Interleukin-6 (IL-6) Activates the NOTCH1 Signaling Pathway Through E-Proteins in Endometriotic Lesions

• Published in: The journal of clinical endocrinology and metabolism Vol. 105; no. 5; pp. 1316 - 1326
• Main Authors: Song, Yong, Su, Ren-Wei, Joshi, Niraj R, Kim, Tae Hoon, Lessey, Bruce A, Jeong, Jae-Wook, Fazleabas, Asgerally T
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01-05-2020; Copyright Oxford University Press
• Subjects: Adolescent; Adult; Animals; Basic Helix-Loop-Helix Transcription Factors - metabolism; Basic Helix-Loop-Helix Transcription Factors - physiology; Binding sites; Case-Control Studies; Cells, Cultured; Clinical; Endometriosis; Endometriosis - genetics; Endometriosis - metabolism; Endometriosis - pathology; Endometrium; Endometrium - drug effects; Endometrium - metabolism; Endometrium - pathology; Epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelium; Female; Gene Expression Regulation - drug effects; Humans; Interleukin 6; Interleukin-6 - pharmacology; Interleukin-6 - physiology; Lesions; Mice; Middle Aged; Notch1 protein; Papio; Peritoneal Diseases - genetics; Peritoneal Diseases - metabolism; Peritoneal Diseases - pathology; Peritoneal fluid; Peritoneum; Proteins; Receptor, Notch1 - drug effects; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; siRNA; Transcription Factors - metabolism; Transcription Factors - physiology; Young Adult; endometriosis; E-proteins; NOTCH1; interleukin-6; p38MAPK
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/clinem/dgaa096

Abstract
Context
NOTCH signaling is activated in endometriotic lesions, but the exact mechanisms remains unclear. IL-6, which is increased in the peritoneal fluid of women with endometriosis, induces NOTCH1 through E-proteins including E2A and HEB in cancer.
Objective
To study the role of E-proteins in inducing NOTCH1 expression under the regulation of IL-6 in endometriosis.
Setting and Design
The expression of E-proteins and NOTCH1 was first investigated in endometrium of women with endometriosis and the baboon model of endometriosis. Regulation of E-proteins and NOTCH1 expression was examined after IL-6 stimulation and siRNA mediated inhibition of E2A or/and HEB in human endometriotic epithelial cells (12Z) in vitro, and subsequently following IL-6 treatment in the mouse model of endometriosis in vivo.
Results
E2A, HEB, and NOTCH1 were significantly upregulated in glandular epithelium (GE) of ectopic endometrium compared to eutopic endometrium in both women and the baboon model. IL-6 treatment upregulated the expression of NOTCH1 together with E2A and HEB in 12Z cells. Small interfering RNA inhibition of E2A and HEB or HEB alone decreased NOTCH1 expression. Binding efficiency of both E2A and HEB was significantly higher at the binding sites on the human NOTCH1 promoter after IL-6 treatment. Finally, IL-6 treatment resulted in a significantly increased number of endometriotic lesions along with increased expression of E2A, HEB, and NOTCH1 in GE of the lesions compared with the vehicle group in an endometriosis mouse model.
Conclusions
IL-6 induced NOTCH1 expression is mediated by E-proteins in the ectopic GE cells, which may promote endometriotic lesion development.