Dual specificity phosphatase 1 (DUSP1) regulates a subset of LPS-induced genes and protects mice from lethal endotoxin shock.
Dual specificity phosphatase 1 (DUSP1) regulates a subset of LPS-induced genes and protects mice from lethal endotoxin shock.
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DOI：
10.1084/jem.20051753
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发表时间：
2006-01-23
期刊：
影响因子：
--
通讯作者：
Lang R
中科院分区：
文献类型：
--
作者：
Hammer M;Mages J;Dietrich H;Servatius A;Howells N;Cato AC;Lang R
Toll样受体刺激后丝裂原活化蛋白激酶（MAPK）级联的激活使先天免疫细胞能够快速激活细胞因子基因表达。对感染危险信号的平衡反应要求细胞激活是短暂的。在这里，我们确定了MAPK磷酸酶双特异性磷酸酶1（DUSP 1）作为一个重要的内源性调节炎症反应的脂多糖（LPS）。DUSP 1-缺陷（DUSP 1-/-）骨髓源性巨噬细胞显示出选择性延长p38 MAPK的激活和增加细胞因子的产生。用LPS腹腔内攻击DUSP 1 −/−小鼠，导致致死率增加，白细胞介素（IL）-6和肿瘤坏死因子α的过度产生。转录谱分析显示，DUSP 1控制了LPS诱导的基因的重要部分，包括IL-6和IL-10以及趋化因子CCL 3、CCL 4和CXCL 2。相比之下，内毒素致死性的重要介质干扰素γ和IL-12的表达没有因DUSP 1的缺乏而显著改变。这些数据共同证明了DUSP 1在控制决定内毒素休克结果的LPS诱导基因亚组中的特异性调节作用。
Activation of the mitogen-activated protein kinase (MAPK) cascade after Toll-like receptor stimulation enables innate immune cells to rapidly activate cytokine gene expression. A balanced response to signals of infectious danger requires that cellular activation is transient. Here, we identify the MAPK phosphatase dual specificity phosphatase 1 (DUSP1) as an essential endogenous regulator of the inflammatory response to lipopolysaccharide (LPS). DUSP1-deficient (DUSP1−/−) bone marrow–derived macrophages showed selectively prolonged activation of p38 MAPK and increased cytokine production. Intraperitoneal challenge of DUSP1−/− mice with LPS caused increased lethality and overshooting production of interleukin (IL)-6 and tumor necrosis factor α. Transcriptional profiling revealed that DUSP1 controls a significant fraction of LPS-induced genes, which includes IL-6 and IL-10 as well as the chemokines CCL3, CCL4, and CXCL2. In contrast, the expression of the important mediators of endotoxin lethality, interferon γ and IL-12, was not significantly altered by the absence of DUSP1. These data together demonstrate a specific regulatory role of DUSP1 in controlling a subset of LPS-induced genes that determines the outcome of endotoxin shock.
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影响因子：
64.8
作者：
Zhang, YL;Blattman, JN;Dong, C
通讯作者：
Dong, C
DOI：
10.1073/pnas.091062498
发表时间：
2001-04-24
影响因子：
11.1
作者：
Tusher, VG;Tibshirani, R;Chu, G
通讯作者：
Chu, G
影响因子：
32.4
作者：
Takeda, K;Clausen, BE;Akira, S
通讯作者：
Akira, S
影响因子：
64.5
作者：
SUN, H;CHARLES, CH;TONKS, NK
通讯作者：
TONKS, NK
影响因子：
--
作者：
Vogt, A;Cooley, KA;Lazo, JS
通讯作者：
Lazo, JS