RelB/NF-κB2 regulates corticotropin-releasing hormone in the human placenta.
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.
Department of Obstetrics, Gynecology, and Reproductive Sciences, Maternal-Fetal Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA. wangbi@umdnj.edu
Bingbing
B
Wang
Nataliya
N
Parobchak
Todd
T
Rosen
D000704:Analysis of Variance; D001483:Base Sequence; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004742:Enhancer Elements, Genetic; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D052003:NF-kappa B p52 Subunit / Q000378:metabolism / Q000502:physiology*; D010920:Placenta / Q000166:cytology / Q000378:metabolism*; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology / Q000502:physiology; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D051841:Transcription Factor RelB / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014327:Trophoblasts / Q000378:metabolism
D007976:Leupeptins; D052003:NF-kappa B p52 Subunit; C498206:NFKB2 protein, human; D061988:Proteasome Inhibitors; C497593:RELB protein, human; D051841:Transcription Factor RelB; D011374:Progesterone; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde