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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 2 824-829
Copyright © 2000 by The Endocrine Society

Original Studies

Tumor Necrosis Factor-{alpha} Promotes Proliferation of Endometriotic Stromal Cells by Inducing Interleukin-8 Gene and Protein Expression

Tomio Iwabe, Tasuku Harada, Toshiyuki Tsudo, Yorie Nagano, Souichi Yoshida, Masahiro Tanikawa and Naoki Terakawa

Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago 683-8504, Japan

Address all correspondence and requests for reprints to: Tomio Iwabe, M.D, Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago 683-8504, Japan.

Endometriosis, a common disease among women of reproductive age, is characterized by the presence of endometrial-like tissue outside the uterus. We and others showed that several cytokine levels, including interleukin-8 (IL-8) and tumor necrosis factor-{alpha} (TNF{alpha}), are elevated in the peritoneal fluid of women with endometriosis compared with those in women without endometriosis. We also demonstrated that the addition of IL-8 to the culture medium stimulated the proliferation of cultured endometriotic stromal cells. TNF{alpha} is a multipotent cytokine that induces IL-8 production in various cell types. Therefore, we hypothesized that TNF{alpha} may also contribute to the pathogenesis of endometriosis by inducing the production of IL-8. To test this hypothesis, we analyzed the peritoneal fluid concentrations of IL-8 and TNF{alpha} using enzyme-linked immunosorbent assay (ELISA). We observed a significant correlation between the levels of TNF{alpha} and IL-8 in the peritoneal fluid of endometriosis patients. We also obtained the endometriotic stromal cells from chocolate cyst linings of the ovary. The expression of the receptors for TNF{alpha} (TNFR) was examined by RT-PCR. We observed the expression of both TNFR-I and TNFR-II genes in endometriotic stromal cells. The expression of IL-8 gene and protein was analyzed by Northern blot hybridization and enzyme-linked immunosorbent assay, respectively. TNF{alpha} induced the gene and protein expression of IL-8 in endometriotic stromal cells in a dose-dependent fashion. The addition of TNF{alpha} promoted the proliferation of the endometriotic stromal cells, and the stimulatory effects of TNF{alpha} were abolished by adding anti-IL-8 antibody. We demonstrated for the first time that TNF{alpha} stimulated proliferation of endometriotic stromal cells through induction of IL-8 gene and protein expression. We concluded that the TNF{alpha} may be one of the essential factors for the pathogenesis of endometriosis.




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