Bruton's tyrosine kinase is required for lipopolysaccharide-induced tumor necrosis factor alpha production.
Bruton's tyrosine kinase is required for lipopolysaccharide-induced tumor necrosis factor alpha production.
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DOI：
10.1084/jem.20021845
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发表时间：
2003-06-16
期刊：
影响因子：
--
通讯作者：
Foxwell BM
中科院分区：
文献类型：
--
作者：
Horwood NJ;Mahon T;McDaid JP;Campbell J;Mano H;Brennan FM;Webster D;Foxwell BM
脂多糖（LPS）是革兰氏阴性菌的产物，是骨髓/巨噬细胞产生肿瘤坏死因子(TNF)α的有效介质。能够阻断导致TNFα产生的信号事件的抑制剂可以为治疗感染性休克和其他炎症性疾病提供有用的治疗方法。广谱酪氨酸抑制剂已知可以抑制TNFα的产生，然而，没有特定的酪氨酸激酶家族被证明对这一过程至关重要。在这里，我们发现来自x连锁无球蛋白血症患者的布鲁顿酪氨酸激酶（Btk）缺陷的单核细胞受到LPS诱导的TNFα产生的损害，并且LPS在正常单核细胞中迅速诱导Btk激酶活性。此外，腺病毒在正常人单核细胞中过表达Btk可促进TNFα的产生。我们利用荧光素酶报告腺病毒构建体检测了Btk在TNFα产生中的作用，并确定了Btk的过表达可通过3 '非翻译区稳定TNFα mRNA。LPS刺激还诱导了相关酪氨酸激酶Tec的激活，这表明Tec家族激酶是LPS诱导的TNFα生成的重要组成部分。这项研究首次提供了明确的证据，表明Tec家族的酪氨酸激酶，特别是Btk，是lps诱导的tnf - α产生的关键因素，因此可能为干预炎症状况提供有价值的治疗靶点。
Lipopolysaccharide (LPS), a product of Gram-negative bacteria, is potent mediator of tumor necrosis factor (TNF)α production by myeloid/macrophage cells. Inhibitors capable of blocking the signaling events that result in TNFα production could provide useful therapeutics for treating septic shock and other inflammatory diseases. Broad spectrum tyrosine inhibitors are known to inhibit TNFα production, however, no particular family of tyrosine kinases has been shown to be essential for this process. Here we show that the Bruton's tyrosine kinase (Btk)-deficient mononuclear cells from X-linked agammaglobulinemia patients have impaired LPS-induced TNFα production and that LPS rapidly induces Btk kinase activity in normal monocytes. In addition, adenoviral overexpression of Btk in normal human monocytes enhanced TNFα production. We examined the role of Btk in TNFα production using luciferase reporter adenoviral constructs and have established that overexpression of Btk results in the stabilization of TNFα mRNA via the 3′ untranslated region. Stimulation with LPS also induced the activation of related tyrosine kinase, Tec, suggesting that the Tec family kinases are important components for LPS-induced TNFα production. This study provides the first clear evidence that tyrosine kinases of the Tec family, in particular Btk, are key elements of LPS-induced TNFα production and consequently may provide valuable therapeutic targets for intervention in inflammatory conditions.
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影响因子：
56.9
作者：
NOVOGRODSKY, A;VANICHKIN, A;LEVITZKI, A
通讯作者：
LEVITZKI, A
DOI：
10.1084/jem.186.7.1027
发表时间：
1997-10-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Crowley MT;Costello PS;Fitzer-Attas CJ;Turner M;Meng F;Lowell C;Tybulewicz VL;DeFranco AL
通讯作者：
DeFranco AL
影响因子：
5.4
作者：
BEATY, CD;FRANKLIN, TL;WILSON, CB
通讯作者：
WILSON, CB
影响因子：
4.6
作者：
JANSSON, L;HOLMDAHL, R
通讯作者：
HOLMDAHL, R
DOI：
10.1073/pnas.96.10.5668
发表时间：
1999-05-11
影响因子：
11.1
作者：
Bondeson, J;Foxwell, B;Feldmann, M
通讯作者：
Feldmann, M