Enhanced TLR-mediated NF-IL6 dependent gene expression by Trib1 deficiency.
Enhanced TLR-mediated NF-IL6 dependent gene expression by Trib1 deficiency.
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DOI：
10.1084/jem.20070183
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发表时间：
2007-09-03
期刊：
影响因子：
--
通讯作者：
Akira S
中科院分区：
文献类型：
--
作者：
Yamamoto M;Uematsu S;Okamoto T;Matsuura Y;Sato S;Kumar H;Satoh T;Saitoh T;Takeda K;Ishii KJ;Takeuchi O;Kawai T;Akira S
Toll样受体（TLR）识别多种微生物组分并介导下游信号转导途径，所述下游信号转导途径最终导致核因子κB（NF-κB）和促分裂原活化蛋白（MAP）激酶的活化。据报道，Trib 1参与NF-κB和MAP激酶的调节以及体外基因表达。为了阐明Trib 1在TLR介导的反应中的生理功能，我们通过基因打靶产生了Trib 1缺陷小鼠。微阵列分析显示，Trib 1缺陷型巨噬细胞表现出脂多糖诱导基因的表达模式失调，而TLR介导的MAP激酶和NF-κB的激活是正常的。发现Trib 1与NF-IL 6（也称为CCAAT/增强子结合蛋白β）相关。NF-IL 6缺陷型细胞表现出与Trib 1缺陷型细胞相反的表型。此外，Trib 1的过表达通过下调NF-IL 6蛋白表达来抑制NF-IL 6依赖性基因的表达。相反，Trib 1缺陷细胞表现出增强的NF-IL 6 DNA结合活性与增加量的NF-IL 6蛋白。这些结果表明，Trib 1是NF-IL 6蛋白表达的负调控因子，并在TLR介导的信号传导中调节NF-IL 6依赖性基因表达。
Toll-like receptors (TLRs) recognize a variety of microbial components and mediate downstream signal transduction pathways that culminate in the activation of nuclear factor κB (NF-κB) and mitogen-activated protein (MAP) kinases. Trib1 is reportedly involved in the regulation of NF-κB and MAP kinases, as well as gene expression in vitro. To clarify the physiological function of Trib1 in TLR-mediated responses, we generated Trib1-deficient mice by gene targeting. Microarray analysis showed that Trib1-deficient macrophages exhibited a dysregulated expression pattern of lipopolysaccharide-inducible genes, whereas TLR-mediated activation of MAP kinases and NF-κB was normal. Trib1 was found to associate with NF-IL6 (also known as CCAAT/enhancer-binding protein β). NF-IL6–deficient cells showed opposite phenotypes to those in Trib1-deficient cells in terms of TLR-mediated responses. Moreover, overexpression of Trib1 inhibited NF-IL6–dependent gene expression by down-regulating NF-IL6 protein expression. In contrast, Trib1-deficient cells exhibited augmented NF-IL6 DNA-binding activities with increased amounts of NF-IL6 proteins. These results demonstrate that Trib1 is a negative regulator of NF-IL6 protein expression and modulates NF-IL6–dependent gene expression in TLR-mediated signaling.
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影响因子：
30.5
作者：
Yamamoto, Masahiro;Okamoto, Toru;Akira, Shizuo
通讯作者：
Akira, Shizuo
DOI：
10.1111/j.1432-1033.1997.t01-1-00660.x
发表时间：
1997-09-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Wilkin, F;SuarezHuerta, N;Maenhaut, C
通讯作者：
Maenhaut, C
影响因子：
64.5
作者：
TANAKA, T;AKIRA, S;KISHIMOTO, T
通讯作者：
KISHIMOTO, T
影响因子：
4.8
作者：
Kiss-Toth, E;Bagstaff, SM;Dower, SK
通讯作者：
Dower, SK
影响因子：
4.4
作者：
Uematsu, S;Matsumoto, M;Akira, S
通讯作者：
Akira, S