Combined 17β-Estradiol with TCDD Promotes M2 Polarization of Macrophages in the Endometriotic Milieu with Aid of the Interaction between Endometrial Stromal Cells and Macrophages

PLoS One. 2015 May 7;10(5):e0125559. doi: 10.1371/journal.pone.0125559. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Line
  • Coculture Techniques
  • Drug Synergism
  • Endometriosis / etiology*
  • Endometriosis / metabolism
  • Estradiol / pharmacology*
  • Female
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Macrophage Activation / drug effects
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Polychlorinated Dibenzodioxins / pharmacology*
  • STAT3 Transcription Factor / metabolism
  • Stromal Cells / cytology*

Substances

  • Polychlorinated Dibenzodioxins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Estradiol

Grants and funding

This work was supported by grants from Shanghai Natural Science Foundation of China (14ZR1423900 to YW) and National Natural Science Foundation of China (NSFC) (81470064 to YW, and 81270749 to Y-PK).