Possible involvement of thrombin/protease-activated receptor 1 system in the pathogenesis of endometriosis.
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.
Hirota
Yasushi
Y
Department of Obstetrics and Gynecology, University of Tokyo, Tokyo 113-8655, Japan.
Osuga
Yutaka
Y
Hirata
Tetsuya
T
Yoshino
Osamu
O
Koga
Kaori
K
Harada
Miyuki
M
Morimoto
Chieko
C
Nose
Emi
E
Yano
Tetsu
T
Tsutsumi
Osamu
O
Taketani
Yuji
Y
D018932:Chemokine CCL2 / Q000235:genetics; D051546:Cyclooxygenase 2; D017931:DNA Primers; D004715:Endometriosis / Q000209:etiology / Q000503:physiopathology*; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D044463:Receptor, PAR-1 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013917:Thrombin / Q000235:genetics / Q000502:physiology*
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D017931:DNA Primers; D016209:Interleukin-8; D008565:Membrane Proteins; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D013917:Thrombin