title: Corticotropin-releasing hormone interacts with interleukin-1β to regulate prostaglandin H synthase-2 expression in human myometrium during pregnancy and labor.
abstract: BACKGROUND
  The onset of labor appears to involve the activation of myometrial inflammatory pathways, and transcription factors such as nuclear factor-κB (NF-κB) control expression of the contraction-associated proteins required to induce a procontractile phenotype. These responses might involve CRH, which integrates immune and neuroendocrine systems.
  
  
  OBJECTIVE
  In human myometrium we investigated cyclooxygenase 2 (PGHS2) expression and regulation by CRH and the proinflammatory cytokine IL-1β before and after labor.
  
  
  METHODS
  Myometrial tissues obtained from pregnant women at term before (n = 12) or during labor (n = 10) and pathological cases of choriamnionitis-associated term labor (n = 5) were used to isolate primary myocytes and investigate in vitro, CRH effects on basal and IL-1β regulated p65 activation and PGHS2 expression.
  
  
  RESULTS
  In nonlaboring myometrial cells, CRH was unable to induce NF-κB nuclear translocation; however, it altered the temporal dynamics of IL-1β-driven NF-κB nuclear entry by initially delaying entry and subsequently prolonging retention. These CRH-R1-driven effects were associated with a modest inhibitory action in the early phase (within 2 hours) of IL-1β stimulated PGHS2 mRNA expression, whereas prolonged stimulation for 6-18 hours augmented the IL-1β effects. The early-phase effect required intact protein kinase A activity and was diminished after the onset of labor. The presence of chorioamnionitis led to exaggerated PGHS2 mRNA responses to IL-1β but diminished effects of CRH.
  
  
  CONCLUSIONS
  CRH is involved in the inflammatory regulation of PGHS2 expression before and during labor; these actions might be important in priming and preparing the myometrium for labor and cellular adaptive responses to inflammatory mediators.
authors.affiliation: Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom.
authors.forename: Danijela
authors.initials: D
authors.lastname: Markovic
authors.forename: Muhammad F
authors.initials: MF
authors.lastname: Bari
authors.forename: Buyu
authors.initials: B
authors.lastname: Lu
authors.forename: Manu
authors.initials: M
authors.lastname: Vatish
authors.forename: Dimitris K
authors.initials: DK
authors.lastname: Grammatopoulos
mesh_terms: D000328:Adult; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002821:Chorioamnionitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D007743:Labor, Obstetric / Q000276:immunology / Q000378:metabolism*; D009215:Myometrium / Q000166:cytology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011247:Pregnancy; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D012333:RNA, Messenger / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D046509:Tissue Culture Techniques; D051996:Transcription Factor RelA / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: C508585:IL1B protein, human; D053583:Interleukin-1beta; D016328:NF-kappa B; C498143:RELA protein, human; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D051996:Transcription Factor RelA; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human