Peroxisome Proliferator-Activated Receptor-γ Activation Induces 11β-Hydroxysteroid Dehydrogenase Type 1 Activity in Human Alternative Macrophages

Objective-11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) catalyzes the intracellular reduction of inactive cortisone to active cortisol, the natural ligand activating the glucocorticoid receptor (GR). Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a nuclear receptor controlling inflammation, lipid metabolism, and the macrophage polarization state. In this study, we investigated the impact of macrophage polarization on the expression and activity of 11 beta-HSD1 and the role of PPAR gamma therein. Methods and Results-11 beta-HSD1 gene expression is higher in proinflammatory M1 and anti-inflammatory M2 macrophages than in resting macrophages, whereas its activity is highest in M2 macrophages. Interestingly, PPAR gamma activation induces 11 beta-HSD1 enzyme activity in M2 macrophages but not in resting macrophages or M1 macrophages. Consequently, human M2 macrophages displayed enhanced responsiveness to the 11 beta-HSD1 substrate cortisone, an effect amplified by PPAR gamma induction of 11 beta-HSD1 activity, as illustrated by an increased expression of GR target genes. Conclusion-Our data identify a positive cross-talk between PPAR gamma and GR in human M2 macrophages via the induction of 11 beta-HSD1 expression and activity. (Arterioscler Thromb Vasc Biol. 2012;32:677-685.)