IκBε provides negative feedback to control NF-κB oscillations, signaling dynamics, and inflammatory gene expression

NF-kappa B signaling is known to be critically regulated by the NF-kappa B-inducible inhibitor protein I kappa B alpha. The resulting negative feedback has been shown to produce a propensity for oscillations in NF-kappa B activity. We report integrated experimental and computational studies that demonstrate that another I kappa B isoform, I kappa B epsilon, also provides negative feedback on NF-kappa B activity, but with distinct functional consequences. Upon stimulation, NF-kappa B-induced transcription of I kappa B epsilon is delayed, relative to that of I kappa B alpha, rendering the two negative feedback loops to be in antiphase. As a result, I kappa B epsilon has a role in dampening I kappa B alpha-mediated oscillations during long-lasting NF-kappa B activity. Furthermore, we demonstrate the requirement of both of these distinct negative feedback regulators for the termination of NF-kappa B activity and NF-kappa B-mediated gene expression in response to transient stimulation. Our findings extend the capabilities of a computational model of I kappa B-NF-kappa B signaling and reveal a novel regulatory module of two antiphase negative feedback loops that allows for the fine-tuning of the dynamics of a mammalian signaling pathway.