Department of Obstetrics and Gynecology, University of Tokyo, Tokyo 113-8655, Japan
Address all correspondence and requests for reprints to: Yutaka Osuga, Department of Obstetrics and Gynecology, University of Tokyo, Tokyo 113-8655, Japan. E-mail: yutakaos-tky{at}umin.ac.jp.
Endometriosis is known to be associated with local inflammatoryreactions. Given the emerging concept of thrombin and its specificreceptor, protease-activated receptor 1 (PAR1), as importantplayers in inflammation and cell proliferation, we investigatedwhether thrombin and PAR1 might be involved in the pathophysiologyof the disease, using a primary cell culture system of endometriotictissues. PAR1 mRNA was expressed in primary endometriotic stromalcells (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-Larginine chloromethyl ketone (PPACK) together with thrombininhibited the thrombin-induced secretion of IL-8 and MCP-1.Thrombin, but not SFLLRN, activated matrix metalloproteinase-2in ESCs, and the effect was inhibited by PPACK. Thrombin andSFLLRN increased proliferating cell nuclear antigen-positiveratio of ESCs, indicating their cell proliferation-stimulatingeffects. The thrombin-induced increase in proliferating cellnuclear antigen-positive ratio was diminished by PPACK. Thesefindings imply that the thrombin system might be involved inthe pathophysiology of endometriosis, stimulating inflammatoryresponses of endometriotic cells and their mitogenic activity.
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