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Evidence for the Presence of Protease-Activated Receptor 2 and Its Possible Implication in Remodeling of Human Endometrium

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.

Protease-activated receptor 2 (PAR2) is activated by various proteases released from the leukocytes, such as neutrophils and mast cells. Because these leukocytes reside in the endometrium, we speculated that PAR2 might be activated there. In this study, we investigated the presence and possible roles of PAR2 in the endometrium. During the menstrual cycle, the expression of PAR2 mRNA in human endometrial tissues is increased from the late secretory phase to the menstrual phase and in early pregnancy. In vitro, PAR2 agonist peptide (PAR2AP) stimulated IL-8 production in both endometrial epithelial cells (EECs) and stromal cells (ESCs). PAR2AP also stimulated the mRNA expression of stem cell factor, a known activator for mast cells, in ESCs, and activated matrix metalloproteinase-7, an epithelial cell-specific matrix metalloproteinase, in EECs. In addition, PAR2AP significantly increased the 5-bromo-2'-deoxyuridine incorporation in ESCs. PAR2AP induced the phosphorylation of three MAPKs, i.e. p38 MAPK, p42/44 MAPK, and stress-activated protein kinase/c-Jun N-terminal kinase, in ESCs. Inhibitors of all three MAPKs inhibited PAR2AP-induced secretion of IL-8 in both EECs and ESCs. This is the first report demonstrating the presence of PAR2 in the human endometrium. The increased expression of PAR2 around the menstrual period, its up-regulation of molecules important for endometrial remodeling, and its mitogenic effect on endometrial cells raise the expectation of the possible involvement of PAR2 in menstruation and other architectural changes of the endometrium occurring during the menstrual cycle. MAPKs may mediate PAR2 functions in these processes.

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