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Tumor Necrosis Factor--Induced Interleukin-8 (IL-8) Expression in Endometriotic Stromal Cells, Probably through Nuclear Factor-B Activation: Gonadotropin-Releasing Hormone Agonist Treatment Reduced IL-8 Expression

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

Address all correspondence and requests for reprints to: Yasuko Sakamoto, M.D., Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago 683-8504, Japan. E-mail: sakayasu{at}grape.med.tottori-u.ac.jp.

Endometriosis, a common disease among women of reproductive age, is characterized by the presence of endometrial-like tissue outside the uterus. We previously reported that TNF promoted proliferation of endometriotic stromal cells by inducing IL-8 gene and protein expression. We hypothesize that TNF may induce IL-8 production in endometriotic cells through nuclear factor-B (NF-B) activation. Western blot analyses and electrophoretic mobility shift assays revealed that incubation with TNF induced the expression of phosphorylated inhibitor B (p-IB) and activation of NF-B in endometriotic stromal cells. The NF-B inhibitor, N-tosyl-L-phenylalanine chloromethyl ketone, reduced TNF-induced IL-8 gene and protein expression. The medical treatment of endometriosis with GnRH agonist (GnRHa) has been shown to induce hypoestrogenemia and reduce the observable number of endometriotic implants. We compare the expression of IL-8 gene and protein in endometriotic stromal cells of patients treated with GnRHa and those of patients without treatment before laparoscopic cystectomy for endometrioma. The addition of TNF (0.1 ng/ml) significantly increased protein and gene expression of IL-8 in the cells of patients without GnRHa treatment, but this expression was not observed in the cells of patients with GnRHa. The addition of estradiol (E2; 10^-7 M) enhanced the expression of IL-8. However, in the cells of patients who received GnRHa treatment, TNF and E2 did not show any significant effect. In endometriotic stromal cells without GnRHa treatment, TNF and E2 increased the expression of p-IB. In contrast, TNF and E2 had no significant effect on the expression of p-IB in cells that received GnRHa treatment. These findings demonstrate that NF-B activation is critical for TNF-induced IL-8 expression in endometriotic stromal cells. The current study showed for the first time that GnRHa treatment attenuated the expression of IL-8 by reducing TNF-induced NF-B activation.

Abbreviations: E2, Estradiol; EMSA, electrophoretic mobility shift assay; FBS, fetal bovine serum; GnRHa, GnRH agonist; NF-B, nuclear factor-B; PF, peritoneal fluid; p-IB, phosphorylated inhibitor B; TPCK, N-tosyl-L-phenylalanine chloromethyl ketone.

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