Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

Toll-like receptor 4 (TLR4) signalling is implicated in normal on-time labour in mice (#17)

Hanan Hamimi Binti Wahid 1 , Camilla Dorian 1 , Lachlan Moldenhauer 1 , Mark Hutchinson 1 , Sarah Robertson 1
  1. Research Centre for Reproductive Health, School of Paediatrics and Reproductive Health, Robinson Institute, The University of Adelaide, Adelaide, South Australia, Australia

The timing and progression of normal term labour is linked with an inflammation-like response in the gestational tissues. The nature of the initiating events in term labour, and how these relate to the pathophysiological inflammatory events of preterm labour, is poorly understood. TLR4 is a receptor for several endogenous damage-associated molecular patterns (DAMPs) released from the fetus and/or gestational tissues in late gestation. In this study we investigated the physiological role for Toll-like receptor 4 (TLR4) in normal term delivery. Mice with a null mutation in the Tlr4 gene (Tlr4-/- mice) and wild-type BALB/c controls were mated to males of the same genotype, gestation length, and perinatal parameters were recorded. Expression of uterine activation and inflammatory pathway genes were quantified by qPCR in the uterus, decidua, placenta, fetal membrane and fetal brain which was recovered on gestational day (gd) 16.5, 17.5, 18.5 and 19.5 in a second group of wild-type and Tlr4-/- females. In additional experiments, wild-type mice were administered a small TLR4 antagonist or PBS control on gd 16.5-17.5 and the effect on gestational length and perinatal parameters were recorded. The time of normal term parturition was delayed in Tlr4-/- mice compared with wild-type controls. In Tlr4-/- females delayed labour was accompanied by a lower expression of Ptgfr and Oxtr mRNA in both the uterine and decidual tissues, when compared to wild-type mice. The pro-inflammatory Il1b mRNA and anti-inflammatory Il10 mRNA were also downregulated in the placenta, fetal membrane, and fetal brain of Tlr4 -/- mice, when compared to the wild-type females. Administration of the TLR4 antagonist to wild-type mice in late gestation caused a delay in the time of delivery. These results imply a critical role for TLR4 in initiation or progression of the events of parturition and delivery.