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Sci. Signal., 14 January 2014
Vol. 7, Issue 308, p. ra6
[DOI: 10.1126/scisignal.2004764]

RESEARCH ARTICLES

Switching of the Relative Dominance Between Feedback Mechanisms in Lipopolysaccharide-Induced NF-{kappa}B Signaling

Myong-Hee Sung1*, Ning Li2{dagger}, Qizong Lao1{dagger}, Rachel A. Gottschalk2, Gordon L. Hager1*, and Iain D. C. Fraser2*

1 Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
2 Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

{dagger} These authors contributed equally to this work.

Abstract: A fundamental goal in biology is to gain a quantitative understanding of how appropriate cell responses are achieved amid conflicting signals that work in parallel. Through live, single-cell imaging, we monitored both the dynamics of nuclear factor {kappa}B (NF-{kappa}B) signaling and inflammatory cytokine transcription in macrophages exposed to the bacterial product lipopolysaccharide (LPS). Our analysis revealed a previously uncharacterized positive feedback loop involving induction of the expression of Rela, which encodes the RelA (p65) NF-{kappa}B subunit. This positive feedback loop rewired the regulatory network when cells were exposed to LPS above a distinct concentration. Paradoxically, this rewiring of NF-{kappa}B signaling in macrophages (a myeloid cell type) required the transcription factor Ikaros, which promotes the development of lymphoid cells. Mathematical modeling and experimental validation showed that the RelA positive feedback overcame existing negative feedback loops and enabled cells to discriminate between different concentrations of LPS to mount an effective innate immune response only at higher concentrations. We suggest that this switching in the relative dominance of feedback loops ("feedback dominance switching") may be a general mechanism in immune cells to integrate opposing feedback on a key transcriptional regulator and to set a response threshold for the host.

* Corresponding author. E-mail: sungm{at}mail.nih.gov (M.-H.S.); hagerg{at}mail.nih.gov (G.L.H.); fraseri{at}niaid.nih.gov (I.D.C.F.)

Citation: M.-H. Sung, N. Li, Q. Lao, R. A. Gottschalk, G. L. Hager, I. D. C. Fraser, Switching of the Relative Dominance Between Feedback Mechanisms in Lipopolysaccharide-Induced NF-{kappa}B Signaling. Sci. Signal. 7, ra6 (2014).

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Cracking the NF-{kappa}B Code.
K. E. Tkach, J. E. Oyler, and G. Altan-Bonnet (2014)
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