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

Jennifer E Fenner¹, Robyn Starr^2, 4, Ann L Cornish^2, 4, Jian-Guo Zhang², Donald Metcalf², Robert D Schreiber³, Kathleen Sheehan³, Douglas J Hilton², Warren S Alexander² & Paul J Hertzog¹

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

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

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

⁴  Present addresses: St Vincent's Institute for Medical Research, Fitzroy 3065, Australia (R.S.), and Department of Microbiology and Immunology, University of Melbourne, Melbourne 3010, Australia (A.L.C.).

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- and IFN-) and mice deficient in interferon- 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-. 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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