OVARIAN-STEROID HORMONES REGULATE GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR SYNTHESIS BY UTERINE EPITHELIAL-CELLS IN THE MOUSE

Uterine epithelial cells have been shown by in vitro studies to be a p otent source of the inflammatory cytokine granulocyte-macrophage colon y-stimulating factor (GM-CSF), and the luminal and glandular epitheliu m has been confirmed as the predominant site of GM-CSF expression in t he intact endometrium by in situ hybridization. To examine the role of ovarian steroid hormones in GM-CSF synthesis, GMCSF bioactivity has b een measured in the supernatants of short-term primary cultures of end ometrial cells prepared from mice in which steroid levels were perturb ed by ovariectomy and steroid replacement or by steroid antagonists. G M-CSF production was found to fluctuate in cells harvested at differen t times during the estrous cycle, peaking at estrus. Endometrial cells derived from ovariectomized mice produced 25-fold less GM-CSF than di d cells from estrous mice, and production was increased if ovariectomi zed mice were pretreated with estrogen, but not progesterone, 3 h or m ore before harvest. This estrogen-induced increase was inhibited by co administration of progesterone or by induction of a decidual response and was blocked by the estrogen antagonist ZK 119,010. By contrast, pr etreatment of mice with the anti-progestin RU486 significantly elevate d GM-CSF output in cells from ovariectomized mice given estrogen and p rogesterone in combination and antagonized the inhibition of GM-CSF re lease seen in cells harvested from mice treated with hCG. These studie s demonstrate that GM-CSF synthesis and/or release by uterine epitheli al cells is stimulated by estrogen, with progesterone having a moderat e inhibitory effect. Analysis of GM-CSF mRNA expression in uterine epi thelial cell cultures and in intact uteri from steroid hormone-treated ovariectomized mice by quantitative reverse transcription-polymerase chain reaction indicated that the effects of estrogen and progesterone on GM-CSF release are mediated at least in part at the transcriptiona l level. These findings implicate GM-CSF as a local mediator of steroi d-driven remodeling events in the cycling and preimplantation endometr ium, possibly acting through the recruitment and behavioral regulation of granulocytes and macrophages.