Possible involvement of thrombin/protease-activated receptor 1 system in the pathogenesis of endometriosis
Possible involvement of thrombin/protease-activated receptor 1 system in the pathogenesis of endometriosis
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DOI：
10.1210/jc.2004-0493
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发表时间：
2005-06-01
影响因子：
5.8
通讯作者：
Taketani, Y
中科院分区：
文献类型：
--
作者：
Hirota, Y;Osuga, Y;Taketani, Y
已知子宫内膜异位症与局部炎症反应有关。鉴于凝血酶及其特异性受体，蛋白酶激活受体1（PAR 1），作为炎症和细胞增殖的重要参与者的新兴概念，我们研究了凝血酶和PAR 1是否可能参与疾病的病理生理学，使用原代细胞培养系统的炎症组织。原代子宫内膜异位基质细胞（ESCs）中表达PAR 1 mRNA。凝血酶和PAR 1激动肽SFLLRN（Ser-Phe-Leu-Leu-Arg-Asp）可增加IL-8、单核细胞趋化蛋白-1（MCP-1）和环氧合酶-2（考克斯-2）的mRNA表达以及IL-8和MCP-1的蛋白分泌。加入凝血酶抑制剂D-苯丙氨酰-L-脯氨酰-L-精氨酸氯甲基酮（PPACK）和凝血酶一起抑制凝血酶诱导的IL-8和MCP-1的分泌。凝血酶，而不是SFLLRN，激活基质金属蛋白酶-2在胚胎干细胞，并抑制PPACK的效果。凝血酶和SFLLRN增加ESCs增殖细胞核抗原阳性率，表明其细胞增殖刺激作用。凝血酶诱导的增殖细胞核抗原阳性率的增加被PPACK减弱。这些发现提示凝血酶系统可能参与子宫内膜异位症的病理生理过程，刺激增生细胞的炎症反应及其促有丝分裂活性。
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.