title: The specificity of innate immune responses is enforced by repression of interferon response elements by NF-κB p50.
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 κB (NF-κB) and interferon (IFN) regulatory factor (IRF) transcription factor families bind to the κB 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-κB 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-κB 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-κB and IRF signaling systems cooperate to regulate antimicrobial immunity.
authors.affiliation: Signaling Systems Laboratory, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Cheng
authors.forename: Kristyn E
authors.initials: KE
authors.lastname: Feldman
authors.forename: James
authors.initials: J
authors.lastname: Lee
authors.forename: Shilpi
authors.initials: S
authors.lastname: Verma
authors.forename: De-Bin
authors.initials: DB
authors.lastname: Huang
authors.forename: Kim
authors.initials: K
authors.lastname: Huynh
authors.forename: Mikyoung
authors.initials: M
authors.lastname: Chang
authors.forename: Julia V
authors.initials: JV
authors.lastname: Ponomarenko
authors.forename: Shao-Cong
authors.initials: SC
authors.lastname: Sun
authors.forename: Chris A
authors.initials: CA
authors.lastname: Benedict
authors.forename: Gourisankar
authors.initials: G
authors.lastname: Ghosh
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D015342:DNA Probes; D006801:Humans; D007113:Immunity, Innate; D007372:Interferons / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D052002:NF-kappa B p50 Subunit / Q000502:physiology*
chemical_list: D015342:DNA Probes; D052002:NF-kappa B p50 Subunit; D007372:Interferons