Abstract
The goal of this study is to elucidate the effects of 17β-estradiol and TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) on macrophage phenotypes in the endometriotic milieu. Co-culture of endometrial stromal cells (ESCs) and U937 cells (macrophage cell line) was performed to simulate the endometriotic milieu and to determine the effects of 17β-estradiol and/or TCDD on IL10, IL12 production and HLA-DR, CD86 expression by U937 macrophages. We found that combining 17β-estradiol with TCDD has a synergistic effect on inducing M2 activation when macrophages are co-cultured with ESCs. Moreover, the combination of 17β-estradiol and TCDD significantly enhanced STAT3 and P38 phosphorylation in macrophages. Differentiation of M2 macrophages induced by 17β-estradiol and TCDD were effectively abrogated by STAT3 and P38MAPK inhibitors, but not by ERK1/2 and JNK inhibitors. In conclusion, 17β-estradiol and TCDD in the ectopic milieu may lead to the development of endometriosis by inducing M2 polarization of macrophages through activation of the STAT3 and P38MAPK pathways.
Highlights
Endometriosis, a chronic inflammatory disease, is a gynecological disorder which has a complex, multifactorial etiology, leading to severe pelvic pain and, in some cases, infertility
Neither IL-10 nor IL-12 secretion was detected in primary endometrial stromal cells (ESCs), even after 72 h of culture
17β-estradiol did not affect IL12 secretion or CD86 expression by U937 cells (p>0.05;Fig 3A). 0.01–100nM 17β-estradiol decreased HLA-DR expression in U937 co-cultured with ESCs (p
Summary
Endometriosis, a chronic inflammatory disease, is a gynecological disorder which has a complex, multifactorial etiology, leading to severe pelvic pain and, in some cases, infertility. A leading theory as to its etiology is that endometriosis is caused by retrograde displacement of eutopic endometrium into the pelvis and its subsequent implantation on peritoneal surfaces. Peritoneal macrophages isolated from patients with endometriosis were found. Combined E2 and TCDD Promotes M2 Macrophage Polarization to have poor phagocytic capacity; this and other phenotypic and functional alterations were associated with disease severity[1,2]. Our previous work has indicated that macrophages are involved in ectopic adhesion, implantation, and growth of the endometriotic tissue, as opposed to clearing[3,4,5,6,7]
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