The Stress-responsive Heme Oxygenase (HO)-1 Isoenzyme is Increased in Labouring Myometrium where it Regulates...

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.

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.

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.

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.