Regulation of 3beta-hydroxysteroid dehydrogenase type 1 and type 2 gene expression and function in the human ovarian surface epithelium by cytokines

Georgia Papacleovoulou, Kirsten Hogg, K Scott Fegan, Hilary O D Critchley, Stephen G Hillier, J Ian Mason

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)379-392
Number of pages14
JournalMOLECULAR HUMAN REPRODUCTION
Volume15
Issue number6
DOIs
Publication statusPublished - Jun 2009

Keywords

  • 17-Hydroxysteroid Dehydrogenases
  • Adult
  • Cell Line
  • Cells, Cultured
  • Cytokines
  • Epithelium
  • Female
  • Gene Expression Regulation
  • Humans
  • Immunohistochemistry
  • In Vitro Techniques
  • Interleukin-1alpha
  • Interleukin-4
  • Middle Aged
  • Ovarian Neoplasms
  • Ovary
  • Young Adult

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