title: Novel roles for hypoxia and prostaglandin E2 in the regulation of IL-8 during endometrial repair.
abstract: The endometrium has a remarkable capacity for efficient repair; however, factors involved remain undefined. Premenstrual progesterone withdrawal leads to increased prostaglandin (PG) production and local hypoxia. Here we determined human endometrial expression of interleukin-8 (IL-8) and the roles of PGE(2) and hypoxia in its regulation. Endometrial biopsy specimens (n = 51) were collected. Endometrial cells and explants were exposed to 100 nmol/L of PGE(2) or 0.5% O(2). The endometrial IL-8 concentration peaked during menstruation (P < 0.001) and had a significant proangiogenic effect. IL-8 was increased by PGE(2) and hypoxia in secretory but not proliferative explants, which suggests that exposure to progesterone is essential. In vitro progesterone withdrawal induced significant IL-8 up-regulation in proliferative explants primed with progestins, but only in the presence of hypoxia. Epithelial cells treated simultaneously with PGE(2) and hypoxia demonstrated synergistic increases in IL-8. Inhibition of HIF-1 by short hairpin RNA abolished hypoxic IL-8 induction, and inhibition of NF-κB by an adenoviral dominant negative inhibitor decreased PGE(2)-induced IL-8 expression (P > 0.05). Increased menstrual IL-8 is consistent with a role in repair. Progesterone withdrawal, hypoxia, and PGE(2) regulate endometrial IL-8 by acting via HIF-1 and NF-κB. Hence, progesterone withdrawal may activate two distinct pathways to initiate endometrial repair.
authors.affiliation: University of Edinburgh Centre for Reproductive Biology, The Queen's Medical Research Institute, Edinburgh, Scotland.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Maybin
authors.forename: Nikhil
authors.initials: N
authors.lastname: Hirani
authors.forename: Henry N
authors.initials: HN
authors.lastname: Jabbour
authors.forename: Hilary O D
authors.initials: HO
authors.lastname: Critchley
mesh_terms: D000328:Adult; D015687:Cell Hypoxia / Q000187:drug effects; D015232:Dinoprostone / Q000494:pharmacology*; D004448:Echinomycin / Q000494:pharmacology; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D008598:Menstruation / Q000187:drug effects; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011374:Progesterone / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015203:Reproducibility of Results; D015854:Up-Regulation / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects*
chemical_list: C508606:CXCL8 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011374:Progesterone; D004448:Echinomycin; D015232:Dinoprostone