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Interleukin-8 Induces Proliferation of Endometrial Stromal Cells: a Potential Autocrine Growth Factor¹

Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06520

Address all correspondence and requests for reprints to: Aydin Arici, Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520-8063. E-mail: Aydin.Arici{at}Yale.edu

Abstract

Proliferation of endometrium is dependent on sex steroid hormones, but specific growth factors are likely to play an important role in regulating this process. A number of cytokines and growth factors are synthesized in the endometrium in response to sex steroid hormones and act to regulate endometrial function. Endometrial cells produce interleukin-8 (IL-8) both in vivo and in vitro. We hypothesized that IL-8, a neutrophil chemoattractant/activating factor and a potent angiogenic agent that has been shown to stimulate growth in other cell types, may directly stimulate proliferation of endometrial cells. We first investigated the effect of IL-8 and mouse antihuman-IL-8 neutralizing antibody on endometrial stromal cell proliferation using both a colorimetric assay and thymidine uptake. We then investigated the modulation of endometrial stromal cell IL-8 production and proliferation by antisense oligonucleotides specific for IL-8. There was a concentration-dependent increase of cell proliferation with IL-8 (2-fold at 1 ng/mL; P < 0.01 between control and concentrations above 0.01 ng/mL) and a concentration-dependent inhibition of cell proliferation with anti-IL-8 antibody (to 30% of the control at 1 µg/mL; P < 0.01 between control and concentrations above 0.1 µg/mL). IL-8 antisense oligonucleotide treatment decreased IL-8 production by endometrial stromal cells in culture as well as cell proliferation when it is compared with scrambled (nonsense) oligonucleotide treatment (P < 0.01). Addition of IL-8 (1 ng/mL) reversed the proliferation inhibitory effect of IL-8 antisense oligonucleotides. We propose that IL-8 may act as an autocrine growth factor in the endometrium, and suggest that it may also play a role in the pathogenesis of endometriosis.

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