Peroxisome proliferator-activated receptor-γ activation induces 11β-hydroxysteroid dehydrogenase type 1 activity in human alternative macrophages.

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Chinetti-Gbaguidi, Giulia | Bouhlel, Mohamed Amine | Copin, Corinne | Duhem, Christian | Derudas, Bruno | Neve, Bernardette | Noel, Benoit | Eeckhoute, Jerome | Lefebvre, Philippe | Seckl, Jonathan, R. | Staels, Bart

Edité par CCSD ; American Heart Association -

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

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