Proteome-Wide Effect of 17-β-Estradiol and Lipoxin A4 in an Endometriotic Epithelial Cell Line

Abstract

Endometriosis affects approximately 10% of women of reproductive age. This chronic, gynecological inflammatory disease results in a decreased quality of life for patients, with the main symptoms including chronic pelvic pain and infertility. The steroid hormone 17-β Estradiol (E2) plays a key role in the pathology. Our previous studies showed that the anti-inflammatory lipid Lipoxin A4 (LXA4) acts as an estrogen receptor-alpha agonist in endometrial epithelial cells, inhibiting certain E2-mediated effects. LXA4 also prevents the progression of endometriosis in a mouse model via anti-proliferative mechanisms and by impacting mediators downstream of ER signaling. The aim of the present study was therefore to examine global proteomic changes evoked by E2 and LXA4 in endometriotic epithelial cells. E2 impacted a greater number of proteins in endometriotic epithelial cells than LXA4. Interestingly, the combination of E2 and LXA4 resulted in a reduced number of regulated proteins, with LXA4 mediating a suppressive effect on E2-mediated signaling. These proteins are involved in diverse pathways of relevance to endometriosis pathology and metabolism, including mRNA translation, growth, proliferation, proteolysis, and immune responses. In summary, this study sheds light on novel pathways involved in endometriosis pathology and further understanding of signaling pathways activated by estrogenic molecules in endometriotic epithelial cells.

The Inflammatory Role of Pro-Resolving Mediators in Endometriosis: An Integrative Review

“…In these studies, patients were at least 3–6 months without hormonal or anti-inflammatory treatment. ESCs were treated in cell culture with the mediator under investigation, and the evaluation was carried out through several types of laboratory analysis [ 7 , 19 , 30 , 31 , 33 , 34 , 35 ]. Rasheed et al analyzed in vitro halogenic stem cells by adding serum from patients diagnosed with endometriosis to evaluate cell differentiation and the expression of ANXA1 [ 37 ].…”

“…LXA4 reduced pro-inflammatory cytokines in lesions, ESCs and peritoneal fluid cells during in vivo and in vitro experiments. Among the studied cytokines, treatment with LXA4 reduced the expression of interleukine 1β (IL-1β), interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 16 (IL-16), vascular endothelial growth factor (VEGF), TNF, transforming growth factor (TGF)-β1 and TGF-β2 [ 19 , 27 , 29 , 31 , 32 , 33 ].…”

“…Further, the inhibition of E2-induced p38 MAPK and ERK phosphorylation is mediated by the FPR2/ALX in vitro [ 7 ]. In a proteomic analysis, the combined treatment with E2 and LXA4 resulted in reduced regulated proteins, with LXA4 mediating a suppressive effect on E2-mediated inflammatory cell signaling [ 33 ].…”

Effect of interleukin‐1β and lipoxin A4 in human endometriotic stromal cells: Proteomic analysis

“…To identify endometriosis biomarkers, several sample types including serum, peritoneal fluid, endometriotic lesion and endometriotic epithelial cell have been used. 19,[28][29][30][31] In this study, we first obtained primary ESC, and then used them as an in vitro model to identify altered proteins after treatment with IL-1β or LXA 4 . To our knowledge, endometriosis is also an inflammatory disease.…”

“…12,15 Data from our research group and others have shown that LXA 4 elicits anti-inflammatory, anti-angiogenic and antiproliferative actions in endometriotic stromal cells (ESC) and glandular epithelial cells, by reducing the expression of inflammatory factors and estrogen signaling. [16][17][18][19] Although the roles of IL-1β and LXA 4 have been intensively studied, little is known about the effect of LXA 4 on IL-1β in endometriosis. To understand the modulation mechanisms of LXA 4 in preventing the development and progression of endometriosis by influencing the effect of IL-1β, a study of the proteome in response to treatment with IL-1β or LXA 4 is essential.…”