11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyses the intracellular reduction of inactive cortisone to active cortisol, the natural ligand activating the glucocorticoid receptor (GR). Peroxisome Proliferator-Activated Receptor gamma (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 PPAR therein.
Methods and Results
11β-HSD1 gene expression is higher in pro-inflammatory M1 and anti-inflammatory M2 macrophages than in resting macrophages (RM), whereas its activity is highest in M2 macrophages. Interestingly, PPARγ activation induces 11β-HSD1 enzyme activity in M2 macrophages, but not in RM or M1 macrophages. Consequently, human M2 macrophages displayed enhanced responsiveness to the 11β-HSD1 substrate cortisone, an effect amplified by PPAR -induction of 11β-HSD1 activity, as illustrated by an increased expression of GR target genes.
Our data identify a positive cross-talk between PPARγ and GR in human M2 macrophages via the induction of 11β-HSD1 expression and activity.
Keywords: 11-beta-Hydroxysteroid Dehydrogenase Type 1, biosynthesis, genetics, Cells, Cultured, Cortisone, metabolism, Enzyme Induction, Genes, Reporter, Humans, Hydrocortisone, metabolism, Inflammation, enzymology, genetics, immunology, Interleukin-4, metabolism, Macrophages, drug effects, enzymology, immunology, PPAR gamma, agonists, genetics, metabolism, RNA Interference, Receptors, Glucocorticoid, metabolism, Thiazolidinediones, pharmacology, Time Factors, Transfection
Keywords: 11beta-HSDI, PPARgamma, human alternative macrophages, inflammation, GR