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Sci. Signal., 22 February 2011
Vol. 4, Issue 161, p. ra11
[DOI: 10.1126/scisignal.2001501]


The Specificity of Innate Immune Responses Is Enforced by Repression of Interferon Response Elements by NF-{kappa}B p50

Christine S. Cheng1,2,3, Kristyn E. Feldman1,2, James Lee1,2, Shilpi Verma4, De-Bin Huang2, Kim Huynh2, Mikyoung Chang5, Julia V. Ponomarenko6, Shao-Cong Sun5, Chris A. Benedict4, Gourisankar Ghosh2, and Alexander Hoffmann1,2,3*

1 Signaling Systems Laboratory, University of California–San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
2 Department of Chemistry and Biochemistry, University of California–San Diego, La Jolla, CA 92093, USA.
3 San Diego Center for Systems Biology, University of California–San Diego, La Jolla, CA 92093, USA.
4 Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
5 Department of Immunology, University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston, TX 77030, USA.
6 San Diego Supercomputer Center, University of California–San Diego, La Jolla, CA 92093, USA.

Abstract: The specific binding of transcription factors to cognate sequence elements is thought to be critical for the generation of specific gene expression programs. Members of the nuclear factor {kappa}B (NF-{kappa}B) and interferon (IFN) regulatory factor (IRF) transcription factor families bind to the {kappa}B site and the IFN response element (IRE), respectively, of target genes, and they are activated in macrophages after exposure to pathogens. However, how these factors produce pathogen-specific inflammatory and immune responses remains poorly understood. Combining top-down and bottom-up systems biology approaches, we have identified the NF-{kappa}B p50 homodimer as a regulator of IRF responses. Unbiased genome-wide expression and biochemical and structural analyses revealed that the p50 homodimer repressed a subset of IFN-inducible genes through a previously uncharacterized subclass of guanine-rich IRE (G-IRE) sequences. Mathematical modeling predicted that the p50 homodimer might enforce the stimulus specificity of composite promoters. Indeed, the production of the antiviral regulator IFN-β was rendered stimulus-specific by the binding of the p50 homodimer to the G-IRE–containing IFNβ enhancer to suppress cytotoxic IFN signaling. Specifically, a deficiency in p50 resulted in the inappropriate production of IFN-β in response to bacterial DNA sensed by Toll-like receptor 9. This role for the NF-{kappa}B p50 homodimer in enforcing the specificity of the cellular response to pathogens by binding to a subset of IRE sequences alters our understanding of how the NF-{kappa}B and IRF signaling systems cooperate to regulate antimicrobial immunity.

* To whom correspondence should be addressed. E-mail: ahoffmann{at}

Citation: C. S. Cheng, K. E. Feldman, J. Lee, S. Verma, D.-B. Huang, K. Huynh, M. Chang, J. V. Ponomarenko, S.-C. Sun, C. A. Benedict, G. Ghosh, A. Hoffmann, The Specificity of Innate Immune Responses Is Enforced by Repression of Interferon Response Elements by NF-{kappa}B p50. Sci. Signal. 4, ra11 (2011).

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