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IB provides negative feedback to control NF-B oscillations, signaling dynamics, and inflammatory gene expression

Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093

Correspondence to Alexander Hoffmann: ahoffmann{at}ucsd.edu

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

Abbreviations used in this paper: EMSA, electrophoretic mobility shift assay; IKK, IB kinase; MEF, murine embryonic fibroblast; RPA, RNase protection assay.

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