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Thalidomide Inhibits Tumor Necrosis Factor--Induced Interleukin-8 Expression in Endometriotic Stromal Cells, Possibly through Suppression of Nuclear Factor-B Activation

NetForce Co. Ltd. (T.Y., H.M., K.W., K.I.), Nagoya, Aichi 453-0801, Japan; Department of Obstetrics and Gynecology (H.K., M.S., N.K., T.T.), Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan; Computer Technology Integration Co. Ltd. (T.K.), Nagoya, Aichi 450-0003, Japan; and Department of Knowledge-Based Information Engineering (N.K., H.S.), Toyohashi University of Technology, Toyohashi Aichi 441-8580, Japan

Address all correspondence and requests for reprints to: Hiroshi Kobayashi, M.D., Ph.D., Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Handayama 1-20-1, Hamamatsu, Shizuoka 431-3192, Japan. E-mail: hirokoba{at}hama-med.ac.jp.

Objective: Endometriosis, a common disease among women of reproductive age, is characterized by the presence of endometrial-like tissue outside the uterus. TNF- induces IL-8 production in endometriotic cells through nuclear factor-B (NF-B) activation. Thalidomide (Thal) inhibits inflammation by down-regulating the expression of proinflammatory cytokines in tumor cells and inflammatory cells. However, the mechanism of Thal action in human endometriotic stromal cells has not yet been elucidated.

Main Outcome Measures: We examined whether Thal abrogates TNF--induced up-regulation of IL-8 expression in endometriotic stromal cells.

Results: Here, we show 1) that treatment of endometriotic stromal cells with TNF- increased the expression of phosphorylated IB and degradation of total IB, which in turn activates NF-B; 2) Thal significantly inhibits the TNF--induced expression of phosphorylated IB and degradation of IB; 3) TNF- activation induced increased nuclear translocation of NF-B, which was inhibited by pretreatment with either Thal or N-tosyl-L-phenylalanine chloromethyl ketone, an NF-B inhibitor. Thal did not enhance the N-tosyl-L-phenylalanine chloromethyl ketone’s action; and 4) Pretreatment with Thal reduced TNF--induced IL-8 protein production as well as mRNA expression.

Conclusion: The current study showed for the first time that Thal treatment attenuated the expression of IL-8 by reducing TNF--induced NF-B activation.

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