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Anti-inflammatory and proliferative responses in human and ovine ovarian surface epithelial cells

Department of Reproductive and Developmental Sciences and ¹ Human Reproductive Sciences Unit, Medical Research Council, Centre for Reproductive Biology, University of Edinburgh, The Chancellor’s Building, 49 Little France Crescent, Old Dalkeith Road, Edinburgh EH16 4SB, UK and ² FibroGen, Inc., 225 Gateway Boulevard, South San Francisco, CA 94080, USA

Correspondence should be addressed to O Gubbay; Email: ogubby{at}staffmail.ed.ac.uk

The majority of ovarian cancers (>90%) are believed to derive from the ovarian surface epithelium (OSE); a single layer covering the entire surface of the ovary. At ovulation, the OSE cell layer undergoes an inflammatory response, involving cell death and growth, in order to overcome ovarian surface rupture. Abnormalities during these processes are believed to contribute to the development of tumours. Using primary cultures of OSE cells, we have compared anti-inflammatory and proliferative responses directly between human and ovine OSE cells to further establish the use of ovine OSE cells as a suitable model system for the study of human OSE cells. In order to compare effects of inflammatory stimulation, expression and activity of 11ßhydroxysteroid dehydrogenase (11ßHSD) type 1 was measured in OSE cells in response to interleukin (IL)-1. As previously identified in human OSE cells, treatment of ovine OSE cells with IL-1 stimulated a concomitant increase of 11ßHSD type 1 mRNA (31-fold; P < 0.05) and oxoreductase activity, indicating an increased production of anti-inflammatory cortisol. To compare the growth of human and ovine OSE cells, OSE cell number was measured in response to treatment with gonadotropins or growth factors. In the presence of FSH, LH or human chorionic gonadotropin (hCG), ovine and human OSE cell growth was similarly stimulated >1.2-fold (P < 0.05). In the presence of connective tissue growth factor (CTGF) and more significantly insulin growth factor I (IGF-I), human and ovine OSE cell growth was also similarly stimulated >1.2-fold (P < 0.05) and >1.5-fold (P < 0.01), respectively. The induction of both human and ovine OSE cell growth by IGF-I or hCG was further shown to be dependent on activation of the MAP kinase/extracellular-signal-regulated kinase (ERK) pathway. Stimulation of ovine OSE cell growth by hepatocyte growth factor (HGF) was similarly shown to be ERK-dependent; however, for human OSE cells, HGF only mildly stimulated ERK phosphorylation and failed to stimulate OSE cell growth. The demonstration that human and ovine OSE cells share similarities at the level of cell signalling, gene expression and cellular growth supports the use of ovine OSE cells as a suitable model for the study of human OSE cells.

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