Received for publication September 4, 2007.
Revised November 3, 2007.
Accepted for publication November 5, 2007.

PPAR- contributes to the anti-inflammatory activity of glucocorticoids

Abstract

Glucocorticoids (GCs) are effective anti-inflammatory agents widely used in therapeutic approach to treatment of acute and chronic inflammatory diseases. Previous results suggest that Peroxisome proliferator activated receptor alpha- (PPAR-), an intracellular transcription factor activated by fatty acids, plays a role in control of inflammation. With the aim to characterize the role of PPAR- in GC-mediated anti-inflammatory activity, we tested the efficacy of dexamethasone (DEX), a synthetic GC specific for GR, in an experimental model of lung inflammation, carrageenan-induced pleurisy, comparing mice lacking PPAR- (PPARKO) 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, as compared to 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 to WT mice, as evaluated by inhibition of NF-kB, of TNF- production, of cell migration, of cycloxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) activation. Interestingly enough, macrophages from PPAR-KO were less susceptible to DEX-induced COX-2 inhibition in vitro as compared to WT mice. However, PPAR-Ñ transfection in PPAR-KO macrophages, with consequent receptor expression, resulted in reconstitution of susceptibility to DEX-induced COX-2 inhibition to levels comparable to that obtained in WT macrophages. Notably, 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.

Key words: Nitric oxide, Glucorticoids/Mineralocorticoids, PPARs, NFkappaB, Immunocytochemistry, Apoptosis

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