The SOCS-1 story

SOCS-1 is an intracellular protein able to block the differentiation of leukemic M1 cells inducible by interferon γ (IFN-γ) or regulators using the gp130 receptor. Its transient production is readily inducible by cytokine stimulation, and SOCS-1 appears to be a negative feedback molecule, modulating or suppressing receptor signaling activated by at least eight cytokines. Mice lacking SOCS-1 develop a lethal neonatal syndrome including liver damage, depletion of T and B lymphocytes, and granulocyte-macrophage infiltration of the liver, lungs, pancreas, heart, and skin. These and the associated hematologic abnormalities in SOCS-1−/− mice can all be mimicked by the neonatal injection of high doses of IFN-γ. The lethal neonatal disease in SOCS-1−/− mice is preventable by injection of antibodies to IFN-γ or by crossing SOCS-1−/− mice with IFN-γ2/− mice, identifying IFN-γ as being essential for the initiation of the neonatal disease and death. IFN-γ appears not to be overproduced in SOCS-1−/− mice, and the lethal disease may arise from hyperresponsiveness of −/− cells to normal levels of IFN-γ. SOCS-1−/− mice allowed to survive the neonatal period by cross-mating with IFN-γ2/− mice may well ultimately develop other disease states, because loss of SOCS-1 potentially renders them hyperresponsive to other cytokine signaling.