gw0742 and myelin-oligodendrocyte-glycoprotein-(35-55)

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.

Topics: Animals; Brain; CD4-Positive T-Lymphocytes; Cell Proliferation; Encephalomyelitis, Autoimmune, Experimental; Female; Gene Expression; Glycoproteins; Homeodomain Proteins; Humans; Interferon-gamma; Interleukin-12; Interleukin-17; Leukocytes, Mononuclear; Lipopolysaccharides; Lymphocyte Activation; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin-Oligodendrocyte Glycoprotein; Myeloid Cells; Nuclear Receptor Subfamily 1, Group F, Member 3; Peptide Fragments; PPAR delta; Spinal Cord; T-Box Domain Proteins; T-Lymphocytes, Helper-Inducer; Th1 Cells; Thiazoles; Tumor Necrosis Factor-alpha

Agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma) exert anti-inflammatory and anti-proliferative effects which led to testing of these drugs in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. In contrast, the effect of PPARdelta (PPARdelta) agonists in EAE is not yet known. We show that oral administration of the selective PPARdelta agonist GW0742 reduced clinical symptoms in C57BL/6 mice that had been immunized with encephalitogenic myelin oligodendrocyte glycoprotein (MOG) peptide. In contrast to previous results with PPARgamma agonists, GW0742 only modestly attenuated clinical symptoms when the drug was provided simultaneously with immunization, but a greater reduction was observed if administered during disease progression. Reduced clinical symptoms were accompanied by a reduction in the appearance of new cortical lesions, however cerebellar lesion load was not reduced. Treatment of T-cells with GW0742 either in vivo or in vitro did not reduce IFNgamma production; however GW0742 reduced astroglial and microglial inflammatory activation and IL-1beta levels in EAE brain. RTPCR analysis showed that GW0742 increased expression of some myelin genes. These data demonstrate that PPARdelta agonists, like other PPAR ligands, can exert protective actions in an autoimmune model of demyelinating disease.

Topics: Animals; Brain; Concanavalin A; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation, Enzymologic; Glycoproteins; Immunohistochemistry; Interferon-gamma; Lymphocyte Activation; Lymphocytes; Mice; Mice, Inbred C57BL; Myelin Basic Protein; Myelin-Oligodendrocyte Glycoprotein; Neuroglia; Peptide Fragments; PPAR delta; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Severity of Illness Index; Thiazoles; Time Factors