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This version published online on March 8, 2005
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-0493
A more recent version of this article appeared on June 1, 2005
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Submitted on March 12, 2004
Accepted on March 2, 2005

Possible involvement of thrombin/ protease-activator receptor 1 (PAR1) system in the pathogenesis of endometriosis

Yasushi Hirota, Yutaka Osuga*, Tetsuya Hirata, Osamu Yoshino, Kaori Koga, Miyuki Harada, Chieko Morimoto, Emi Nose, Tetsu Yano, Osamu Tsutsumi, and Yuji Taketani

Department of Obstetrics and Gynecology, University of Tokyo, Tokyo 113-8655, Japan

* To whom correspondence should be addressed. E-mail: yutakaos-tky{at}umin.ac.jp.

Endometriosis is known to be associated with local inflammatory reactions. Given the emerging concept of thrombin and its specific receptor, protease activated receptor 1 (PAR1), as important players in inflammation and cell proliferation, we investigated whether thrombin and PAR1 might be involved in the pathophysiology of the disease, using a primary cell culture system of endometriotic tissues. PAR1 mRNA was expressed in primary endometriotic stromal cells (ESC). Thrombin and SFLLRN, a PAR1 agonist peptide, increased the mRNA expression of IL-8, MCP-1 and COX-2 and the protein secretion of IL-8 and MCP-1 in ESC. The addition of thrombin inhibitor PPACK together with thrombin inhibited the thrombin-induced secretion of IL-8 and MCP-1. Thrombin, but not SFLLRN, activated MMP-2 in ESC, and the effect was inhibited by PPACK. Thrombin and SFLLRN increased proliferating cell nuclear antigen (PCNA)-positive ratio of ESC, indicating their cell proliferation-stimulating effects. The thrombin-induced increase in PCNA-positive ratio was diminished by PPACK. These findings imply that the thrombin system might be involved in the pathophysiology of endometriosis, stimulating inflammatory responses of endometriotic cells and their mitogenic activity.
Key words: Thrombin • Protease-activated receptor 1 (PAR1) • Endometriosis • Inflammation • Cell proliferation




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