Crosstalk between estradiol and NFκB signaling pathways on placental leptin expression

in Reproduction
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  • 1 Departamento de Química Biológica, Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
  • 2 Universidad de Buenos Aires, CONICET, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Buenos Aires, Argentina
  • 3 Departamento de Bioquímica Médica y Biología Molecular, Hospital Universitario Virgen Macarena, Facultad de Medicina, Universidad de Sevilla, Sevilla, España
  • 4 Hospital Nacional Profesor Alejandro Posadas, Buenos Aires, Argentina

Correspondence should be addressed to C Varone; Email: cvarone@qb.fcen.uba.ar
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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 17β-estradiol upregulates placental leptin expression through genomic and non-genomic mechanisms. To improve the knowledge of estrogen receptor mechanisms in regulating leptin gene expression, we examined transcription nuclear factor kappa B (NFκB) 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 NFκB signaling. We also found that the overexpression of p65 subunit, the active form of NFκB, induces leptin expression. Moreover, downregulation of estrogen receptor alpha (ERα), through a specific siRNA, abolished NFκB effect on leptin expression. We also demonstrated that ERα enhanced NFκB signaling pathway activation in trophoblastic cells. Estradiol treatment significantly increased p65 expression and phosphorylation of the inhibitory protein κB alpha (IκBα). A reporter plasmid containing NFκB 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 ERα produced a complete displacement of p65 protein to the nucleus. Finally, immunoprecipitation experiments showed the presence of a complex containing ERα and NFκB. All these evidences suggest a cooperative behavior between ERα and NFκB transcription factors to induce leptin transcription.

 

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