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CRH targets the human myometrium during pregnancy. The efficiency of CRH actions is determined by expression of functional receptors (CRH-R), which are dynamically regulated. Studies in myometrial tissue biopsies using quantitative RT-PCR demonstrated that the onset of labor, term or preterm, is associated with a significant 2- to 3-fold increase in CRH-R1 mRNA levels. Detailed analysis of myometrial CRH-R1 mRNA variants showed a decline of the pro-CRH-R1 mRNA encoding the CRH-R1beta variant during labor and increased mRNA levels of CRH-R1d mRNA. Studies in myometrial cells identified IL-1beta as an important regulator of myometrial CRH-R1 gene expression because prolonged treatment of myometrial cells with IL-1beta (1 ng/ml) for 18 h induced expression of CRH-R1 mRNA levels by 1.5- to 2-fold but significantly attenuated CRH-R1beta mRNA expression by 70%. In contrast, IL-1beta had no effect on CRH-R1d mRNA expression. Studies using specific inhibitors suggest that ERK1/2, p38 MAPK, and downstream nuclear translocation of nuclear factor-kappaB mediate IL-1beta effects on myometrial CRH-R1 gene. However, the increased CRH-R1 mRNA expression was associated with a dampening of the receptor efficacy to activate the adenylyl cyclase/cAMP signaling cascade. Thus, our findings suggest that IL-1beta is an important regulator of CRH-R1 expression and functional activity, and this interaction might play a role in the transition of the uterus from quiescence to active contractions necessary for the onset of parturition.

Original publication

DOI

10.1210/en.2007-0095

Type

Journal article

Journal

Endocrinology

Publication Date

07/2007

Volume

148

Pages

3205 - 3213

Keywords

Blotting, Western, Butadienes, Cells, Cultured, Coumarins, Cyclic AMP, Cyclooxygenase 2, Female, Gene Expression, Humans, I-kappa B Kinase, Imidazoles, Interleukin-1beta, Labor Onset, Membrane Proteins, Microscopy, Confocal, Mitogen-Activated Protein Kinase 3, Myocytes, Smooth Muscle, Myometrium, NF-kappa B, Nitriles, Pregnancy, Pyridines, RNA, Messenger, Receptors, Corticotropin-Releasing Hormone, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, p38 Mitogen-Activated Protein Kinases