Function of C/EBPδ in a regulatory circuit that discriminates between transient and persistent TLR4-induced signals
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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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Most prior mammalian regulatory circuit reconstruction studies assumed a single fixed network.
“Most of these studies have relied upon computational circuit-reconstruction algorithms that assume one ‘fixed’ network.”
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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
- Venue
- Nature Immunology
- Published
- 2009-03-08
- Volume
- 10
- Issue
- 4
- Pages
- 437-443
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- 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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