Suppressor of cytokine signaling-1 attenuates the duration of interferon gamma signal transduction in vitro and in vivo.
Suppressor of cytokine signaling-1 (SOCS-1) is a cytokine-inducible intracellular protein that functions to negatively regulate cytokine signal transduction pathways. Studies in vitro have shown that constitutive overexpression of SOCS-1 inhibits signaling in response to a range of cytokines, including interferons (IFN). Mice lacking SOCS-1 die from a complex disease characterized by liver degeneration and massive inflammation. Whereas there is clear evidence of increased IFNgamma signaling in SOCS-1(-/-) mice, it is unclear to what extent this is due to increased IFNgamma levels or to increased IFNgamma sensitivity. Here we have used SOCS-1(-/-) IFNgamma(-/-) mice, which remain healthy and produce no endogenous IFNgamma, to demonstrate that in vitro and in vivo hepatocytes lacking SOCS-1 exhibit a prolonged response to IFNgamma and that this correlates with a dramatically increased sensitivity to the toxic effects of IFNgamma in vivo. Thus, SOCS-1 is required for the timely attenuation of IFNgamma signaling in vivo.
Brysha
M
M
Cooperative Research Center for Cellular Growth Factors and the Walter and Eliza Hall Institute for Medical Research, PO Royal Melbourne Hospital, Newtown New South Wales 2042, Australia.
Zhang
J G
JG
Bertolino
P
P
Corbin
J E
JE
Alexander
W S
WS
Nicola
N A
NA
Hilton
D J
DJ
Starr
R
R
D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D012097:Repressor Proteins; D015398:Signal Transduction / Q000502:physiology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins
D002352:Carrier Proteins; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma