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Agonists as Therapy for Autoimmune Disease1
* Department of Neurology, and
Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and
Department of Neurobiology and Developmental Sciences, University of Arkansas for the Medical Sciences, Little Rock, AR 72205
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. PPAR
ligands, which include the naturally occurring PG metabolite 15-deoxy-
12,14-PGJ2 (15d-PGJ2), as well as thiazolidinediones, have been shown to have anti-inflammatory activity. The PPAR
agonists, gemfibrozil, ciprofibrate, and fenofibrate, have an excellent track history as oral agents used to treat hypertriglyceridemia. In the present study, we demonstrate that these PPAR agonists can increase the production of the Th2 cytokine, IL-4, and suppress proliferation by TCR transgenic T cells specific for the myelin basic protein Ac1–11, as well as reduce NO production by microglia. Oral administration of gemfibrozil and fenofibrate inhibited clinical signs of experimental autoimmune encephalomyelitis. More importantly, gemfibrozil was shown to shift the cytokine secretion of human T cell lines by inhibiting IFN- and promoting IL-4 secretion. These results suggest that PPAR agonists such as gemfibrozil and fenofibrate, may be attractive candidates for use in human inflammatory conditions such as multiple sclerosis.
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