Suppressor of cytokine signaling-1 in T cells and macrophages is critical for preventing lethal inflammation
Suppressor of cytokine signaling-1 in T cells and macrophages is critical for preventing lethal inflammation
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DOI：
10.1182/blood-2004-08-3049
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发表时间：
2005-09-01
期刊：
影响因子：
20.3
通讯作者：
Kay, TWH
中科院分区：
文献类型：
--
作者：
Chong, MMW;Metcalf, D;Kay, TWH
促炎和抗炎细胞因子之间的平衡调节炎症。反过来，细胞内的信号抑制物又有助于细胞因子的负调控。其中一种是细胞因子信号转导抑制因子-1(SOCS-1)。SOCS1(-/-)小鼠在3周大时死于肝脏炎症和脂肪坏死。在这里，我们利用SOCS1的cre/IoxP缺失来研究特定细胞/组织在炎症性疾病中的作用。SOCS-1缺乏髓系细胞和淋巴细胞，但不只是淋巴细胞，小鼠在50到250天龄时患病。这些小鼠出现了脾肿大和T细胞/巨噬细胞渗透到许多器官，包括肝、肺、胰腺和肌肉。这些小鼠体内也存在异常高水平的促炎细胞因子--干扰素-γ、肿瘤坏死因子和白介素12，以及被激活的T细胞。SOCS1(Null)细胞对多种细胞因子包括IL-1、IL-2和IL-12具有超敏反应，无需T细胞受体(TCR)连接即可产生干扰素-γ。此外，SOCS1(空)巨噬细胞产生过量的IL-1 2和肿瘤坏死因子，以响应其他细胞因子，包括干扰素-γ。因此，T细胞和巨噬细胞之间失调的细胞因子网络与这种炎症性疾病有关。这些发现表明，SOCS-1在T细胞和巨噬细胞中对于预防失控的炎症都是至关重要的。
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.