Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4 (original) (raw)

Nature volume 441, pages 173–178 (2006)Cite this article

A Corrigendum to this article was published on 21 February 2008

Abstract

The innate immune system is absolutely required for host defence, but, uncontrolled, it leads to inflammatory disease. This control is mediated, in part, by cytokines that are secreted by macrophages. Immune regulation is extraordinarily complex, and can be best investigated with systems approaches (that is, using computational tools to predict regulatory networks arising from global, high-throughput data sets). Here we use cluster analysis of a comprehensive set of transcriptomic data derived from Toll-like receptor (TLR)-activated macrophages to identify a prominent group of genes that appear to be regulated by activating transcription factor 3 (ATF3), a member of the CREB/ATF family of transcription factors. Network analysis predicted that ATF3 is part of a transcriptional complex that also contains members of the nuclear factor (NF)-κB family of transcription factors. Promoter analysis of the putative ATF3-regulated gene cluster demonstrated an over-representation of closely apposed ATF3 and NF-κB binding sites, which was verified by chromatin immunoprecipitation and hybridization to a DNA microarray. This cluster included important cytokines such as interleukin (IL)-6 and IL-12b. ATF3 and Rel (a component of NF-κB) were shown to bind to the regulatory regions of these genes upon macrophage activation. A kinetic model of Il6 and Il12b messenger RNA expression as a function of ATF3 and NF-κB promoter binding predicted that ATF3 is a negative regulator of Il6 and Il12b transcription, and this hypothesis was validated using _Atf3_-null mice. ATF3 seems to inhibit Il6 and Il12b transcription by altering chromatin structure, thereby restricting access to transcription factors. Because ATF3 is itself induced by lipopolysaccharide, it seems to regulate TLR-stimulated inflammatory responses as part of a negative-feedback loop.

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Acknowledgements

We acknowledge A. Ozinsky, I. Shmulevich, W. Longabaugh and L. Hood for discussions. We thank A. Nachman, A. Clark and C. Baldwin for technical assistance. This work was supported by a Fellowship from the Alberta Heritage Foundation for Medical Research (to M.G.) and the NIH (to A.A.)

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Authors and Affiliations

  1. Institute for Systems Biology, Seattle, Washington, 98103, USA
    Mark Gilchrist, Vesteinn Thorsson, Bin Li, Alistair G. Rust, Martin Korb, Kathleen Kennedy, Hamid Bolouri & Alan Aderem
  2. Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio, 43210, USA
    Tsonwin Hai

Authors

  1. Mark Gilchrist
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  2. Bin Li
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  3. Alistair G. Rust
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  4. Martin Korb
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  5. Kathleen Kennedy
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  6. Tsonwin Hai
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  7. Hamid Bolouri
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  8. Alan Aderem
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Corresponding author

Correspondence toAlan Aderem.

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Gilchrist, M., Thorsson, V., Li, B. et al. Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4.Nature 441, 173–178 (2006). https://doi.org/10.1038/nature04768

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Editorial Summary

You can't beat the systems

Systems biology, the field that exploits data collected by genomics, proteomics and all-the-other-omics to analyse living organisms at a higher level than conventional biology, is touted as a powerful tool for dissecting complex systems. But until now it has not been particularly effective in identifying basic mechanisms in mammals. The immune response is well suited to systems analysis; mouse models are well defined and circulating cells can be purified and cultured. Gilchrist et al. have used a systems approach to kinetic modelling of TLR4-stimulated macrophages and arrive at a prediction that the transcription factor ATF3 is a negative regulator of the innate immune response, acting via chromatin remodelling. So, probably for the first time, the tools of systems biology have revealed a novel regulatory mechanism in the immune response and a possible new drug target.