title: The mitogenic potential of heparin-binding epidermal growth factor in the human endometrium is mediated by the epidermal growth factor receptor and is modulated by tumor necrosis factor-alpha.
abstract: Heparin-binding epidermal growth factor (HB-EGF), a member of the epidermal growth factor (EGF) family, is implicated in a variety of biological processes, including reproduction. Previous studies describe increased levels of HB-EGF in the human endometrium during the midsecretory stage of the menstrual cycle, suggesting a function for HB-EGF in implantation of the human blastocyst. Here we have investigated the expression and function of the soluble and transmembrane forms of HB-EGF in the human endometrium. We show that the expression of the transmembrane form of HB-EGF in the human endometrium is modulated according to the stage of the menstrual cycle. We present data demonstrating that both the soluble and transmembrane forms of HB-EGF induce DNA synthesis in human endometrial stromal cells. Furthermore, TNFalpha has a cooperative effect on HB-EGF, EGF, TGFalpha, and betacellulin-induced DNA synthesis in stromal cells, suggesting roles for the EGF family and TNFalpha in regeneration and maturation of human endometrium. Induction of DNA synthesis by HB-EGF and its modulation by TNFalpha in endometrial stromal cells are mediated by the EGF receptor and not the HB-EGF receptor ErbB4. Our data suggest key functions for HB-EGF, TNFalpha, and the EGF receptor in endometrial maturation, via autocrine/paracrine and juxtacrine pathways, in preparation for embryo implantation.
authors.affiliation: Nuffield Department of Obstetrics and Gynecology, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom OX3 9DU.
authors.forename: Katya
authors.initials: K
authors.lastname: Chobotova
authors.forename: Mary-Elizabeth
authors.initials: ME
authors.lastname: Muchmore
authors.forename: Janet
authors.initials: J
authors.lastname: Carver
authors.forename: Hyung-J
authors.initials: HJ
authors.lastname: Yoo
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Manek
authors.forename: William J
authors.initials: WJ
authors.lastname: Gullick
authors.forename: David H
authors.initials: DH
authors.lastname: Barlow
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Mardon
mesh_terms: D000328:Adult; D066259:Betacellulin; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004717:Endometrium / Q000166:cytology / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism / Q000502:physiology*; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D008597:Menstrual Cycle / Q000378:metabolism; D008875:Middle Aged; D008934:Mitogens / Q000502:physiology*; D010766:Phosphorylation; D066247:Receptor, ErbB-4; D012995:Solubility; D017154:Stromal Cells / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: C587851:BTC protein, human; D066259:Betacellulin; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008934:Mitogens; D016211:Transforming Growth Factor alpha; D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor; D004247:DNA; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4