Transient IkappaB kinase activity mediates temporal NF-kappaB dynamics in response to a wide range of tumor necrosis factor-alpha doses.
Dynamic properties of signaling pathways control their behavior and function. We undertook an iterative computational and experimental investigation of the dynamic properties of tumor necrosis factor (TNF)alpha-mediated activation of the transcription factor NF-kappaB. Surprisingly, we found that the temporal profile of the NF-kappaB activity is invariant to the TNFalpha dose. We reverse engineered a computational model of the signaling pathway to identify mechanisms that impart this important response characteristic, thus predicting that the IKK activity profile must transiently peak at all TNFalpha doses to generate the observed NF-kappaB dynamics. Experimental confirmation of this prediction emphasizes the importance of mechanisms that rapidly down-regulate IKK following TNFalpha activation. A refined computational model further revealed signaling characteristics that ensure robust TNFalpha-mediated cell-cell communication over considerable distances, allowing for fidelity of cellular inflammatory responses in infected tissue.
Cheong
Raymond
R
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland 21218, USA.
Bergmann
Adriel
A
Werner
Shannon L
SL
Regal
Joshua
J
Hoffmann
Alexander
A
Levchenko
Andre
A
D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D051550:I-kappa B Kinase / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase