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 intrace llular protein that functions to negatively regulate cytokine signal transd uction pathways. Studies in vitro have shown that constitutive over express ion of SOCS-1 inhibits signaling in response to a range of cytokines, inclu ding interferons (IFN). Mice lacking SOCS-1 die from a complex disease char acterized by liver degeneration and massive inflammation. Whereas there is clear evidence of increased IFN gamma signaling in SOCS-1(-/-) mice, it is unclear to what extent this is due to increased IFN gamma levels or to incr eased IFN gamma sensitivity. Here we have used SOCS-1(-/-) IFN gamma (-/-) mice, which remain healthy and produce no endogenous IFN gamma to demonstra te that in vitro and in vivo hepatocytes lacking SOCS-1 exhibit a prolonged response to IFN gamma and that this correlates with a dramatically increas ed sensitivity to the toxic effects of IFN gamma in vivo. Thus, SOCS-1 is r equired for the timely attenuation of IFN gamma signaling in vivo.