title: Peroxisome proliferator-activated receptor-alpha contributes to the anti-inflammatory activity of glucocorticoids.
abstract: 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-alpha (PPAR-alpha), 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-alpha 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-alpha (PPAR-alphaKO) with wild-type (WT) mice. We also tested the possible synergism of combined treatment with DEX and clofibrate, a PPAR-alpha agonist. Results indicate that DEX-mediated anti-inflammatory activity is weakened in PPAR-alphaKO mice compared with WT controls, and that is increased in WT mice when combined with PPAR-alpha agonist treatment. In particular, DEX was less effective in PPAR-alphaKO, compared with WT mice, as evaluated by inhibition of NF-kappaB, of TNF-alpha production, of cell migration, of cycloxygenase-2 (COX-2) and inducible nitric-oxide synthase activation. Interestingly enough, macrophages from PPAR-alphaKO were less susceptible to DEX-induced COX-2 inhibition in vitro compared with WT mice. However, PPAR-alpha transfection in PPAR-alphaKO 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-alpha agonist treatment. These results indicate that PPAR-alpha can contribute to the anti-inflammatory activity of GCs.
authors.affiliation: Dipartimento Clinico e Sperimentale di Medicina e Farmacologia, Torre Biologica, Policlinico Universitario, 98123 Messina, Italy. salvator@unime.it
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Stefano
authors.initials: S
authors.lastname: Bruscoli
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Concetta
authors.initials: C
authors.lastname: Crisafulli
authors.forename: Valerio
authors.initials: V
authors.lastname: Donato
authors.forename: Rosanna
authors.initials: R
authors.lastname: Di Paola
authors.forename: Enrico
authors.initials: E
authors.lastname: Velardi
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Nocentini
authors.forename: Carlo
authors.initials: C
authors.lastname: Riccardi
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000819:agonists / Q000096:biosynthesis* / Q000172:deficiency; D010998:Pleurisy / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D047493:PPAR alpha