title: A dual negative regulation model of Toll-like receptor 4 signaling for endotoxin preconditioning in human endotoxemia.
abstract: 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.
authors.affiliation: Chemical Engineering, Rutgers University, Piscataway, NJ 08854, USA. qiany@eden.rutgers.edu
authors.forename: Qian
authors.initials: Q
authors.lastname: Yang
authors.forename: Steven E
authors.initials: SE
authors.lastname: Calvano
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Lowry
authors.forename: Ioannis P
authors.initials: IP
authors.lastname: Androulakis
mesh_terms: D003198:Computer Simulation; D019446:Endotoxemia / Q000378:metabolism*; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D058539:Phosphatidylinositol 3-Kinase; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases