Interleukin-6 (IL-6) activates the NOTCH1 signaling pathway through E-proteins in endometriotic lesions
Song, Yong et al. (2020), Interleukin-6 (IL-6) activates the NOTCH1 signaling pathway through E-proteins in endometriotic lesions, Dryad, Dataset, https://doi.org/10.5061/dryad.1zcrjdfnh
Context: NOTCH signaling is activated in endometriotic lesions but the exact mechanisms remains unclear. Interleukin-6 (IL-6), which is increased in the peritoneal fluid of women with endometriosis, induces NOTCH1 through E-proteins including E2A and HEB in cancer development.
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 E2A, HEB 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 subsequent following in vivo 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 baboon model. IL-6 treatment upregulated the expression of NOTCH1 together with E2A and HEB in 12Z cells. siRNA 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 the increased expression of E2A, HEB and NOTCH1 in GE of the lesions compared with the vehicle treated 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.
National Institutes of Health, Award: R01 HD042280