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In Vivo and in Vitro Evidence Suggest That HB-EGF Regulates Endometrial Expression of Human Decay-Accelerating Factor

Departments of Obstetrics and Gynecology (S.L.Y.) and Statistics (P.L.S.), Columbia, Missouri 65212; Department of Obstetrics and Gynecology, University of North Carolina (B.A.L., M.A.F., W.R.M.), Chapel Hill, North Carolina 27599; The Permanente Medical Group, Inc. (M.J.M.), Sacramento, California 95815; Department of Obstetrics and Gynecology, University of California (M.J.M.), Davis, California 95817; and Department of Obstetrics and Gynecology, University of Texas Medical Branch (B.J.N.), Galveston, Texas 77555

Address all correspondence and requests for reprints to: Dr. Steven L. Young, Department of Obstetrics and Gynecology, University of Missouri, N625 HSC, 1 Hospital Drive, Columbia, Missouri 65212. E-mail: . youngst{at}health.missouri.edu

Abstract

Human endometrium expresses the critical complement component C3 in a cyclic fashion, with the highest expression in the secretory phase. As activated complement can kill cells, self or foreign, the secretory endometrial epithelium protects itself by concomitant expression of complement-protective proteins. The objectives of our present study were to describe the spatial and temporal regulation of the complement-protective protein decay-accelerating factor (DAF) in human endometrium and to identify local regulators of its expression. To describe the cyclic regulation of DAF, immunohistochemistry was performed using the IH4 monoclonal antibody on secretory phase endometrial biopsies taken from normal fertile volunteers in LH-timed cycles (n = 114). DAF expression in human endometrium was predominantly localized to the apical membrane of glandular and luminal epithelium. DAF expression, as assessed by histological scoring analysis, was minimal in the proliferative and early secretory phases and increased markedly on approximately day LH +7 (lumen) and LH +8 (glands). Maximal expression was seen in both glands and lumen by LH +8, and this persisted into menses. Using the RL95-2 endometrial epithelial cancer cell line as a model system, we next examined the cellular regulation of DAF. Treatment with E2 and progesterone, alone or in combination, had little effect on DAF expression. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) treatment increased cell surface and total DAF protein, increasing the signal by 260% on flow cytometry and by 200% on Western blot analysis. Stimulation of DAF protein expression was dose dependent, with maximal expression seen at 1 ng/ml. The stimulatory effects of HB-EGF were also observed at the mRNA level. EGF had effects similar to those of HB-EGF on DAF mRNA and protein expression, suggesting that the HB-EGF effect was mediated at least in part by the Her1 EGF receptor subunit. These studies suggest that DAF expression in the midsecretory phase is stimulated by HB-EGF or other members of the EGF family and may function to protect the epithelial integrity of human endometrium in the face of increased complement expression.

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