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INFLAMMATION AND IMMUNOPHARMACOLOGY

Peroxisome Proliferation-Activated Receptor (PPAR) Is Not Necessary for Synthetic PPAR Agonist Inhibition of Inducible Nitric-Oxide Synthase and Nitric Oxide

Department of Medicine, Medical University of South Carolina, Charleston, South Carolina (M.B.C., J.L.S., J.Z., G.S.G.); Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (C.J.N., F.J.G.); and Medical Research Service, Ralph H. Johnson VA Medical Center, Charleston, South Carolina (G.S.G.)

Peroxisome proliferation-activated receptor (PPAR) agonists inhibit inducible nitric-oxide synthase (iNOS), tumor necrosis factor-, and interleukin-6. Because of these effects, synthetic PPAR agonists, including thiazolidinediones, are being studied for their impact on inflammatory disease. The anti-inflammatory concentrations of synthetic PPAR agonists range from 10 to 50 µM, whereas their binding affinity for PPAR is in the nanomolar range. The specificity of synthetic PPAR agonists for PPAR at the concentrations necessary for anti-inflammatory effects is thus in question. We report that PPAR is not necessary for the inhibition of iNOS by synthetic PPAR agonists. RAW 264.7 macrophages possess little PPAR, yet lipopolysaccharide (LPS)/interferon (IFN)-induced iNOS was inhibited by synthetic PPAR agonists at 20 µM. Endogenous PPAR was inhibited by the transfection of a dominant-negative PPAR construct into murine mesangial cells. In the transfected cells, synthetic PPAR agonists inhibited iNOS production at 10 µM, similar to nontransfected cells. Using cells from PPAR Cre/lox conditional knockout mice, baseline and LPS/IFN-induced nitric oxide levels were higher in macrophages lacking PPAR versus controls. However, synthetic PPAR agonists inhibited iNOS at 10 µM in the PPAR-deficient cells, similar to macrophages from wild-type mice. These results indicate that PPAR is not necessary for inhibition of iNOS expression by synthetic PPAR agonists at concentrations over 10 µM. Intrinsic PPAR function, in the absence of synthetic agonists, however, may play a role in inflammatory modulation.

Address correspondence to: Dr. Gary S. Gilkeson, Division of Rheumatology and Immunology, Medical University of South Carolina, 96 Jonathon Lucas St., Suite 912, P.O. Box 25063, Charleston, SC 29425. E-mail: gilkeson{at}musc.edu

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