A Computational Model of Lipopolysaccharide-Induced Nuclear Factor Kappa B Activation: A Key Signalling Pathway in Infection-Induced Preterm Labour

Abstract

Preterm birth is the single biggest cause of significant neonatal morbidity and mortality, and the incidence is rising. Development of new therapies to treat and prevent preterm labour is seriously hampered by incomplete understanding of the molecular mechanisms that initiate labour at term and preterm. Computational modelling provides a new opportunity to improve this understanding. It is a useful tool in (i) identifying gaps in knowledge and informing future research, and (ii) providing the basis for an in silico model of parturition in which novel drugs to prevent or treat preterm labour can be “tested”. Despite their merits, computational models are rarely used to study the molecular events initiating labour. Here, we present the first attempt to generate a dynamic kinetic model that has relevance to the molecular mechanisms of preterm labour. Using published data, we model an important candidate signalling pathway in infection-induced preterm labour: that of lipopolysaccharide (LPS) -induced activation of Nuclear Factor kappa B. This is the first model of this pathway to explicitly include molecular interactions upstream of Nuclear Factor kappa B activation. We produced a formalised graphical depiction of the pathway and built a kinetic model based on ordinary differential equations. The kinetic model accurately reproduced published in vitro time course plots of Lipopolysaccharide-induced Nuclear Factor kappa B activation in mouse embryo fibroblasts. In this preliminary work we have provided proof of concept that it is possible to build computational models of signalling pathways that are relevant to the regulation of labour, and suggest that models that are validated with wet-lab experiments have the potential to greatly benefit the field.

Fatty Acid Oxidation Changes and the Correlation with Oxidative Stress in Different Preeclampsia-Like Mouse Models

“…LPS may participate in the development of PE through other inflammation pathways. LPS can activate macrophagocytes to produce interleukin 1, 6 and tumor necrosis factor, which act on endothelial cells and activate an NF-κB inflammation pathway [27] and finally induce endothelial injury and PE-like symptoms.…”

Investigating the Role of TNF-α and IFN-γ Activation on the Dynamics of iNOS Gene Expression in LPS Stimulated Macrophages

“…An effective tool for understanding the dynamics of complex biological systems is in silico modeling. Theoretical models are useful for aggregating empirical observations into quantitative descriptions of the temporal outcome of biochemical interactions in signal transduction cascades and gene expression systems [ 10 , 11 ]. For the present study, we developed an integrated computational model of the macrophage proinflammatory response to infection and consequential activation of iNOS gene expression.…”

Effect of oleic acid supplementation on prostaglandin production in maternal endometrial and fetal allantochorion cells isolated from late gestation ewes

“…The bacterial endotoxin lipopolysaccharide (LPS) increases the activities of phospholipase (PL)A2 and PTGS2, and inhibits PGDH [25,26]. LPS induces NFkB activation which is a key signalling pathway in infection-induced preterm labour [27].…”