title: Evidence for the presence of protease-activated receptor 2 and its possible implication in remodeling of human endometrium.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Hirota
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Osuga
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hirata
authors.forename: Kaori
authors.initials: K
authors.lastname: Koga
authors.forename: Osamu
authors.initials: O
authors.lastname: Yoshino
authors.forename: Miyuki
authors.initials: M
authors.lastname: Harada
authors.forename: Chieko
authors.initials: C
authors.lastname: Morimoto
authors.forename: Emi
authors.initials: E
authors.lastname: Nose
authors.forename: Tetsu
authors.initials: T
authors.lastname: Yano
authors.forename: Osamu
authors.initials: O
authors.lastname: Tsutsumi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Taketani
mesh_terms: D000328:Adult; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D004717:Endometrium / Q000166:cytology* / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D008597:Menstrual Cycle / Q000502:physiology*; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D044464:Receptor, PAR-2 / Q000235:genetics* / Q000378:metabolism*; D019089:Stem Cell Factor / Q000235:genetics; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D016209:Interleukin-8; D012333:RNA, Messenger; D044464:Receptor, PAR-2; D019089:Stem Cell Factor; D020928:Mitogen-Activated Protein Kinases; D020783:Matrix Metalloproteinase 7