title: Increased c-Jun N-terminal kinase activation in human endometriotic endothelial cells.
abstract: Endometriosis is a common inflammatory gynecological disease characterized by the presence of endometrial tissue outside of the uterine cavity. The c-Jun N-terminal kinase (JNK) is a subfamily of the mitogen-activated protein kinases (MAPKs) involved in cellular processes ranging from cytokine expression to apoptosis, and is activated in response to inflammation and cellular stress. We hypothesized that inflammatory cytokines in the peritoneal microenvironment increase JNK MAPK activity in endometriotic endothelial cells, and that human endometrial endothelial cells (HEECs) may be involved in inflammatory pathogenesis of endometriosis. Thus, we evaluated the expression of the total- and phosphorylated-(phospho)-JNK in endometrial and endometriotic endothelial cells in vivo, and in HEECs treated with normal peritoneal fluid (NPF), endometriotic peritoneal fluid (EPF), and the inflammatory cytokines interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) in vitro. Phospho-JNK immunoreactivity in HEECs in normal endometrium was significantly higher in the early proliferative and late secretory phases compared to other phases. Both eutopic and ectopic HEECs from the early secretory phase also revealed higher phospho-JNK immunoreactivity, compared to their respective cycle-matched normal HEECs. Moreover, HEECs treated with EPF showed significantly higher phospho-JNK levels compared to that in HEECs treated with NPF. In conclusion, our in vivo and in vitro findings suggest that increased phosphorylation of JNK in HEECs from women with endometriosis is likely due to high level of IL-1β and TNF-α in peritoneal fluid; this in turn may up-regulate inflammatory cytokine expression and thus play a role in the pathogenesis of endometriosis.
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, 06520-8063, USA.
authors.forename: Yesim Hulya
authors.initials: YH
authors.lastname: Uz
authors.forename: William
authors.initials: W
authors.lastname: Murk
authors.forename: Idil
authors.initials: I
authors.lastname: Bozkurt
authors.forename: Gulnur
authors.initials: G
authors.lastname: Kizilay
authors.forename: Aydin
authors.initials: A
authors.lastname: Arici
authors.forename: Umit Ali
authors.initials: UA
authors.lastname: Kayisli
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D004715:Endometriosis / Q000201:enzymology / Q000473:pathology; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D048031:JNK Mitogen-Activated Protein Kinases