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PNAS 106 (24): 9619-9624

Copyright © 2009 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / BIOCHEMISTRY

Kinetic control of negative feedback regulators of NF-{kappa}B/RelA determines their pathogen- and cytokine-receptor signaling specificity

Vincent F.-S. Shiha,b, Jeffrey D. Kearnsa,b, Soumen Basaka,b, Olga V. Savinovab, Gourisankar Ghoshb, and Alexander Hoffmanna,b,1

aSignaling Systems Laboratory and bDepartment of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0375

Edited by Jurg Tschopp, University of Lausanne, Epalinges, Switzerland, and accepted by the Editorial Board March 30, 2009

Received for publication December 8, 2008.

Abstract: 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.

Key Words: inflammation • mathematical modeling • NF-kappaB • pathogen


Author contributions: V.F.-S.S., J.D.K., S.B., O.V.S., G.G., and A.H. designed research; V.F.-S.S., J.D.K., S.B., and O.V.S. performed research; J.D.K. contributed new reagents/analytic tools; V.F.-S.S., J.D.K., S.B., O.V.S., G.G., and A.H. analyzed data; and V.F.-S.S., G.G., and A.H. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission. J.T. is a guest editor invited by the Editorial Board.

This article contains supporting information online at www.pnas.org/cgi/content/full/0812367106/DCSupplemental.

1To whom correspondence should be addressed. E-mail: ahoffmann{at}ucsd.edu


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