Sulindac suppresses nuclear factor-kappaB activation and RANTES gene and protein expression in endometrial stromal cells from women with endometriosis.
BACKGROUND
The 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.


OBJECTIVE
The 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.


METHODS
This was a clinical experimental study.


METHODS
The study was conducted at a university hospital.


RESULTS
The 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).


CONCLUSIONS
We 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.
Wieser
Fritz
F
Division of Gynecological Endocrinology and Reproductive Medicine, University of Vienna, Austria.
Vigne
Jean-Louis
JL
Ryan
Isabelle
I
Hornung
Daniela
D
Djalali
Schima
S
Taylor
Robert N
RN
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism*; D004715:Endometriosis / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism*; D013467:Sulindac / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018946:Chemokine CCL5; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D013467:Sulindac