Document Type
Article
Publication Date
8-19-2016
Abstract
Background: Progesterone promotes uterine relaxation and is essential for the maintenance of pregnancy. Withdrawal of progesterone activity and increased inflammation within the uterine tissues are key triggers for parturition. Progesterone actions in myometrial cells are mediated by two progesterone receptor (PR) isoforms, PR-A and PR-B, that function as ligand-activated transcription factors. PR-B mediates relaxatory actions of progesterone, in part, by decreasing myometrial cell responsiveness to pro-inflammatory stimuli. These same pro-inflammatory stimuli promote the expression of PR-A which inhibits the anti-inflammatory activity of PR-B. Competitive interaction between the progesterone receptors then augments myometrial responsiveness to pro-inflammatory stimuli. The interaction between PR-B transcriptional activity and inflammation in the pregnancy myometrium is examined using a dynamical systems model in which quiescence and labor are represented as phase-space equilibrium points. Our model shows that PR-B transcriptional activity and the inflammatory load determine the stability of the quiescent and laboring phenotypes. The model is tested using published transcriptome datasets describing the mRNA abundances in the myometrium before and after the onset of labor at term. Surrogate transcripts were selected to reflect PR-B transcriptional activity and inflammation status. Results: The model coupling PR-B activity and inflammation predicts contractile status (i.e., laboring or quiescent) with high precision and recall and outperforms uncoupled single and two-gene classifiers. Linear stability analysis shows that phase space bifurcations exist in our model that may reflect the phenotypic states of the pregnancy uterus. The model describes a possible tipping point for the transition of the quiescent to the contractile laboring phenotype. Conclusions: Our model describes the functional interaction between the PR-A:PR-B hypothesis and tissue level inflammation in the pregnancy uterus and is a first step in more sophisticated dynamical systems modeling of human partition. The model explains observed biochemical dynamics and as such will be useful for the development of a range of systems-based models using emerging data to predict preterm birth and identify strategies for its prevention.
Keywords
dynamical systems, inflammation, myometrium, parturition, progesterone receptor
Publication Title
BMC Systems Biology
Grant
T32HL007567; HD069819
Funder
National Institutes of Health (NIH); Clinical and Translational Science Collaborative, Case Western Reserve School of Medicine; March of Dimes Ohio Prematurity Research Collaborative; The Global Alliance to Prevent Prematurity and Stillbirth; Eunice Kennedy Shriver National Institute of Child Health and Human Development
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Brubaker, D., Barbaro, A., R. Chance, M. et al. A dynamical systems model of progesterone receptor interactions with inflammation in human parturition. BMC Syst Biol 10, 79 (2016). https://doi.org/10.1186/s12918-016-0320-1