7beta-hydroxy-epiandrosterone modulation of 15-deoxy-delta12,14-prostaglandin J2, prostaglandin D2 and prostaglandin E2 production from human mononuclear cells.
7beta-hydroxy-epiandrosterone (7beta-OH-EPIA) has been shown to be cytoprotective in various organs including the brain. It has also been shown that prostaglandin D2 (PGD2) and its spontaneous metabolite 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) are also cytoprotective. It is possible that these prostaglandins derived from circulating mononuclear cells may mediate the actions of 7beta-OH-EPIA. The aim of this study, therefore, was to ascertain the effect of 7beta-OH-EPIA (in the absence or presence of tumour necrosis factor-alpha (TNF-alpha)), a pro-inflammatory stimulus, on the biosynthesis of PGD2, PGE2 and 15d-PGJ2 from human mononuclear cells. Prostaglandins were measured by enzyme immunoassay (EIA). 7beta-OH-EPIA alone induced a concentration-dependant increase in the production of PGD2. TNF-alpha increased PGD2 levels which were enhanced by 7beta-OH-EPIA. 7beta-OH-EPIA increased 15d-PGJ2 levels both in the absence and presence of TNF-alpha. 7beta-OH-EPIA alone had no effect on PGE2 biosynthesis but suppressed TNF-alpha-induced PGE2 circa 50%. 7beta-OH-EPIA also increased the level of free arachidonic acid and radiolabelled prostaglandins in cells pre-incubated with radiolabelled arachidonic acid, indicating that the increase may occur via the enhanced release of substrate arachidonic acid. 7beta-OH-EPIA did not affect levels of the anti-inflammatory cytokine IL-10 indicating that this is an unlikely mechanism by which 7beta-OH-EPIA induces its actions but more likely exerts its effects via the production of cytoprotective prostaglandins.
Davidson
Jillian
J
Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, United Kingdom.
Wulfert
Ernst
E
Rotondo
Dino
D
D000738:Androsterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; C531236:7-hydroxyandrosterone; C508609:IL10 protein, human; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016718:Arachidonic Acid; D000738:Androsterone; D015232:Dinoprostone; D015230:Prostaglandin D2