Regulation of 3β-hydroxysteroid dehydrogenase type 1 and type 2 gene expression and function in the human ovarian surface epithelium by cytokines
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
1Correspondence address. Tel: +44-131-242-6442; Fax: +44-131-242-6441; E-mail: j.i.mason{at}ed.ac.uk
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. 3β-Hydroxysteroid dehydrogenase (3β-HSD) drives the intracrine generation of progestogens and androgens that potentially affect cell survival and proliferation. We therefore investigated the regulation of 3β-HSD along with downstream steroid signalling in hOSE. Double immunofluorescence of cultured primary hOSE cells confirmed the expression of 3β-HSD protein Interleukin (IL). IL-1
treatment of primary cells to mimic ovulation-associated inflammation suppressed 3β-HSD1 expression and stimulated 3β-HSD2 mRNA (P < 0.001), without affecting total 3β-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 3β-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. 3β-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 3β-HSD expression in EOC although further studies are required for confirmation.
Key words: human ovarian surface epithelium/3β-HSD/ovulation/cytokines/ovarian cancer
Submitted on October 21, 2008; resubmitted on March 11, 2009; accepted on March 16, 2009.