Neutralization of interferon-gamma in neonatal SOCS1-/- mice prevents fatty degeneration of the liver but not subsequent fatal inflammatory disease.
Mice lacking the suppressor of cytokine signalling-1 (SOCS1) die within weeks of birth with extensive fatty degeneration of the liver, consistent with acute hepatic toxicity to interferon-gamma (IFN-gamma), and inflammation of multiple organs. We show here that treatment for 1 week from birth with neutralizing antibody to IFN-gamma rescues SOCS1-/- mice from lethal liver disease but the mice subsequently succumb to chronic inflammatory lesions characterized by T-lymphocyte infiltration of skeletal muscle, pancreas, lung, liver and skin. Elevated blood levels of eosinophils, neutrophils and platelets were also observed and the thymic lymphocyte population was depleted of CD4+ CD8+ T cells and showed a reduced CD4 : CD8 ratio. All T-cell populations in thymus, spleen and lymph node exhibited an increased proportion of cells bearing the activation marker CD44. These data suggest an important role for SOCS1 in T-lymphocyte regulation.
Bullen
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The Walter and Eliza Hall Institute of Medical Research and the Cooperative Research Centre for Cellular Growth Factors, Post Office, Royal Melbourne Hospital, Victoria, Australia. bullen@wehi.edu.au
Darwiche
R
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Metcalf
D
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Handman
E
E
Alexander
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WS
D000818:Animals; D000831:Animals, Newborn; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002908:Chronic Disease; D005234:Fatty Liver / Q000276:immunology / Q000517:prevention & control*; D006520:Hepatitis, Animal / Q000276:immunology / Q000517:prevention & control*; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D001616:beta-Galactosidase / Q000378:metabolism
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; D001616:beta-Galactosidase