interferon-gamma