TNF-like weak inducer of apoptosis (TWEAK) activates proinflammatory signaling pathways and gene expression through the activation of TGF-beta-activated kinase 1.
TNF-like weak inducer of apoptosis (TWEAK) activates proinflammatory signaling pathways and gene expression through the activation of TGF-beta-activated kinase 1.
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DOI：
10.4049/jimmunol.0803357
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发表时间：
2009-02-15
期刊：
影响因子：
--
通讯作者：
Kumar A
中科院分区：
文献类型：
--
作者：
Kumar M;Makonchuk DY;Li H;Mittal A;Kumar A
TWEAK是最近发现的一种促炎细胞因子，通过与靶细胞中的Fn 14受体结合发挥作用。虽然TWEAK已被证明可以调节几种生物反应，但TWEAK诱导的信号通路仍然知之甚少。在本研究中，我们验证了TAK 1参与TWEAK诱导的NF-κB和MAPK活化以及促炎蛋白表达的假设。TWEAK增加了培养的成肌细胞和成纤维细胞中TAK 1的磷酸化和激酶活性。与野生型MEF相比，TAK 1-deficinet（TAK 1-/-）小鼠胚胎成纤维细胞（MEF）中NF-κB的活化受到显著抑制。TAK 1的缺失还抑制了TWEAK诱导的IκB激酶的激活以及IκBα蛋白的磷酸化和降解。然而，在TWEAK处理的野生型和TAK 1 −/− MEF中，p100蛋白水平没有差异。此外，TWEAK诱导的NF-κB转录激活在TAK 1 −/− MEF和显性阴性TAK 1或TAK 1 siRNA转染的C2 C12成肌细胞中显著降低。TAK 1也是激活AP-1响应TWEAK所必需的。与野生型MEF相比，TWEAK处理后，TAK 1 −/− MEF中JNK 1和p38 MAPK的激活受到显著抑制，但ERK 1/2或Akt激酶的激活没有受到抑制。与野生型MEF相比，TAK 1 −/− MEF中TWEAK诱导的促炎基因如MMP-9、CCL-2和VCAM-1的表达也减少。TWEAK诱导的NF-κB活化和MMP-9表达与Akt激酶的上游激活有关。总的来说，我们的研究表明，TAK 1和Akt是TWEAK诱导的促炎信号和基因表达的重要组成部分。
TWEAK is a relatively recently identified proinflammatory cytokine which functions through binding to Fn14 receptor in target cells. Although TWEAK has been shown to modulate several biological responses, the TWEAK-induced signaling pathways remain poorly understood. In this study, we tested the hypothesis that TAK1 is involved in TWEAK-induced activation of NF-κB and MAPK, and expression of proinflammatory protein. TWEAK increased the phosphorylation and kinase activity of TAK1 in cultured myoblast and fibroblast cells. The activation of NF-κB was significantly inhibited in TAK1-deficinet (TAK1−/−) mouse embryonic fibroblasts (MEF) compared to wild-type MEF. Deficiency of TAK1 also inhibited the TWEAK-induced activation of IκB kinase and phosphorylation and degradation of IκBα protein. However, there was no difference in the levels p100 protein in TWEAK-treated wild-type and TAK1−/− MEF. Furthermore, TWEAK-induced transcriptional activation of NF-κB was significantly reduced in TAK1−/− MEF and in C2C12 myoblasts transfected with a dominant-negative TAK1 or TAK1 siRNA. TAK1 was also required for the activation of AP-1 in response to TWEAK. Activation of JNK1 and p38 MAPK but not ERK1/2 or Akt kinase was significantly inhibited in TAK1−/− MEF compared to wild-type MEF upon treatment with TWEAK. TWEAK-induced expression of proinflammatory genes such as MMP-9, CCL-2 and VCAM-1 was also reduced in TAK1−/− MEF compared to wild-type MEF. Furthermore, the activation of NF-κB and the expression of MMP-9 in response to TWEAK involved the upstream activation of Akt kinase. Collectively, our study demonstrates that TAK1 and Akt are the important components of the TWEAK-induced proinflammatory signaling and gene expression.
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影响因子：
64.5
作者：
Maecker, H;Varfolomeev, E;Ashkenazi, A
通讯作者：
Ashkenazi, A
影响因子：
4.4
作者：
Kaplan, MJ;Lewis, EE;Richardson, BC
通讯作者：
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影响因子：
4.8
作者：
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DOI：
10.1073/pnas.0603089103
发表时间：
2006-08-01
影响因子：
11.1
作者：
Liu, Hong-Hsing;Xie, Min;Chen, Zhijian J.
通讯作者：
Chen, Zhijian J.
影响因子：
4.8
作者：
Hanafusa, H;Ninomiya-Tsuji, J;Nishida, E
通讯作者：
Nishida, E