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.

Recent progress in histochemistry and cell biology

“…They also play an important role in inflammatory processes of endometriosis, e.g., by chemoattraction of leukocytes and in the regulation of inflammation (Luk et al 2005). To evaluate the involvement of human endometrial endothelial cells (HEECs) in inflammatory pathogenesis of endometriosis Uz et al (2011) determined the expression of the total-and phosphorylated-(phospho)-cJun N-terminal kinase (JNK) in endometrial and endometriotic endothelial cells. JNK belongs to a subfamily of mitogenactivated protein kinases (MAPKs) and is known to be activated in response to inflammation and cellular stress.…”

Pathogenesis of endometriosis: The role of initial infection and subsequent sterile inflammation (Review)

“…IL-1β and TNF-α in peritoneal fluid are able to activate c-Jun N-terminal kinase (JNK) in eutopic endometrial cells from women with endometriosis, which in turn may upregulate inflammatory cytokine expression (10). JNK is also activated in response to cellular stress (10).…”

“…Cytokines and growth factors may be significant in endometriosis-associated inflammation (3,10,15). Principal molecular factors of inflammation-associated angiogenesis, lymphangiogenesis and neurogenesis should be identified to develop novel therapeutic strategies for this disorder.…”

Progesterone Resistance and Targeting the Progesterone Receptors: A Therapeutic Approach to Endometriosis

“…Of these, JAK1 and JNK1 appeared to be down regulated in the presence of RU-486. These observations are intriguing as JNK activity is unregulated in women with endometriosis (Uz et al, 2011) and in a Scid mouse experimental model of endometriosis, JNK inhibitor treatment reduces disease burden (Altan et al, 2008).…”