A dual negative regulation model of Toll-like receptor 4 signaling for endotoxin preconditioning in human endotoxemia

We discuss a model illustrating how the outcome of repeated endotoxin administration experiments can emerge as a natural consequence of the tightly regulated signaling pathways and also highlight the importance of a dual negative feedback regulation including PI3K/Akt and IRAK-M (IRAK3). We identify the relative time scales of the onset and the magnitude of the stimulus as key determinants of outcome in repeated administration experiments. The results of our simulations involve potentiated response, tolerance, and protective tolerance. Moreover, the knockout of negative regulators shows that IRAK-M is a necessary and sufficient factor for generation of endotoxin tolerance (ET). The effects of the knockout of IRAK-M gene or administration of PI3K inhibitor do yield predictions that have been verified experimentally. Finally, the pretreatment with PI3K inhibitor reveals the interaction between these two negative regulations.

► We explore models describing the outcome of repeated endotoxin administration.
► The response emerges as a natural consequence of tightly regulated signaling pathways.
► We identify the importance of a dual negative feedback regulation including PI3K/Akt and IRAK-M (IRAK3).
► Our model predicts potentiated response, tolerance, and protective tolerance and evaluates the effect of knockout of negative regulators showing that IRAK-M is a necessary and sufficient factor for generation of endotoxin tolerance.
► The pretreatment with PI3K inhibitor reveals the interaction between the two negative regulations.