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-κB signaling module, IκBα is known as a negative feedback regulator, but the newly characterized inhibitor IκBδ is also inducibly expressed in response to inflammatory stimuli. To examine IκBδ's roles in inflammatory signaling, we mathematically modeled the 4-IκB-containing NF-κB signaling module and developed a computational phenotyping methodology of general applicability. We found that IκBδ, like IκBα, can provide negative feedback, but each functions stimulus-specifically. Whereas IκBδ attenuates persistent, pathogen-triggered signals mediated by TLRs, the more prominent IκBα does not. Instead, IκBα, which functions more rapidly, is primarily involved in determining the temporal profile of NF-κB 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 iκbα−/− mouse was rescued. Finally, we found that IκBδ provides signaling memory owing to its long half-life; it integrates the inflammatory history of the cell to dampen NF-κB responsiveness during sequential stimulation events.