Peroxisome Proliferator-Activated Receptor-α 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-␣ (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.

Acute Psychological Stress Accelerates Reverse Cholesterol Transport via Corticosterone-Dependent Inhibition of Intestinal Cholesterol Absorption

“…PPARα also has been found to modulate the anti-inflammatory effect of glucocorticoids in inflammatory lung and bowel models in mice. 50,51 Of note, the distinct upregulation of ABCG5 and ABCA1 induced by exogenous CORT suggested the involvement of PPARα-independent regulatory pathways. Particularly, it appeared that high levels of CORT, most likely via a coordinated effect of PPARα and LXRα, exerted redundant effects on the enterocyte net cholesterol balance (ie, by decreasing NPC1L1 gene expression levels and upregulating ABC transporters).…”

PPARα blocks glucocorticoid receptor α-mediated transactivation but cooperates with the activated glucocorticoid receptor α for transrepression on NF-κB

“…S1C). Recently, Riccardi and colleagues (11) tested the efficacy of DEX in carrageenan-induced pleurisy in PPAR␣ KO and WT mice. These authors found that the DEXmediated antiinflammatory activity was lower in PPAR␣ KO compared with WT mice.…”

Lipids Derived from Virulent Francisella tularensis Broadly Inhibit Pulmonary Inflammation via Toll-Like Receptor 2 and Peroxisome Proliferator-Activated Receptor α

“…Additionally, others have shown that activation of PPAR␥ by other microbial ligands induces suppression of host inflammatory responses in vitro and in vivo (22). The presence of PPAR␣ is required for modulation of inflammation following exposure to LPS or sepsis in vivo (23)(24)(25)(26). Therefore, we hypothesized that suppression of inflammatory responses mediated by SchuS4 lipids in macrophages may require either PPAR␥ or PPAR␣.…”