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Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity

Nature Immunology volume 7, pages 33–39 (2006)Cite this article

Abstract

Suppressor of cytokine signaling 1 (SOCS1) is a critical regulator of cytokine signaling and immune responses. SOCS1-deficient mice develop severe inflammatory disease, but are very resistant to viral infections. Using neutralizing antibody to type I interferon (IFN-α and IFN-β) and mice deficient in interferon-γ or type I interferon receptor components (IFNAR1 or IFNAR2), we demonstrate here that SOCS1 deficiency amplified type I interferon antiviral and proinflammatory actions independently of interferon-γ. The mechanism of the suppression of type I interferon responses by SOCS1 was distinct from that of other cytokines. SOCS1 associated with and regulated IFNAR1- but not IFNAR2-specific signals, abrogating tyrosine phosphorylation of transcription factor STAT1 and reducing the duration of antiviral gene expression. Thus, SOCS1 is an important in vivo inhibitor of type I interferon signaling and contributes to balancing its beneficial antiviral versus detrimental proinflammatory effects on innate immunity.

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Figure 1: Viral replication and interferon secretion from SFV-infected neonatal mice with targeted mutation of Socs1.
Figure 2: IFN-γ responses do not affect the 'hyper-resistance' of Socs1−/− mice to viral infection.
Figure 3: Type I interferon mediates resistance to SFV in Socs1−/−Ifng−/− mice.
Figure 4: Mechanism of SOCS1 suppression of type I interferon antiviral signaling.
Figure 5: IFNAR1 and SOCS1 show a direct interaction.

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Acknowledgements

Supported by the National Health and Medical Research Council of Australia.

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Author notes

  1. Robyn Starr

    Present address: St Vincent's Institute for Medical Research, Fitzroy, 3065, Australia

  2. Ann L Cornish

    Present address: Department of Microbiology and Immunology, University of Melbourne, Melbourne, 3010, Australia

Authors and Affiliations

  1. Centre for Functional Genomics and Human Disease, Monash Institute of Medical Research, Monash University, Clayton, 3168, Australia

    Jennifer E Fenner & Paul J Hertzog

  2. The Walter and Eliza Hall Institute for Medical Research and The Cooperative Research Center For Cellular Growth Factors, Parkville, 3050, Australia

    Robyn Starr, Ann L Cornish, Jian-Guo Zhang, Donald Metcalf, Douglas J Hilton & Warren S Alexander

  3. Department of Pathology and Immunology, Center for Immunology, Washington University, St. Louis, 63110, Missouri, USA

    Robert D Schreiber & Kathleen Sheehan

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Correspondence to Paul J Hertzog.

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Fenner, J., Starr, R., Cornish, A. et al. Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity. Nat Immunol 7, 33–39 (2006). https://doi.org/10.1038/ni1287

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