Function of C/EBPdelta in a regulatory circuit that discriminates between transient and persistent TLR4-induced signals.
Nat Immunol, 2009/4;10(4):437-43.
Litvak V[1], Ramsey SA, Rust AG, Zak DE, Kennedy KA, Lampano AE, Nykter M, Shmulevich I, Aderem A
Affiliations
PMID: 19270711DOI: 10.1038/ni.1721
Impact factor: 31.25
Abstract
The innate immune system is like a double-edged sword: it is absolutely required for host defense against infection, but when uncontrolled, it can trigger a plethora of inflammatory diseases. Here we use systems-biology approaches to predict and confirm the existence of a gene-regulatory network involving dynamic interaction among the transcription factors NF-kappaB, C/EBPdelta and ATF3 that controls inflammatory responses. We mathematically modeled transcriptional regulation of the genes encoding interleukin 6 and C/EBPdelta and experimentally confirmed the prediction that the combination of an initiator (NF-kappaB), an amplifier (C/EBPdelta) and an attenuator (ATF3) forms a regulatory circuit that discriminates between transient and persistent Toll-like receptor 4-induced signals. Our results suggest a mechanism that enables the innate immune system to detect the duration of infection and to respond appropriately.
MeSH terms
Activating Transcription Factor 3; Animals; Bone Marrow Cells; CCAAT-Enhancer-Binding Protein-delta; Cells, Cultured; Escherichia coli Infections; Gene Regulatory Networks; Immunity, Innate; Interleukin-6; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Genetic; NF-kappa B; Systems Biology; Toll-Like Receptor 4
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