Interleukin-6 (IL-6) activates the NOTCH1 signaling pathway through E-proteins in endometriotic lesions

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.