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Peroxisome Proliferator-Activated Receptor- Contributes to the Anti-Inflammatory Activity of Glucocorticoids

Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy (S.C., E.M., C.C., R.D.P.); IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy (S.C., E.M., E.E.); Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy (S.B., V.D., E.V., G.N., C.R.); and Department of Experimental Pharmacology, University of Naples "Federico II", Naples, Italy (E.E.)

Glucocorticoids (GCs) are effective anti-inflammatory agents widely used in the therapeutic approach to treatment of acute and chronic inflammatory diseases. Previous results suggest that peroxisome proliferator-activated receptor- (PPAR-), an intracellular transcription factor activated by fatty acids, plays a role in the control of inflammation. With the aim of characterizing the role of PPAR- in GC-mediated anti-inflammatory activity, we tested the efficacy of dexamethasone (DEX), a synthetic GC specific for glucocorticoid receptor, in an experimental model of lung inflammation, carrageenan-induced pleurisy, comparing mice lacking PPAR- (PPAR-KO) with wild-type (WT) mice. We also tested the possible synergism of combined treatment with DEX and clofibrate, a PPAR- agonist. Results indicate that DEX-mediated anti-inflammatory activity is weakened in PPAR-KO mice compared with WT controls, and that is increased in WT mice when combined with PPAR- agonist treatment. In particular, DEX was less effective in PPAR-KO, compared with WT mice, as evaluated by inhibition of NF-B, of TNF- production, of cell migration, of cycloxygenase-2 (COX-2) and inducible nitric-oxide synthase activation. Interestingly enough, macrophages from PPAR-KO were less susceptible to DEX-induced COX-2 inhibition in vitro compared with WT mice. However, PPAR- transfection in PPAR-KO macrophages, with consequent receptor expression, resulted in reconstitution of susceptibility to DEX-induced COX-2 inhibition to levels comparable with that obtained in WT macrophages. It is noteworthy that the DEX effect on macrophages in vitro was significantly increased in WT cells when combined with PPAR- agonist treatment. These results indicate that PPAR- can contribute to the anti-inflammatory activity of GCs.

Received for publication September 3, 2007.

Accepted for publication November 5, 2007.

Address correspondence to: Dr. Salvatore Cuzzocrea, Dipartimento Clinico e Sperimentale di Medicina e Farmacologia, Torre Biologica, Policlinico Universitario, 98123 Messina, Italy. E-mail: salvator{at}unime.it

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