Inflammatory Mediators of Pre-Term Labor

Intrauterine infection/inflammation (IUI), also known as chorioamnionitis, is a condition that occurs when bacteria from the urogenital tract ascends to the uterus and infects the membranes surrounding the fetus as well as the amniotic fluid. It is well established that IUI contributes to preterm labor and can led to devastating health outcomes for both the pregnant individual and the fetus. Not all IUI cases end in preterm delivery, however, thus necessitating research to identify the specific inflammatory mediators that drive IUI-induced preterm labor.

A recent study in PLOS Biology sought to address this gap in knowledge using non-human primate models of IUI in which pregnant rhesus macaques were intra-amniotically injected with either live Escherichia coli or with the gram-negative bacterial membrane component lipopolysaccharid (LPS). While neutrophil infiltration into maternal and fetal placental tissue and upregulation of pro-inflammatory cytokines were observed in both LPS and E. coli treated animals, live bacteria induced the greatest increase in expression of inflammatory markers, including interleukin-6 (IL-6) and prostaglandins PGE2 and PGF2α. Importantly, preterm labor was only observed in E. coli treated dams and occurred even after antibiotic administration in 6 of 8 treated dams.

The authors next wanted to determine the anatomical location of these pro-inflammatory signals and used a novel technique, dual RNAscope fluorescence, to co-localize IL6 and PTGS2 mRNA expression with activated neutrophils (defined as being myeloperoxidase (MPO) positive). MPO+ neutrophils expressing PTGS2 were observed in the maternal tissue (decidua) and the outermost fetal tissue (chorion) in both treatment groups, however, far more MPO+PTGS2+ neutrophils were observed in the innermost fetal membrane (amnion) of animals treated with E. coli. Additionally, epithelial and mesenchymal cells were found to express IL6 and these IL6+ cells were only observed in the amnion of animals treated with E. coli.

Finally, Cappelleti et al. compared the chorioamnion-decidua tissue gene expression profiles of E. coli-exposed animals that did or did not experience preterm labor. Tissue from the preterm labor group showed upregulation of genes involved in neutrophil-mediated immunity and degranulation and regulation of IL-6 production.

This study is one of the first to define inflammatory features of infection capable of triggering preterm birth. Specifically, Cappelletti and colleagues showed that the magnitude of the inflammatory response and the upregulation of specific pathways–such as those related to IL-6 and prostaglandin production–are critical contributors to preterm labor. Literature in the field of immunology often focuses on the presence and clearance of inflammation, however, this research demonstrates the importance of understanding the specific mechanisms underlying different tiers of the inflammatory response. Of further interest was the observation that IUI-triggered preterm labor could not be rescued by antibiotics as the inflammatory environment persisted despite bacterial clearance. Thus, a deeper understanding of the immunological microbiological, and pharmacological processes existing at the complex maternal-fetal interface will be necessary for the creation of novel intervention strategies to protect against infection induced preterm labor.