Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity.
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-alpha and IFN-beta) and mice deficient in interferon-gamma 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-gamma. 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.
Fenner
Jennifer E
JE
Centre for Functional Genomics and Human Disease, Monash Institute of Medical Research, Monash University, Clayton 3168, Australia.
Starr
Robyn
R
Cornish
Ann L
AL
Zhang
Jian-Guo
JG
Metcalf
Donald
D
Schreiber
Robert D
RD
Sheehan
Kathleen
K
Hilton
Douglas J
DJ
Alexander
Warren S
WS
Hertzog
Paul J
PJ
D000818:Animals; D000831:Animals, Newborn; D015139:Blotting, Southern; D002352:Carrier Proteins / Q000276:immunology* / Q000378:metabolism; D047468:Immunoprecipitation; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000276:immunology / Q000378:metabolism; D012097:Repressor Proteins / Q000276:immunology* / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D014777:Virus Diseases / Q000276:immunology*
D002352:Carrier Proteins; C508032:Ifnar1 protein, mouse; C508034:Ifnar2 protein, mouse; D007370:Interferon Type I; D008565:Membrane Proteins; D017471:Receptors, Interferon; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053633:Receptor, Interferon alpha-beta