• Fritz Wieser, Jean-Louis Vigne, Isabelle Ryan, Daniela Hornung, Schima Djalali, and Robert N Taylor.
• Division of Gynecological Endocrinology and Reproductive Medicine, University of Vienna, Austria.
• J. Clin. Endocrinol. Metab. 2005 Dec 1; 90 (12): 6441-7.

ContextThe nuclear factor-kappaB (NF-kappaB) pathway is a critical mediator of RANTES (regulated on activation, normal T cell expressed and secreted) gene regulation and therefore represents a potential target for therapy of endometriosis-associated symptoms.ObjectiveThe objective of this study was to investigate the effects of the antiinflammatory drug sulindac on NF-kappaB activation, NF-kappaB-mediated gene expression, RANTES gene and protein expression in endometrial stromal cells isolated from women with endometriosis, and unaffected controls.DesignThis was a clinical experimental study.SettingThe study was conducted at a university hospital.ResultsThe inflammatory response in endometriosis is augmented by a 5-fold increased TNFalpha-induced RANTES secretion from ectopic endometriotic stromal cells, compared with normal endometrial stromal cells (P < 0.05). Western blot analysis revealed basal activation of NF-kappaB in endometriotic cells, which could be suppressed by sulindac. EMSAs showed that sulindac dramatically decreased NF-kappaB activation and diminished TNFalpha and IL-1beta-induced NF-kappaB DNA binding activity. Sulindac pretreatment resulted in a significant decrease in TNFalpha-induced luciferase activity of NF-kappaB response element and -477 bp RANTES promoter constructs in normal and endometriotic stromal cells. The addition of sulindac to IL-1beta- and TNFalpha-treated endometriotic stromal cells also resulted in a 4-fold inhibition of RANTES protein secretion (P < 0.05).ConclusionsWe have demonstrated that sulindac exerts strong antiinflammatory effects by suppression of NF-kappaB translocation, inhibition of NF-kappaB-mediated gene transcription, RANTES gene expression, and protein secretion in normal and endometriotic stromal cells. These results suggest that drugs targeting the NF-kappaB pathway may be beneficial in the treatment of endometriosis-associated symptoms.

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