OBJECTIVE: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the intracellular reduction of inactive cortisone to active cortisol, the natural ligand activating the glucocorticoid receptor (GR). Peroxisome proliferator- activated receptor-gamma (PPARgamma) 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 11beta-HSD1 and the role of PPARgamma therein. METHODS AND RESULTS: 11beta-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, PPARgamma activation induces 11beta-HSD1 enzyme activity in M2 macrophages but not in resting macrophages or M1 macrophages. Consequently, human M2 macrophages displayed enhanced responsiveness to the 11beta-HSD1 substrate cortisone, an effect amplified by PPARgamma induction of 11beta-HSD1 activity, as illustrated by an increased expression of GR target genes. CONCLUSION: Our data identify a positive cross-talk between PPARgamma and GR in human M2 macrophages via the induction of 11beta-HSD1 expression and activity.