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Published online 30 May 2006. doi:10.1083/jcb.200510155
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 173, Number 5, 659-664
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 I{kappa}B{varepsilon} provides negative feedback to control NF-{kappa}B oscillations, signaling dynamics, and inflammatory gene expression

Jeffrey D. Kearns, Soumen Basak, Shannon L. Werner, Christine S. Huang, and Alexander Hoffmann

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-{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{varepsilon}, 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{varepsilon} 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{varepsilon} 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.

Abbreviations used in this paper: EMSA, electrophoretic mobility shift assay; IKK, I{kappa}B kinase; MEF, murine embryonic fibroblast; RPA, RNase protection assay.


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