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-κB, C/EBPδ and ATF3 that controls inflammatory responses. We mathematically modeled transcriptional regulation of the genes encoding interleukin 6 and C/EBPδ and experimentally confirmed the prediction that the combination of an initiator (NF-κB), an amplifier (C/EBPδ) 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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Janeway, C.A. & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).
Aderem, A. & Ulevitch, R.J. Toll-like receptors in the induction of the innate immune response. Nature 406, 782–787 (2000).
Medzhitov, R. Toll-like receptors and innate immunity. Nat. Rev. Immunol. 1, 135–145 (2001).
Nathan, C. Points of control in inflammation. Nature 420, 846–852 (2002).
Kobayashi, K.S. & Flavell, R.A. Shielding the double-edged sword: negative regulation of the innate immune system. J. Leukoc. Biol. 75, 428–433 (2004).
Barnes, P.J. & Karin, M. Nuclear factor-κB: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336, 1066–1071 (1997).
Bouma, G. & Strober, W. The immunological and genetic basis of inflammatory bowel disease. Nat. Rev. Immunol. 3, 521–533 (2003).
Liew, F.Y., Xu, D., Brint, E.K. & O'Neill, L.A.J. Negative regulation of toll-like receptor-mediated immune responses. Nat. Rev. Immunol. 5, 446–458 (2005).
Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006).
Kawai, T. & Akira, S. Pathogen recognition with Toll-like receptors. Curr. Opin. Immunol. 17, 338–344 (2005).
Royet, J., Reichhart, J.M. & Hoffmann, J.A. Sensing and signaling during infection in Drosophila. Curr. Opin. Immunol. 17, 11–17 (2005).
Takeda, K. & Akira, S. TLR signaling pathways. Semin. Immunol. 16, 3–9 (2004).
Jenner, R.G. & Young, R.A. Insights into host responses against pathogens from transcriptional profiling. Nat. Rev. Microbiol. 3, 281–294 (2005).
Beutler, B. Tlr4: Central component of the sole mammalian LPS sensor. Curr. Opin. Immunol. 12, 20–26 (2000).
Taylor, P.R. et al. Macrophage receptors and immune recognition. Annu. Rev. Immunol. 23, 901–944 (2005).
Gordon, S. Alternative activation of macrophages. Nat. Rev. Immunol. 3, 23–35 (2003).
Boldrick, J.C. et al. Stereotyped and specific gene expression programs in human innate immune responses to bacteria. Proc. Natl. Acad. Sci. USA 99, 972–977 (2002).
Nau, G.J. et al. Human macrophage activation programs induced by bacterial pathogens. Proc. Natl. Acad. Sci. USA 99, 1503–1508 (2002).
Roach, J.C. et al. Transcription factor expression in lipopolysaccharide-activated peripheral-blood-derived mononuclear cells. Proc. Natl. Acad. Sci. USA 104, 16245–16250 (2007).
Aderem, A. Systems biology: its practice and challenges. Cell 121, 511–513 (2005).
Kitano, H. Computational systems biology. Nature 420, 206–210 (2002).
Suthram, S., Sittler, T. & Ideker, T. The plasmodium protein network diverges from those of other eukaryotes. Nature 438, 108–112 (2005).
Ideker, T., Galitski, T. & Hood, L. A new approach to decoding life: Systems biology. Annu. Rev. Genomics Hum. Genet. 2, 343–372 (2001).
Aderem, A. & Smith, K.D. A systems approach to dissecting immunity and inflammation. Semin. Immunol. 16, 55–67 (2004).
Bolouri, H. & Davidson, E.H. Transcriptional regulatory cascades in development: initial rates, not steady state, determine network kinetics. Proc. Natl. Acad. Sci. USA 100, 9371–9376 (2003).
Smith, J., Theodoris, C. & Davidson, E.H. A gene regulatory network subcircuit drives a dynamic pattern of gene expression. Science 318, 794–797 (2007).
Gilchrist, M. et al. Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4. Nature 441, 173–178 (2006).
Hoffmann, A., Levchenko, A., Scott, M.L. & Baltimore, D. The IκB-NF-κB signaling module: temporal control and selective gene activation. Science 298, 1241–1245 (2002).
Ramsey, S.A. et al. Dual feedback loops in the GAL regulon suppress cellular heterogeneity in yeast. Nat. Genet. 38, 1082–1087 (2006).
Alon, U. Network motifs: theory and experimental approaches. Nat. Rev. Genet. 8, 450–461 (2007).
Flo, T.H. et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432, 917–921 (2004).
Ramsey, S.A. et al. Uncovering a macrophage transcriptional program by integrating evidence from motif scanning and expression dynamics. PLOS Comput. Biol. 4, e1000021 (2008).
Li, Q. & Verma, I.M. NF-κB regulation in the immune system. Nat. Rev. Immunol. 2, 725–734 (2002).
Lekstrom-Himes, J. & Xanthopoulos, K.G. Biological role of the CCAAT/enhancer-binding protein family of transcription factors. J. Biol. Chem. 273, 28545–28548 (1998).
Kovács, K.A., Steinmann, M., Magistretti, P.J., Halfon, O. & Cardinaux, J.R. CCAAT/enhancer-binding protein family members recruit the coactivator CREB-binding protein and trigger its phosphorylation. J. Biol. Chem. 278, 36959–36965 (2003).
Johnson, W.E. et al. Model-based analysis of tiling-arrays for ChIP-chip. Proc. Natl. Acad. Sci. USA 103, 12457–12462 (2006).
Longabaugh, W.J.R., Davidson, E.H. & Bolouri, H. Computational representation of developmental genetic regulatory networks. Dev. Biol. 283, 1–16 (2005).
We thank M. Gilchrist, E. Gold and C. Rosenberger for discussions and critical reading of the manuscript; and A. Nachman, I. Podolsky, C. Lorang and T. Stolyar for technical assistance. Supported by Irvington Institute Fellowship Program of the Cancer Research Institute (V.L.) and the National Institutes of Health (A.A.).
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Litvak, V., Ramsey, S., Rust, A. et al. Function of C/EBPδ in a regulatory circuit that discriminates between transient and persistent TLR4-induced signals. Nat Immunol 10, 437–443 (2009). https://doi.org/10.1038/ni.1721
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