Suppressor of cytokine signaling-1 in T cells and macrophages is critical for preventing lethal inflammation

MMW Chong, D Metcalf, E Jamieson, WS Alexander… - Blood, 2005 - ashpublications.org
MMW Chong, D Metcalf, E Jamieson, WS Alexander, TWH Kay
Blood, 2005ashpublications.org
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 …
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/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 γ (IFN-γ), tumor necrosis factor (TNF), and interleukin-12 (IL-12), and activated T cells circulating in these mice. Socs1null T cells were found to be hypersensitive to multiple cytokines, including IL-1, IL-2, and IL-12, resulting in IFN-γ production without requiring T-cell receptor (TCR) ligation. Additionally, Socs1null macrophages produced excessive amounts of IL-12 and TNF in response to other cytokines, including IFN-γ. 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. (Blood. 2005;106:1668-1675)
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