Suppressor of cytokine signaling-1 in T cells and macrophages is critical for preventing lethal inflammation.
The balance between pro- and anti-inflammatory cytokines modulates inflammation. Intracellular inhibitors of signaling, in turn, contribute to the negative regulation of cytokines. One of these inhibitors is suppressor of cytokine signaling-1 (SOCS-1). Socs1(-/-) mice die by 3 weeks of age with inflammation and fatty necrosis of the liver. Here, cre/loxP deletion of Socs1 was used to investigate the contribution of specific cells/tissues to inflammatory disease. Mice with SOCS-1 deficiency in myeloid and lymphoid cells, but not lymphoid alone, became ill at 50 to 250 days of age. These mice developed splenomegaly and T-cell/macrophage infiltration of many organs, including liver, lung, pancreas, and muscle. There were also abnormally high levels of the proinflammatory cytokines interferon gamma (IFN-gamma), tumor necrosis factor (TNF), and interleukin-12 (IL-12), and activated T cells circulating in these mice. Socs1(null) T cells were found to be hypersensitive to multiple cytokines, including IL-1, IL-2, and IL-12, resulting in IFN-gamma production without requiring T-cell receptor (TCR) ligation. Additionally, Socs1(null) macrophages produced excessive amounts of IL-12 and TNF in response to other cytokines, including IFN-gamma. A dysregulated cytokine network between T cells and macrophages is thus associated with this inflammatory disease. These findings indicate that SOCS-1 is critical in both T cells and macrophages for preventing uncontrolled inflammation.
Chong
Mark M W
MM
St Vincent's Institute, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
Metcalf
Donald
D
Jamieson
Emma
E
Alexander
Warren S
WS
Kay
Thomas W H
TW
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000276:immunology / Q000494:pharmacology*; D002352:Carrier Proteins / Q000276:immunology / Q000494:pharmacology*; D019070:Cell Lineage / Q000187:drug effects / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control*; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D023461:Myeloid Progenitor Cells / Q000187:drug effects / Q000276:immunology; D012097:Repressor Proteins / Q000276:immunology / Q000494:pharmacology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002352:Carrier Proteins; D008070:Lipopolysaccharides; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma