Inhibition of Carrageenan-Induced Cutaneous Inflammation by PPAR Agonists Is Dependent on Hepatocyte-Specific Retinoid X ReceptorAlpha

It has been proposed that PPAR-dependent, accelerated catabolism of proinflammatory mediators may contribute to the fast resolution of inflammation. Because retinoid X receptors are obligate heterodimer partners of PPARs, we investigated the impact of deleting hepatocyte-specific RXRalpha on the antiedema effect of PPAR agonists. In wild-type mice (WT), pretreatment with the PPARalpha agonist perfluorooctanoic acid diminished carrageenan-induced paw edema by 66 +/- 10%. This effect was essentially absent (13 +/- 8%) in hepatocyte-specific RXRalpha-deficient mice. Similarly, pretreatment of WT mice with the PPARdelta agonist L-783483 or the PPARgamma agonist L-805645 caused 54 +/- 1% and 38 +/- 8% reduction in carrageenan-induced paw edema, respectively. These effects were also significantly diminished or absent in hepatocyte-specific RXRalpha-deficient mice. In contrast, aspirin reduced carrageenan-induced paw edema equally in WT and hepatocyte-specific RXRalpha-deficient mice. The identification of RXRalpha as an important factor involved in the antiedema effect produced by agonists of the three PPAR subtypes is a significant achievement towards the goal of designing novel, effective anti-inflammatory drugs.