Protease-activated receptor-stimulated interleukin-6 expression in endometriosis-like lesions in an experimental mouse model of endometriosis

Akihiro Shinohara, Shinohara A, Masahiko Kutsukake, Kutsukake M, Mirai Takahashi, Takahashi M, Satoru Kyo, Kyo S, Eiichi Tachikawa, Tachikawa E, Kazuhiro Tamura
Journal of pharmacological sciences · 2012 · doi:10.1254/jphs.11216fp · PMID:22641126
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⚙ AI-generated summary by gemini-2.5-flash-lite, 2026-06-07 ⓘ

This study found that protease-activated receptor activation by agonists like thrombin significantly increased interleukin-6 expression in endometriosis-like lesions in a mouse model.

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This study investigated whether protease-activated receptors (PAR1/2) regulate interleukin-6 (IL-6) expression in endometriosis-like lesions using female nude mice with unilateral ovariectomy followed by intraperitoneal transplantation of immortalized human endometrial epithelial and stromal cells. Endometriosis-like lesions formed mainly around the dissection site, with IL-6 and cyclooxygenase-2 expression enhanced in ovariectomized (uOVX) mice, and in non-uOVX mice IL-6 mRNA and peritoneal IL-6 concentrations were higher in lesions derived from PAR1/2 agonist–pretreated cells (thrombin and a PAR2-activating peptide). IL-6 induction by PAR activation was blocked by serine protease inhibitors, and co-activation of PAR1 and PAR2 in cultured endometrial cells further increased IL-6 expression. The paper’s key limitation is that it uses an experimental mouse model based on transplanted immortalized human endometrial cells rather than patient-derived tissue dynamics. This paper is centrally about endometriosis — it directly tests PAR-mediated IL-6 expression in an experimental endometriosis-like mouse lesion model.

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Abstract

The present study was undertaken to investigate the function of protease-activated receptor (PAR) in endometriotic lesions using a mouse model of endometriosis. Unilateral ovariectomy (uOVX) was performed on female nude mice followed by intraperitoneal transplantation of a suspension mixture of immortalized human endometrial epithelial cells (EM-1) and stromal cells (EtsT-499). Endometriosis-like lesions were observed mostly around the dissection site after transplantation. The expression of interleukin (IL)-6 and cyclooxygenase-2 in the lesions was enhanced in uOVX mice compared to non-uOVX animals. In non-uOVX mice, IL-6 mRNA levels were higher in lesions formed with cells that were pretreated with PAR1/2 agonists (thrombin, 10 U/ml and PAR2-activating peptide, 30 µM) compared to untreated, intact cells. Peritoneal IL-6 concentrations were also increased in the PAR1/2 agonists-treated group. IL-6 expression induced by PAR activation was blocked by the treatment of cells with serine protease inhibitors. In cultured endometrial cells, simultaneous treatment with PAR1 and PAR2 agonists significantly increased the expression of IL-6. These results suggest that peritoneal bleeding may accelerate IL-6 expression in endometriotic lesions in part through the activation of PAR.
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Keywords

endometriosis, endometrial cell, interleukin (IL)-6, protease-activated receptor (PAR), thrombin 2012 Volume 119 Issue 1 Pages 40-51 Details

Abstract

The present study was undertaken to investigate the function of protease-activated receptor (PAR) in endometriotic lesions using a mouse model of endometriosis. Unilateral ovariectomy (uOVX) was performed on female nude mice followed by intraperitoneal transplantation of a suspension mixture of immortalized human endometrial epithelial cells (EM-1) and stromal cells (EtsT-499). Endometriosis-like lesions were observed mostly around the dissection site after transplantation. The expression of interleukin (IL)-6 and cyclooxygenase-2 in the lesions was enhanced in uOVX mice compared to non-uOVX animals. In non-uOVX mice, IL-6 mRNA levels were higher in lesions formed with cells that were pretreated with PAR1/2 agonists (thrombin, 10 U/ml and PAR2-activating peptide, 30 μM) compared to untreated, intact cells. Peritoneal IL-6 concentrations were also increased in the PAR1/2 agonists–treated group. IL-6 expression induced by PAR activation was blocked by the treatment of cells with serine protease inhibitors. In cultured endometrial cells, simultaneous treatment with PAR1 and PAR2 agonists significantly increased the expression of IL-6. These results suggest that peritoneal bleeding may accelerate IL-6 expression in endometriotic lesions in part through the activation of PAR. © 2012 The Japanese Pharmacological Society Favorites & Alerts Recently viewed articles Predecessor

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Endometriosis Interleukin-6 Interleukin-6 Receptors, Proteinase-Activated Receptors, Proteinase-Activated Animals Apoptosis Apoptosis Cells, Cultured Cyclooxygenase 2 Cyclooxygenase 2 Dinoprostone Dinoprostone Disease Models, Animal Endometriosis Endometriosis Endometrium Endometrium Endometrium

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