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-kappa B2 (NF-kappa B)-2 (p100/p52) acts as an endogenous stimulatory signal to regulate CRH by binding to an NF-kappa B enhancer of CRH gene promoter in the human placenta. Nuclear staining of NF-kappa B2 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-kappa B2 (p52). Dexamethasone increased synthesis and nuclear translocation of RelB and NF-kappa B2 (p52) and their association with the CRH gene. In contrast, progesterone, a down-regulator of placental CRH, repressed NF-kappa B2 (p100) processing, nuclear translocation of RelB and NF-kappa B2 (p52), and their association with the CRH gene. Luciferase reporter assay determined that the NF-kappa B enhancer of CRH was sufficient to regulate transcriptional activity of a heterologous promoter in primary cytotrophoblasts. RNA interference-mediated repression of RelB or NF-kappa B2 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-kappa B pathway regulates CRH production in the human placenta and is responsible for the positive regulation of CRH by glucocorticoids. (Molecular Endocrinology 26: 1356-1369, 2012)