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TNF activates an IRF1-dependent autocrine loop leading to sustained expression of chemokines and STAT1-dependent type I interferon–response genes

Nature Immunology volume 9, pages 378–387 (2008)Cite this article

Abstract

Rapid induction of inflammatory genes by tumor necrosis factor (TNF) has been well studied, but little is known about delayed and chronic TNF responses. Here we investigated the kinetics of primary macrophage responses to TNF and discovered that TNF initiates an interferon-β-mediated autocrine loop that sustains expression of inflammatory genes and induces delayed expression of interferon-response genes such as those encoding the transcription factors STAT1 and IRF7, which enhance macrophage responses to stimulation of cytokines and Toll-like receptors. TNF-induced interferon-β production depended on interferon-response factor 1, and downstream gene expression was mediated by synergy between small amounts of interferon-β and canonical TNF-induced signals. Thus, TNF activates a 'feed-forward' loop that sustains inflammation but avoids the potential toxicity associated with the high interferon production induced by stimulation of Toll-like receptors.

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Figure 1: TNF induces late and sustained expression of STAT1 and interferon-response genes in monocytes and macrophages.
Figure 2: TNF signaling is required for gene induction.
Figure 3: Kinetics of TNF-induced gene expression.
Figure 4: Expression of TNF late-response genes is dependent on autocrine IFN-β production.
Figure 5: Synergistic activation of intermediate-response genes by TNF and IFN-β.
Figure 6: Function of TNF in priming and IFN-β production in response to adenoviral transduction and in vivo.
Figure 7: Partial function of IRF3 in TNF-induced expression of late-response genes.
Figure 8: TNF-induced IFN-β production and downstream gene expression mediated by IRF1.

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Acknowledgements

We thank D. Levy (New York University School of Medicine) for providing IFNAR-deficient mice; E. Falck-Pedersen (Weill Medical College of Cornell University) for providing IRF3-deficient bone marrow; A. Ding (Weill Medical College of Cornell University) for MyD88- and TRIF-deficient bone marrow; J. Rutledge for statistical analysis of toxic shock survival; and E. Kelly for critically reviewing the manuscript. Supported by the National Institutes of Health (AR050401, AR46713 and AI46712 to L.B.I.).

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Authors and Affiliations

  1. Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, 10021, New York, USA

    Anna Yarilina, Kyung-Hyun Park-Min, Taras Antoniv, Xiaoyu Hu & Lionel B Ivashkiv

  2. Graduate Program in Immunology and Microbial Pathogenesis, Weill Graduate School of Medical Sciences of Cornell University, New York, 10021, New York, USA

    Lionel B Ivashkiv

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  1. Anna Yarilina
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A.Y. designed and did experiments and wrote the manuscript; K.H.-P.M., T.A. and X.H. did experiments; and L.B.I. designed and supervised the research and wrote the manuscript.

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Correspondence to Lionel B Ivashkiv.

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Yarilina, A., Park-Min, KH., Antoniv, T. et al. TNF activates an IRF1-dependent autocrine loop leading to sustained expression of chemokines and STAT1-dependent type I interferon–response genes. Nat Immunol 9, 378–387 (2008). https://doi.org/10.1038/ni1576

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