Transient IκB kinase activity mediates temporal NF-κB dynamics in response to a wide range of tumor necrosis factor-αdoses

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-kappa B. Surprisingly, we found that the temporal profile of the NF-kappa B activity is invariant to the TNF alpha 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 TNF alpha doses to generate the observed NF-kappa B dynamics. Experimental confirmation of this prediction emphasizes the importance of mechanisms that rapidly down-regulate IKK following TNF alpha activation. A refined computational model further revealed signaling characteristics that ensure robust TNF alpha-mediated cell-cell communication over considerable distances, allowing for fidelity of cellular inflammatory responses in infected tissue.