u-0126 and wedelolactone

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.

Topics: 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; p38 Mitogen-Activated Protein Kinases; Pregnancy; Pyridines; Receptors, Corticotropin-Releasing Hormone; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction