7beta-Hydroxy-epiandrosterone-mediated regulation of the prostaglandin synthesis pathway in human peripheral blood monocytes.
7alpha-Hydroxy-DHEA, 7beta-hydroxy-DHEA and 7beta-hydroxy-EpiA are native metabolites of dehydroepiandrosterone (DHEA) and epiandrosterone (EpiA). Since numerous steroids are reported to interfere with inflammatory and immune processes, our objective was to test the effects of these hydroxysteroids on prostaglandin (PG) production and related enzyme gene expression. Human peripheral blood monocytes were cultured for 4 and 24 h in the presence of each of the steroids (1-100 nM), with and without addition of TNF-alpha (10 ng/mL). Levels of PGE(2), PGD(2) and 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) were measured in the incubation medium, and cell content of cyclooxygenase (COX-2), and PGE and PGD synthases (m-PGES1, H-PGDS, L-PGDS), and peroxisome proliferator activated receptor (PPAR-gamma) was assessed by quantitative RT-PCR and Western blots. Addition of TNF-alpha resulted in elevated PG production and increased COX-2 and m-PGES1 levels. Among the three steroids tested, only 7beta-hydroxy-EpiA decreased COX-2, m-PGES1 and PPAR-gamma expression while markedly decreasing PGE(2) and increasing 15d-PGJ(2) production. These results suggest that 7beta-hydroxy-EpiA is a native trigger of cellular protection through simultaneous activation of 15d-PGJ(2) and depression of PGE(2) synthesis, and that these effects may be mediated by activation of a putative receptor, specific for 7beta-hydroxy-EpiA.
Chaire de Génie Biologique, EA-3199, Conservatoire National des Arts et Métiers, 2 rue Conté, 75003 Paris, France.
Sandrine
S
Le Mée
Olivier
O
Hennebert
Claude
C
Ferrec
Ernst
E
Wülfert
Robert
R
Morfin
D000738:Androsterone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D003470:Culture Media / Q000032:analysis / Q000737:chemistry; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000096:biosynthesis; D015232:Dinoprostone / Q000032:analysis / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000032:analysis / Q000096:biosynthesis; D054834:Lipocalins / Q000032:analysis / Q000096:biosynthesis; D008954:Models, Biological; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D047495:PPAR gamma / Q000032:analysis; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000032:analysis / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D000071876:Prostaglandin-E Synthases; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C477819:15-deoxyprostaglandin J2; C531236:7-hydroxyandrosterone; D003470:Culture Media; D054834:Lipocalins; D047495:PPAR gamma; D014409:Tumor Necrosis Factor-alpha; D000738:Androsterone; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone; D015230:Prostaglandin D2