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Blood, 1 September 2005, Vol. 106, No. 5, pp. 1668-1675.
Prepublished online as a Blood First Edition Paper on May 17, 2005; DOI 10.1182/blood-2004-08-3049.
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IMMUNOBIOLOGY
Suppressor of cytokine signaling-1 in T cells and macrophages is critical for preventing lethal inflammation
Mark M. W. Chong,
Donald Metcalf,
Emma Jamieson,
Warren S. Alexander, and
Thomas W. H. Kay
From St Vincent's Institute, Victoria, Australia; and The Walter and Eliza Hall Institute of Medical Research, Victoria, Australia.
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  (IFN-), 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- 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-. 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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