Cited by 296Immune Response and InflammationNF-κB Signaling PathwaysGene Regulatory Network Analysis

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Function of C/EBPδ in a regulatory circuit that discriminates between transient and persistent TLR4-induced signals

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Litvak, Vladimir, Ramsey, Stephen A, Rust, Alistair G, Zak, Daniel E, Kennedy, Kathleen A, Lampano, Aaron E, Nykter, Matti, Shmulevich, Ilya, Aderem, Alan·2009·Nature Immunology

DOI 10.1038/ni.1721PMC PMC2780024

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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.

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Authors: Litvak, V., Ramsey, S. A., Rust, A. G., Zak, D. E., Kennedy, K. A., Lampano, A. E., Nykter, M., Shmulevich, I., & Aderem, A.
Affiliations: Institute for Systems Biology (US)
Corresponding author: Aderem, Alan
ORCID: Ramsey, Stephen A
Rust, Alistair G
Zak, Daniel E
Lampano, Aaron E
Nykter, Matti
Aderem, Alan
Venue: Nature Immunology
Publisher: Springer Science and Business Media LLC
Published: 2009-03-08
Volume: 10
Issue: 4
Pages: 437-443
ISSN: 1529-2908 (ISSN-L)
1529-2916
DOI: 10.1038/ni.1721
PMC: PMC2780024
OpenAlex: W2036584139
Cited by: 295
References: 52
Citations by year: 2026: 8 · 2025: 12 · 2024: 13 · 2023: 11 · 2022: 11 · 2021: 13 · 2020: 3 · 2019: 9 · 2018: 18 · 2017: 12 · 2016: 15 · 2015: 16 · 2014: 21 · 2013: 28 · 2012: 27
FWCI: 15.10
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Immunology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute of Allergy and Infectious Diseases (R01AI032972, R01AI025032)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
Keywords: C/EBPδ, TLR4, NF-κB, ATF3, transcriptional regulatory networks, gene regulatory networks, innate immunity, interleukin-6, inflammation
MeSH terms: Animals, Bone Marrow Cells, Cells, Cultured, Escherichia coli Infections, Immunity, Innate, Lipopolysaccharides, Macrophages, Mice, Inbred C57BL, Models, Genetic, Interleukin-6, NF-kappa B, Mice, Knockout, Systems Biology, Toll-Like Receptor 4, Mice, Activating Transcription Factor 3, CCAAT-Enhancer-Binding Protein-delta, Gene Regulatory Networks

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Function of C/EBPδ in a regulatory circuit that discriminates between transient and persistent TLR4-induced signals

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