Regulation of 3beta-hydroxysteroid dehydrogenase type 1 and type 2 gene expression and function in the human ovarian surface epithelium by cytokines.
The human ovarian surface epithelium (hOSE) is a squamous-to-cuboidal layer that surrounds the ovary. hOSE undergoes injury and repair cycles as a result of ovulation-induced inflammation, an event relevant to the development of epithelial ovarian cancer (EOC). Locally produced steroids mediate the response to inflammation. 3beta-Hydroxysteroid dehydrogenase (3beta-HSD) drives the intracrine generation of progestogens and androgens that potentially affect cell survival and proliferation. We therefore investigated the regulation of 3beta-HSD along with downstream steroid signalling in hOSE. Double immunofluorescence of cultured primary hOSE cells confirmed the expression of 3beta-HSD protein Interleukin (IL). IL-1alpha treatment of primary cells to mimic ovulation-associated inflammation suppressed 3beta-HSD1 expression and stimulated 3beta-HSD2 mRNA (P < 0.001), without affecting total 3beta-HSD protein and activity or androgen or progesterone receptor (PR) mRNA levels. Conversely, IL-4 as a proxy for a post-ovulatory healing cytokine increased both 3beta-HSD transcripts, total protein and activity (P < 0.01). IL-4 also suppressed androgen receptor expression (P < 0.01) without affecting that of the PR, thereby potentially sustaining both progesterone biosynthesis and its underlying signalling in the ovarian surface. 3beta-HSD protein was immunodetectable in primary ascites of women who were diagnosed with EOC but both mRNA transcripts were diminished relative to normal cells (P < 0.05). Notably, this difference was countered by IL-4 treatment (P < 0.01). We conclude that stimulation by IL-4 could be physiologically relevant to post-ovulatory ovarian healing and suggest a novel therapeutic strategy for the activation of progesterone-associated apoptosis in ovarian cancer. Also, our results suggest an attenuation of 3beta-HSD expression in EOC although further studies are required for confirmation.
Papacleovoulou
Georgia
G
Centre for Reproductive Biology, Reproductive and Developmental Sciences, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Hogg
Kirsten
K
Fegan
K Scott
KS
Critchley
Hilary O D
HO
Hillier
Stephen G
SG
Mason
J Ian
JI
D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004848:Epithelium / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D053582:Interleukin-1alpha / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics; D010053:Ovary / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
D016207:Cytokines; D053582:Interleukin-1alpha; D015847:Interleukin-4; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase