Glucocorticoid receptor-mediated regulation of MMP9 gene expression in human ovarian surface epithelial cells

Objective To obtain proof-of-concept that locally produced anti-inflammatory steroids suppress ovulation-associated extracellular matrix proteases in human ovarian surface epithelial (OSE) cells. Design Primary OSE cell cultures treated with interleukin-1α (IL-1α) (500 pg/mL) as proxy for inflammation, with/without anti-inflammatory steroid (cortisol or progesterone [P], 0.01–1.0 μM). Setting Academic medical center. Patient(s) Sixteen premenopausal women (29–46 years) undergoing surgery for nonmalignant gynecological conditions. Main Outcome Measure(s) Semiquantitative extracellular matrix protease gene expression profiling with verification by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and gelatinase zymography. Result(s) Treatment with IL-1α stimulated messenger RNA (mRNA) expression of several ovulation-associated matrix metalloproteinase genes by OSE cell cultures, including gelatinase B (MMP9) but not gelatinase A (MMP2). The IL-1α-stimulated MMP9 mRNA production was suppressed by cortisol but not P. Cortisol but not P also dose-dependently suppressed IL-1α-stimulated MMP9 gelatinase activity and this effect was blocked by the glucocorticoid receptor antagonist RU486. Conclusion(s) In human OSE cells, stimulation of MMP9 gene expression and proteolytic activity by IL-1α is suppressed by anti-inflammatory cortisol through a glucocorticoid receptor-mediated mechanism. Because IL-1α also generates cortisol formation in OSE by stimulating cortisone reductase activity, these results support a role for intracrine cortisol in minimizing proteolytic damage to the OSE at ovulation.