Suppressor of Cytokine Signaling-1 Attenuates the Duration of Interferon γ 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 IFNγ signaling in SOCS-1−/− mice, it is unclear to what extent this is due to increased IFNγ levels or to increased IFNγ sensitivity. Here we have used SOCS-1−/− IFNγ−/− mice, which remain healthy and produce no endogenous IFNγ, to demonstrate thatin vitro and in vivo hepatocytes lacking SOCS-1 exhibit a prolonged response to IFNγ and that this correlates with a dramatically increased sensitivity to the toxic effects of IFNγin vivo. Thus, SOCS-1 is required for the timely attenuation of IFNγ signaling in vivo.

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