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Biology of Reproduction, Vol 54, 183-196, Copyright © 1996 by Society for the Study of Reproduction
ARTICLES |
SA Robertson, G Mayrhofer and RF Seamark
Department of Obstetrics and Gynaecology, University of Adelaide, South Australia.
Uterine epithelial cells have been shown by in vitro studies to be a potent source of the inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), and the luminal and glandular epithelium has been confirmed as the predominant site of GM-CSF expression in the intact endometrium by in situ hybridization. To examine the role of ovarian steroid hormones in GM-CSF synthesis, GM- CSF bioactivity has been measured in the supernatants of short-term primary cultures of endometrial cells prepared from mice in which steroid levels were perturbed by ovariectomy and steroid replacement or by steroid antagonists. GM-CSF production was found to fluctuate in cells harvested at different times during the estrous cycle, peaking at estrus. Endometrial cells derived from ovariectomized mice produced 25- fold less GM-CSF than did cells from estrous mice, and production was increased if ovariectomized mice were pretreated with estrogen, but not progesterone, 3 h or more before harvest. This estrogen-induced increase was inhibited by coadministration of progesterone or by induction of a decidual response and was blocked by the estrogen antagonist ZK 119,010. By contrast, pretreatment of mice with the anti- progestin RU486 significantly elevated GM-CSF output in cells from ovariectomized mice given estrogen and progesterone in combination and antagonized the inhibition of GM-CSF release seen in cells harvested from mice treated with hCG. These studies demonstrate that GM-CSF synthesis and/or release by uterine epithelial cells is stimulated by estrogen, with progesterone having a moderate inhibitory effect. Analysis of GM-CSF mRNA expression in uterine epithelial 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 transcriptional level. These findings implicate GM-CSF as a local mediator of steroid-driven remodeling events in the cycling and preimplantation endometrium, possibly acting through the recruitment and behavioral regulation of granulocytes and macrophages.
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