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.

Suppressors of cytokine signaling (SOCS): negative regulators of signal transduction.

SOCS-1 was originally identified as an inhibitor of interleukin-6 signal transduction and is a member of a family of proteins (SOCS-1 to SOCS-7 and CIS) that contain an SH2 domain and a conserved carboxyl-terminal SOCS box motif. Mutation studies have established that critical contributions from both the amino-terminal and SH2 domains are essential for SOCS-1 and SOCS-3 to inhibit cytokine signaling. Inhibition of cytokine-dependent activation of STAT3 occurred in cells expressing either SOCS-1 or SOCS-3, but unlike SOCS-1, SOCS-3 did not directly interact with or inhibit the activity of JAK kinases. Although the conserved SOCS box motif appeared to be dispensable for SOCS-1 and SOCS-3 action when overexpressed, this domain interacts with elongin proteins and may be important in regulating protein turnover. In gene knockout studies, SOCS-1(-/-) mice were born but failed to thrive and died within 3 weeks of age with fatty degeneration of the liver and hemopoietic infiltration of several organs. The thymus in SOCS-1(-/-) mice was small, the animals were lymphopenic, and deficiencies in B lymphocytes were evident within hemopoietic organs. We propose that the absence of SOCS-1 in these mice prevents lymphocytes and liver cells from appropriately controlling signals from cytokines with cytotoxic side effects.

Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1.

SOCS-1, a member of the suppressor of cytokine signaling (SOCS) family, was identified in a genetic screen for inhibitors of interleukin 6 signal transduction. SOCS-1 transcription is induced by cytokines, and the protein binds and inhibits Janus kinases and reduces cytokine-stimulated tyrosine phosphorylation of signal transducers and activators of transcription 3 and the gp130 component of the interleukin 6 receptor. Thus, SOCS-1 forms part of a feedback loop that modulates signal transduction from cytokine receptors. To examine the role of SOCS-1 in vivo, we have used gene targeting to generate mice lacking this protein. SOCS-1(-/-) mice exhibited stunted growth and died before weaning with fatty degeneration of the liver and monocytic infiltration of several organs. In addition, the thymus of SOCS-1(-/-) mice was reduced markedly in size, and there was a progressive loss of maturing B lymphocytes in the bone marrow, spleen, and peripheral blood. Thus, SOCS-1 is required for in vivo regulation of multiple cell types and is indispensable for normal postnatal growth and survival.