Suppressor of cytokine signaling-1 in T cells and macrophages is critical for preventing lethal inflammation
- Author(s)
- Chong, MMW; Metcalf, D; Jamieson, E; Alexander, WS; Kay, TWH;
- Details
- Publication Year 2005-09-01,Volume 106,Issue #5,Page 1668-1675
- Journal Title
- BLOOD
- Publication Type
- Journal Article
- Abstract
- 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/IoxP 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) cells were found to be hypersensitive to multiple cytokines, including IL-1, IL-2, and IL-12, resulting in IFN-gamma production with- out requiring T-cell receptor (TCR) ligation. Additionally, Socs1(null) macrophages produced excessive amounts of IL-1 2 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.
- Publisher
- AMER SOC HEMATOLOGY
- Keywords
- TUMOR-NECROSIS-FACTOR; INTERFERON-GAMMA; NATURAL-KILLER; IFN-GAMMA; IN-VIVO; MICE; DIFFERENTIATION; ACTIVATION; REGULATOR; SOCS1
- Publisher's Version
- https://doi.org/10.1182/blood-2004-08-3049
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2005-09-01 12:00:00