Modelling the interactions between TLR4 and IFNβ pathways

Abstract

Bacterial lipopolysaccharide (LPS) association with their connate receptor TLR4 triggers Type I interferon signaling cascade through its MyD88 independent downstream. Compared to plethora of reported empirical data on both TLR4 and Type I interferon pathways, there is no known model to decipher crosstalk mechanisms between these two crucial innate immune pathogen activated pathways regulating vital transcriptional factors such as nuclear factor-κB (NFκB), IFNβ, the interferon-stimulated gene factor-3 (ISGF3) and an important cancer drug target protein kinase-R (PKR). Innate immune system is based on a sensitive balance of intricate interactions. In elucidating these interactions, in silico integration of pathways has great potential. Attempts confined to single pathway may not be effective in truly addressing source of real systems behavior. This is the first report combining toll-like receptor-4 (TLR4) and interferon beta (IFNβ) pathways in a single in silico model, analyzing their interactions, pinpointing the source of delay in PKR late phase activity and limiting the transcription of IFN and PKR by using a method including an statistical physics technique in reaction equations. The model quite successfully recapitulates published interferon regulatory factor-3 (IRF3) and IFNβ data from mouse macrophages and PKR data from mouse embryonic fibroblast cell lines. The simulations end up with an estimate of IRF3, IFNβ, ISGF3 dose dependent profiles mimicking nonlinear dose response characteristic of the system. Involvement of concomitant PKR downstream can unravel elusive mechanisms in specific profiles like NFκB regulation.