RelB/NF-κB2 regulates corticotropin-releasing hormone in the human placenta

Mol Endocrinol. 2012 Aug;26(8):1356-69. doi: 10.1210/me.2012-1035. Epub 2012 Jun 25.


Placental CRH may be part of a clock that governs the length of human gestation. The mechanism underlying differential regulation of CRH in the human placenta is poorly understood. We report here that constitutively activated RelB/nuclear factor-κB2 (NF-κB)-2 (p100/p52) acts as an endogenous stimulatory signal to regulate CRH by binding to an NF-κB enhancer of CRH gene promoter in the human placenta. Nuclear staining of NF-κB2 and RelB in villous syncytiotrophoblasts and cytotrophoblasts was coupled with cytoplasmic CRH in syncytial knots of cytotrophoblasts. Chromatin immunoprecipitation identified that CRH gene associated with both RelB and NF-κB2 (p52). Dexamethasone increased synthesis and nuclear translocation of RelB and NF-κB2 (p52) and their association with the CRH gene. In contrast, progesterone, a down-regulator of placental CRH, repressed NF-κB2 (p100) processing, nuclear translocation of RelB and NF-κB2 (p52), and their association with the CRH gene. Luciferase reporter assay determined that the NF-κB enhancer of CRH was sufficient to regulate transcriptional activity of a heterologous promoter in primary cytotrophoblasts. RNA interference-mediated repression of RelB or NF-κB2 resulted in significant inhibition of CRH at both transcriptional and translational levels and prevented the dexamethasone-mediated up-regulation of CRH transcription and translation. These results suggest that the noncanonical NF-κB pathway regulates CRH production in the human placenta and is responsible for the positive regulation of CRH by glucocorticoids.

MeSH terms

  • Analysis of Variance
  • Base Sequence
  • Cells, Cultured
  • Corticotropin-Releasing Hormone / genetics
  • Corticotropin-Releasing Hormone / metabolism*
  • Dexamethasone / pharmacology
  • Enhancer Elements, Genetic
  • Female
  • Gene Expression Regulation
  • Humans
  • Leupeptins / pharmacology
  • NF-kappa B p52 Subunit / metabolism
  • NF-kappa B p52 Subunit / physiology*
  • Placenta / cytology
  • Placenta / metabolism*
  • Pregnancy
  • Progesterone / pharmacology
  • Progesterone / physiology
  • Promoter Regions, Genetic
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors / pharmacology
  • Signal Transduction
  • Transcription Factor RelB / metabolism
  • Transcription Factor RelB / physiology*
  • Transcription, Genetic
  • Trophoblasts / metabolism


  • Leupeptins
  • NF-kappa B p52 Subunit
  • NFKB2 protein, human
  • Proteasome Inhibitors
  • RELB protein, human
  • Transcription Factor RelB
  • Progesterone
  • Dexamethasone
  • Corticotropin-Releasing Hormone
  • Proteasome Endopeptidase Complex
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde