The influence of interleukin-1β on oxytocin signalling in primary cells of human decidua

Objective: Oxytocin (OT) and its corresponding receptor (OTR), synthesized within the pregnant uterus, play a key role in the process of (preterm) labor as part of a paracrine system that regulates symmetrical contractility. In the setting of intrauterine infection, a major cause of preterm labour and birth, decidua serves as a major source of cytokine production. The present study evaluates the time-dependent effect [0-24 h] of the inflammatory cytokine Interleukin-1β (IL-1β) treatment on OT signalling and OT stimulated prostaglandin release in primary cultures of human decidua. Study design: Primary cultures of human decidua (n = 6) were treated with IL-1β [5 ng/ml] for 0-24h and or indomethacin [100 μM] - an inhibitor of the prostaglandin synthesis - for 0-24 h or for 24 h. OT peptide expression, OTR binding, Inositol triphosphate production (IP₃), and arachidonic acid (AA) as well as prostaglandin (PGE₂) release were measured. Results: IL-1β transiently reduced cytoplasmic OT peptide at 4-6 h of IL-1β incubation, while its secretion into the media was increased after 6 h of stimulation. The later was completely blocked by indomethacin. A decrease in OTR mRNA expression and a loss of OTR binding were detected after 8 h and 16 h of IL-1β treatment, respectively. IL-1β also decreased IP₃ production and AA release, but significantly enhanced OT mediated PGE₂ production. This effect was completely suppressed by the cyclooxygenase-2 (COX-2) inhibitor NS-398. Conclusion: Our data suggest, that IL-1β indirectly increases OT secretion in primary cultures of human decidua in a time dependent fashion through the production of prostaglandins through COX-2 and that this increase in OT peptide may secondarily down-regulate the OTR and its signalling cascade. These findings might explain the poor effectiveness of oxytocin receptor antagonists as tocolytic agents in the setting of intrauterine infection.