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Sulindac Suppresses Nuclear Factor-B Activation and RANTES Gene and Protein Expression in Endometrial Stromal Cells from Women with Endometriosis

Division of Gynecological Endocrinology and Reproductive Medicine (F.W., S.D.), University of Vienna, A-1090 Vienna, Austria; Department of Obstetrics and Gynecology (F.W., J.-L.V., I.R., R.N.T.), Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California 94143-0556; and Department of Obstetrics and Gynecology (D.H.), University of Schleswig-Holstein, 23538 Luebeck, Germany

Address all correspondence and requests for reprints to: Robert N. Taylor, M.D., Ph.D., Department of Gyn/Ob, Emory University School of Medicine, Woodruff Memorial Building, 1639 Pierce Drive, Room 4217, Atlanta, Georgia 30322. E-mail: robert.n.taylor{at}emory.edu.

Context: The nuclear factor-B (NF-B) 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.

Objective: The objective of this study was to investigate the effects of the antiinflammatory drug sulindac on NF-B activation, NF-B-mediated gene expression, RANTES gene and protein expression in endometrial stromal cells isolated from women with endometriosis, and unaffected controls.

Design: This was a clinical experimental study.

Setting: The study was conducted at a university hospital.

Results: The inflammatory response in endometriosis is augmented by a 5-fold increased TNF-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-B in endometriotic cells, which could be suppressed by sulindac. EMSAs showed that sulindac dramatically decreased NF-B activation and diminished TNF and IL-1ß-induced NF-B DNA binding activity. Sulindac pretreatment resulted in a significant decrease in TNF-induced luciferase activity of NF-B response element and –477 bp RANTES promoter constructs in normal and endometriotic stromal cells. The addition of sulindac to IL-1ß- and TNF-treated endometriotic stromal cells also resulted in a 4-fold inhibition of RANTES protein secretion (P < 0.05).

Conclusions: We have demonstrated that sulindac exerts strong antiinflammatory effects by suppression of NF-B translocation, inhibition of NF-B-mediated gene transcription, RANTES gene expression, and protein secretion in normal and endometriotic stromal cells. These results suggest that drugs targeting the NF-B pathway may be beneficial in the treatment of endometriosis-associated symptoms.

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