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

Nature Immunology volume 10, pages 437–443 (2009)Cite this article

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-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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Figure 1: Prediction and confirmation of the existence of an LPS-induced transcription factor network involving NF-κB, C/EBPδ and ATF3.
Figure 2: Mathematical model characterizing the transcriptional regulation of Il6 in TLR4-stimulated macrophages.
Figure 3: Computational simulations of the transcriptional response of Il6 to TLR4 signals of varying duration identify a threshold effect.
Figure 4: Identification of direct targets of C/EBPδ.
Figure 5: The function of C/EBPδ in the restriction of transient and persistent bacterial infections.

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Acknowledgements

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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Authors and Affiliations

  1. Institute for Systems Biology, Seattle, Washington, USA

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

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  1. Vladimir Litvak
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  2. Stephen A Ramsey
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  3. Alistair G Rust
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  4. Daniel E Zak
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Contributions

V.L. designed experiments, did all experimental studies and drafted the manuscript; S.A.R. did data analysis and mathematical modeling; A.G.R., D.E.Z. and M.N. did computational analysis; K.A.K. did microarray experiments; A.E.L. provided technical assistance for experiments, including quantitative real-time PCR, ChIP and in vivo studies; I.S. supervised the computational analysis; and A.A. supervised the study and wrote the manuscript.

Corresponding author

Correspondence to Alan Aderem.

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Supplementary Figures 1–5, Supplementary Tables 1–5 and Supplementary Methods (PDF 2004 kb)

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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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