Kinetic control of negative feedback regulators of NF-κB/RelA determines their pathogen- and cytokine-receptor signaling specificity

Mammalian signaling networks contain an abundance of negative feedback regulators that may have overlapping (fail-safe'') or specific functions. Within the NF-kappa B signaling module, I kappa B alpha is known as a negative feedback regulator, but the newly characterized inhibitor I kappa B delta is also inducibly expressed in response to inflammatory stimuli. To examine I kappa B delta's roles in inflammatory signaling, we mathematically modeled the 4-I kappa B-containing NF-kappa B signaling module and developed a computational phenotyping methodology of general applicability. We found that I kappa B delta, like I kappa B alpha, can provide negative feedback, but each functions stimulus-specifically. Whereas I kappa B delta attenuates persistent, pathogen-triggered signals mediated by TLRs, the more prominent I kappa B alpha does not. Instead, I kappa B alpha, which functions more rapidly, is primarily involved in determining the temporal profile of NF-kappa B signaling in response to cytokines that serve intercellular communication. Indeed, when removing the inducing cytokine stimulus by compound deficiency of the tnf gene, we found that the lethality of i kappa b alpha(-/-) mouse was rescued. Finally, we found that I kappa B delta provides signaling memory owing to its long half-life; it integrates the inflammatory history of the cell to dampen NF-kappa B responsiveness during sequential stimulation events.