Preterm birth has recently become recognized as the primary cause of death in children worldwide under the age of five. Despite a huge research effort over the last few decades, rates of preterm birth in most countries continue to rise.
One of the main reasons for this is our incomplete understanding of the mechanisms that control the timing of human labor. Both hormonal and inflammatory signalling in the uterus have been proposed to regulate the onset of uterine contractions, however, it is unclear which of these is the most important.
Levels of the hormone progesterone increase throughout pregnancy to maintain uterine relaxation in both mice and humans. Removal of progesterone action causes rapid onset of labor. There is also evidence in mice and humans of activation of inflammation within the uterus at the time of onset of labor at term, with increased synthesis of inflammatory cytokines and chemokines as well as an influx of inflammatory cells.
Whether this is a cause or a side-effect of labor is not clear, but we do know that the activation of inflammation in the uterus (e.g. via infection) can cause premature labor in both species. In our study, published in BMC Medicine, we examine the relative contribution of inflammation and progesterone signalling in switching the uterus from a relaxed state to an actively contractile organ.
We began the study by mapping in detail the transcriptional changes that occur in the mouse uterus towards the end of healthy pregnancy at the time of labor onset. This was then compared to uterine transcriptome changes in animals delivering prematurely, following either the inhibition of progesterone signalling (using the progesterone receptor antagonist RU486) or following activation of inflammation (using the bacterial membrane protein, lipopolysaccharide).
This approach enabled us to identify a core set of gene changes shared across all models that are involved in key processes required for labor, including muscle contraction, ion transport and cell adhesion.
This approach enabled us to identify a core set of gene changes shared across all models that are involved in key processes required for labor, including muscle contraction, ion transport and cell adhesion.
Further analyses revealed that withdrawal of progesterone action leads to a similar, temporal pattern of gene changes prior to labor as those observed in animals undergoing normal labor at term. We observed that preterm labor induced by progesterone withdrawal does not involve activation of inflammatory genes, suggesting that uterine inflammation is not a requisite for labor onset in the mouse.
In contrast, lipopolysaccharide-induced preterm labor involved a unique trajectory of inflammatory gene activation that occurred in the presence of high concentrations of circulating progesterone. These results indicate that acute inflammatory activation in the uterus is sufficient to override the relaxant properties of progesterone.
Statistical modelling of the mouse transcriptome profiling data against available human datasets enabled us to show that human labor more closely resembles inflammation-induced preterm labor in the mouse.
Our study improves the understanding of the contribution progesterone and inflammatory signaling make to the onset of labor in the mouse and human. By publishing the first comprehensive, temporal characterization of uterine transcriptome changes preceding the onset of term and preterm labor in the mouse, we provide the research community with a rich source of information that will inform the development of future strategies for the prevention of preterm birth.
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