The Specificity of Innate Immune Responses Is Enforced by Repression of Interferon Response Elements by NF-
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 
B (NF-B) and interferon (IFN) regulatory factor (IRF) transcription factor families bind to the 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-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-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-B and IRF signaling systems cooperate to regulate antimicrobial immunity.
* To whom correspondence should be addressed. E-mail: ahoffmann{at}ucsd.edu
