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


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.


CONCLUSIONS
Our data identify a positive cross-talk between PPARγ and GR in human M2 macrophages via the induction of 11β-HSD1 expression and activity.
Université Lille Nord de France, Lille, France.
Giulia
G
Chinetti-Gbaguidi
Mohamed Amine
MA
Bouhlel
Corinne
C
Copin
Christian
C
Duhem
Bruno
B
Derudas
Bernadette
B
Neve
Benoit
B
Noel
Jerome
J
Eeckhoute
Philippe
P
Lefebvre
Jonathan R
JR
Seckl
Bart
B
Staels
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D003348:Cortisone / Q000378:metabolism; D004790:Enzyme Induction; D017930:Genes, Reporter; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection
C508598:IL4 protein, human; D047495:PPAR gamma; D011965:Receptors, Glucocorticoid; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D015847:Interleukin-4; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; D003348:Cortisone; D006854:Hydrocortisone