title: The Stress-responsive Heme Oxygenase (HO)-1 Isoenzyme is Increased in Labouring Myometrium where it Regulates Contraction-associated Proteins.
abstract: OBJECTIVE
  Sterile inflammation through activation of cytokine receptor signalling pathways and viral or bacterial infection via activation of Toll-like receptors (TLRs) induces a cascade of events that leads to myometrial contractions and spontaneous preterm delivery. In non-pregnant tissues, heme oxygenase-1 (HO-1) is thought to play a central role in regulating the inflammatory response. Thus, the aims of this study were to determine the effect of human term labour on HO-1 expression in human myometrium and to investigate the role of HO-1 in myometrial primary cells in response to cytokine- and TLR ligand-induced inflammation.
  
  
  METHODS
  Localization and expression of HO-1 protein in human myometrial tissues were determined using IHC. Western blot analysis and qRT-PCR were also used to determine HO-1 protein and gene expression, respectively, in human myometrium. siRNA knock-down of HO-1 in myometrial primary cells was used to determine its role in response to inflammatory stimuli.
  
  
  RESULTS
  HO-1 gene expression and protein expression were increased in term labouring myometrium compared with non-labouring myometrium. Bacterial flagellin (TLR5 ligand), viral dsRNA analogue polyinosinic polycytidylic acid (poly(I:C)) (TLR3 ligand) and pro-inflammatory cytokines IL-1β and TNF-α induced pro-inflammatory cytokine (IL-6 and IL-8) mRNA expression and release in myometrial cells. IL-1β also induced COX-2 mRNA expression and prostaglandin release. HO-1 siRNA knock-down significantly decreased the expression and secretion of these prolabour mediators. Additionally, flagellin, poly(I:C), IL-1β, and TNF-α-induced NF-κB transcriptional activity were suppressed in HO-1-deficient myometrial cells.
  
  
  CONCLUSIONS
  Collectively, these findings in myometrium indicate HO-1 expression is increased with labour and exerts pro-inflammatory effects via NF-κB during cytokine- and TLR ligand-induced inflammation.
authors: Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Vic., Australia.|Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Vic., Australia.
authors: Stella
authors: S
authors: Liong
authors: Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Vic., Australia.|Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Vic., Australia.
authors: Martha
authors: M
authors: Lappas
mesh_terms: D002478:Cells, Cultured; D005321:Extraembryonic Membranes / Q000378:metabolism; D005260:Female; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D007743:Labor, Obstetric / Q000378:metabolism*; D009215:Myometrium / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011247:Pregnancy; D047928:Premature Birth / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D014590:Uterine Contraction / Q000378:metabolism*
chemical_list: C508585:IL1B protein, human; D053583:Interleukin-1beta; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1
keywords: HO-1; human labour; infection; inflammation; myometrium