Poster Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Novel non-competitive Interleukin-1 receptor antagonist protects from LPS-induced preterm delivery (#446)

Peck Y Chin 1 , Lachlan M Moldenhauer 1 , William D Lubell 2 , David M Olson 3 , Sylvain Chemtob 4 , Sarah A Robertson 1
  1. Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia
  2. Department of Chemistry, Université de Montréal, Montréal, Québec, Canada
  3. Departments of Obstetrics and Gynaecology, Pediatrics and Physiology, University of Alberta, Edmonton, AB, Canada
  4. Departments of Pediatrics, Opthalmology and Pharmacology, CHU Sainte-Justine Research Centre, Montreal, Quebec, Canada

Premature birth is a common and critical health issue in fetal-maternal medicine with long-term consequences especially for early preterm neonates. The pathophysiology of preterm labour is poorly understood and the causal factors uncertain, but inflammatory mechanisms are clearly implicated. Preterm delivery (PTD) is triggered when bacterial products including lipopolysaccharide (LPS) bind Toll-like receptors (TLRs) to activate inflammation. This results in premature induction of uterine activation proteins, inducing myometrial contractions and PTD in mice. Pro-inflammatory cytokine interleukin-1 beta (IL-1b) has been identified as a major upstream agent, immediately proximal to TLR activation, in the inflammatory pathway to PTD. This project seeks to investigate whether inhibition of IL-1 signalling using a small peptide non-competitive allosteric IL-1 receptor (IL-1R) antagonist rytvela may prevent the parturition cascade caused by LPS-induced inflammation. The effect of administration of IL-1R antagonist in preventing LPS-induced PTD was investigated in B6 mice. Pregnant B6 females were treated with LPS or PBS, with or without co-administration of IL-1R antagonist, on gestational day 16.5 and were either killed 4 hours later for RT-PCR analysis of inflammatory cytokines in gestational tissues, or allowed to deliver pups. PTD occurred in 30% (3/10) LPS-treated mice, but was effectively inhibited in mice given IL-1R antagonist 0% (0/10). IL-1R antagonist treatment resulted in on time birth with normal perinatal characteristics and pup survival rates. Administration of IL-1R antagonist was demonstrated to suppress LPS-induced expression of Il1b, Il6, Tnf and Il12b expression in the fetal brain, placenta and decidua. We conclude that early intervention with IL-1R antagonist acts to suppress the downstream inflammatory cascade can inhibit the progression of LPS-induced PTD by preventing premature activation of uterine activation proteins and subsequent onset of labour in mice. The IL-1 pathway warrants further investigation as a potential target for new prevention or treatment options in women with infection-associated PTD.