Possible Involvement of Thrombin/Protease-Activated Receptor 1 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, Yuji Taketani
The Journal of clinical endocrinology and metabolism · 2005 · vol. 90(6) , pp. 3673–3679 · doi:10.1210/jc.2004-0493 · PMID:15755869 · W2120885075
article OA: bronze CC0 ⤵ 24 in-corpus citations
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Thrombin and its receptor PAR1 activate inflammatory and proliferative pathways in endometriotic stromal cells, suggesting their involvement in endometriosis pathogenesis.

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Abstract

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 (ESCs). Thrombin and SFLLRN (Ser-Phe-Leu-Leu-Arg-Asp), a PAR1 agonist peptide, increased the mRNA expression of IL-8, monocyte chemoattractant protein-1 (MCP-1), and cyclooxygenase-2 (COX-2) and the protein secretion of IL-8 nd MCP-1 in ESCs. The addition of thrombin inhibitor d-phenylalanyl-l-prolyl-l arginine chloromethyl ketone (PPACK) together with thrombin inhibited the thrombin-induced secretion of IL-8 and MCP-1. Thrombin, but not SFLLRN, activated matrix metalloproteinase-2 in ESCs, and the effect was inhibited by PPACK. Thrombin and SFLLRN increased proliferating cell nuclear antigen-positive ratio of ESCs, indicating their cell proliferation-stimulating effects. The thrombin-induced increase in proliferating cell nuclear antigen-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.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Receptor, PAR-1 Thrombin Chemokine CCL2 Chemokine CCL2 Cyclooxygenase 2 DNA Primers Endometriosis Endometriosis Female Humans Interleukin-8 Interleukin-8 Membrane Proteins Prostaglandin-Endoperoxide Synthases Prostaglandin-Endoperoxide Synthases Receptor, PAR-1 Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger RNA, Messenger

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