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This version published online on September 13, 2005
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0972
A more recent version of this article appeared on December 1, 2005
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*Compound via MeSH
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*Endometriosis

Submitted on May 3, 2005
Accepted on September 7, 2005

Sulindac suppresses NF (nuclear factor)-KappaB activation, RANTES gene and protein expression in endometrial stromal cells from women with endometriosis

Fritz Wieser MD, Jean-Louis Vigne PhD, Isabelle Ryan MD, Daniela Hornung MD, Schima Djalali, and Robert N. Taylor MD, PhD*

Division of Gynecological Endocrinology and Reproductive Medicine, University of Vienna, Vienna, Austria, Department of Obstetrics and Gynecology, Center for Reproductive Sciences, University of California San Francisco, San Francisco, California, 94143-0556, Department of Obstetrics and Gynecology, University of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany

* To whom correspondence should be addressed. E-mail: robert.n.taylor{at}emory.edu.

Context: The nuclear factor-kappaB (NF-{kappa}B) pathway is a critical mediator of RANTES (Regulated on Activation, Normal T cell Expressed and Secreted) 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 anti-inflammatory drug sulindac on NF-{kappa}B activation, NF-{kappa}B mediated gene expression, RANTES gene and protein expression in endometrial stromal cells isolated from women with endometriosis and unaffected controls.

Design: Clinical experimental study

Setting: University Hospital

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

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




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