The NFκB inhibitor parthenolide reduces cell proliferation and PGE2 synthesis in human endometriotic stromal cells and inhibits development of endometriosis in murine model

Abstract

Parthenolide is a sesquiterpene lactone derived from the plant feverfew, which has been used in folk medicine for its anti-inflammatory action. We sought to evaluate effects of parthenolide on ESCs, and on endometriotic lesions in a murine model. Aim of this study was to investigate usefulness of parthenolide as a possible therapeutic agent for endometriosis Experimental study. Ectopic endometrial tissue from ovarian chocolate cysts was collected from premenopausal women. ESCs were isolated from these tissues. ESCs were pretreated with parthenolide and exposed to TNFα. After treatment with TNFα, the levels of IL-8 and COX-2 gene expression were evaluated by real-time RT-PCR. After adding TNFα, IL-8 and PGE2 protein expression were determined by ELISA. Cell proliferation after adding TNFα was assessed by BrdU-ELISA. TNFα-induced phosphorylation of signaling pathways was evaluated by Western blot analysis. As an endometriosis model, estradiol-treated ovariectomized mice were injected intraperitoneally with endometrial fragments of donor mice. After 4 weeks of parthenolide injections, the extent of endometriotic lesions was evaluated. With parthenolide pretreatment, TNFα-induced IL-8 gene and protein expression were significantly repressed. TNFα-induced COX-2 expression and PGE2 synthesis were also inhibited. Adding parthenolide significantly suppressed BrdU incorporation of ESCs. Pretreatment with parthenolide inhibited TNFα-induced IκB phosphorylation, although it did not attenuate ERK1/2, p38MAPK, Akt, and JNK1/2 phosphorylation. Using the mice endometriosis model, administrating parthenolide significantly reduced surface area and weight of endometriotic lesions. These findings suggest that parthenolide represses development of endometriosis possibly by suppressing peritoneal inflammatory status through the NFκB pathway.