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.