Activation of protease-activated receptor 2 stimulates proliferation and interleukin (IL)-6 and IL-8 secretion of endometriotic stromal cells

Yasushi Hirota, Yutaka Osuga, Tetsuya Hirata, Miyuki Harada, Chieko Morimoto, Osamu Yoshino, Kaori Koga, Tetsu Yano, Osamu Tsutsumi, Yuji Taketani
Human Reproduction · 2005 · vol. 20(12) , pp. 3547–3553 · doi:10.1093/humrep/dei255 · PMID:16096323 · W2127634478
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Activation of protease-activated receptor 2 stimulates endometriotic stromal cell proliferation and secretion of IL-6 and IL-8, potentially through MAPK signaling.

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Abstract

BACKGROUND: Inflammation has been proposed to play essential roles in the pathophysiology of endometriosis, in which neutrophils and mast cells have been suggested to be involved. We studied whether the protease-activated receptor 2 (PAR2), which is activated by enzymes from neutrophils and mast cells, in endometriotic stromal cells (ESC) has any implication in the development of the disease. METHODS: Cultured ESC were stimulated with various concentrations of a specific PAR2 agonist peptide. Proliferating activity of the cells was determined using immunostaining of proliferating cell nuclear antigen (a cell proliferation marker), 5-bromo-2'-deoxyuridine incorporation into DNA and cell count. The concentrations of interleukin (IL)-6 and IL-8 were measured using specific enzyme-linked immunosorbent assay kits. The phosphorylation of three mitogen-activated protein kinases (MAPK), i.e. p38 MAPK, p42/44 MAPK and stress-activated protein Kinase/c-jun N terminal Kinase, in ESC was examined with Western blot analysis. RESULTS: Activation of PAR2 stimulated the proliferation of ESC and the secretion of IL-6 and IL-8 from ESC in a dose-dependent manner. Activation of PAR2 stimulated the phosphorylation of all three MAPK, and inhibitors of each MAPK suppressed the PAR2 activation-induced proliferation of ESC. CONCLUSIONS: The activation of PAR2 in ESC may be involved in the pathophysiology of endometriosis by inducing the growth and inflammation of endometriotic lesions.

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Condition tags

endometriosis

MeSH descriptors

Endometrium Interleukin-6 Interleukin-8 Mast Cells Neutrophils Receptor, PAR-2 Stromal Cells Blotting, Western Bromodeoxyuridine Bromodeoxyuridine Cell Count Cell Proliferation DNA DNA DNA Dose-Response Relationship, Drug Endometriosis Endometriosis Endometrium Enzyme Activation

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