Crosstalk between estradiol and NFκB signaling pathways on placental leptin expression

SCHANTON, MALENA; MAYMÓ, JULIETA LORENA; CAMISAY, MARÍA FERNANDA; PÉREZ-PÉREZ, ANTONIO; CASALE, ROBERTO; SANCHEZ-MARGALET, VICTOR; ERLEJMAN, ALEJANDRA; VARONE, CECILIA

REPRODUCTION

BIOSCIENTIFICA LTD

Año: 2020

1470-1626

Pregnancy success requires a proper fetal maternal interaction at the establishment of implantation. Leptin has been described as a multitasking cytokine in pregnancy, particularly in the placenta, where it acts as an autocrine hormone. The expression of leptin in normal trophoblastic cells is regulated by different endogenous signals. We have previously reported that 17b-estradiol up-regulates placental leptin expression through genomic and non-genomic mechanisms. To improve the knowledge of estrogen receptor mechanisms in regulating leptin gene expression, we examined nuclear factor kappa B (NFkB) transcription factor effect on estradiol leptin induction in human BeWo cell line and human term placental explants. We demonstrated that estradiol induction effect on leptin expression is blocked by the inhibition of NFkB signaling. We also found that the overexpression of p65 subunit, the active form of NFkB, induces leptin expression. Moreover, downregulation of estrogen receptor alpha (ERa through a specific siRNA, abolished NFkB effect on leptin expression. We also demonstrated that ERa enhanced NFkB signaling pathway activation in trophoblastic cells. Estradiol treatment significantly increased p65 expression and phosphorylation of the inhibitory protein κB alpha (IkB). A reporter plasmid containing NFkB elements was also induced in response to estradiol stimulation. Localization experiments revealed that estradiol treatment induced nuclear localization of overexpressed p65. Moreover, the overexpression of ERa produced a complete displacement of p65 protein to the nucleus. Finally, immunoprecipitation experiments showed the presence of a complex containing ERa nd NFkB. All these evidences suggest a cooperative behavior between ERa and NFkB transcription factors to induce leptin transcription.