Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, 06520-8063, USA.
Histochem Cell Biol. 2011 Jan;135(1):83-91. doi: 10.1007/s00418-010-0770-2. Epub 2010 Dec 18.
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.
子宫内膜异位症是一种常见的炎症性妇科疾病，其特征是子宫内膜组织位于子宫腔外。c-Jun N-末端激酶（JNK）是丝裂原活化蛋白激酶（MAPK）的一个亚家族，参与细胞过程，从细胞因子表达到细胞凋亡，并且在炎症和细胞应激反应中被激活。我们假设，腹腔微环境中的炎症细胞因子会增加子宫内膜异位症内皮细胞中 JNK MAPK 的活性，并且人子宫内膜内皮细胞（HEEC）可能参与子宫内膜异位症的炎症发病机制。因此，我们评估了总-JNK 和磷酸化-JNK 在体内子宫内膜和子宫内膜异位症内皮细胞中的表达，以及在 HEEC 中用正常腹膜液（NPF）、子宫内膜异位症腹膜液（EPF）和炎症细胞因子白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）处理后的表达。在正常子宫内膜的 HEEC 中，磷酸化-JNK 免疫反应性在早期增殖期和晚期分泌期明显高于其他阶段。与相应的周期匹配的正常 HEEC 相比，早分泌期的在位和异位 HEEC 也显示出更高的磷酸化-JNK 免疫反应性。此外，用 EPF 处理的 HEEC 显示出的磷酸化-JNK 水平明显高于用 NPF 处理的 HEEC。总之，我们的体内和体外研究结果表明，子宫内膜异位症妇女 HEEC 中 JNK 的磷酸化增加可能是由于腹膜液中 IL-1β 和 TNF-α 的水平升高；这反过来可能上调炎症细胞因子的表达，从而在子宫内膜异位症的发病机制中发挥作用。
