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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-

Nuffield Department of Obstetrics and Gynecology, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom OX3 9DU; and Research School of Biosciences, University of Kent (W.J.G.), Canterbury, Kent, United Kingdom CT2 7NJ

Address all correspondence and requests for reprints to: Dr. Helen J. Mardon, Nuffield Department of Obstetrics and Gynecology, University of Oxford, Women’s Center, Level 3, John Radcliffe Hospital, Headington, Oxford, United Kingdom OX3 9DU E-mail: hmardon{at}molbiol.ox.ac.uk.

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, TNF has a cooperative effect on HB-EGF, EGF, TGF, and betacellulin-induced DNA synthesis in stromal cells, suggesting roles for the EGF family and TNF in regeneration and maturation of human endometrium. Induction of DNA synthesis by HB-EGF and its modulation by TNF 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, TNF, and the EGF receptor in endometrial maturation, via autocrine/paracrine and juxtacrine pathways, in preparation for embryo implantation.

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