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 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.
Robertson
S A
SA
Department of Obstetrics and Gynaecology, University of Adelaide, South Australia.
Mayrhofer
G
G
Seamark
R F
RF
D000818:Animals; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D003656:Decidua / Q000187:drug effects / Q000502:physiology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D004971:Estrus / Q000502:physiology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000235:genetics; D017403:In Situ Hybridization; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010052:Ovariectomy; D010053:Ovary / Q000378:metabolism*; D011374:Progesterone / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D014599:Uterus / Q000187:drug effects / Q000378:metabolism*
D006063:Chorionic Gonadotropin; D012333:RNA, Messenger; D011374:Progesterone; D004958:Estradiol; D016178:Granulocyte-Macrophage Colony-Stimulating Factor