Loss of IκB kinase β promotes myofibroblast transformation and senescence through activation of the ROS-TGFβ autocrine loop.
Loss of IκB kinase β promotes myofibroblast transformation and senescence through activation of the ROS-TGFβ autocrine loop.
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DOI：
10.1007/s13238-015-0241-6
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发表时间：
2016-05
期刊：
影响因子：
21.1
通讯作者：
Xia Y
中科院分区：
文献类型：
--
作者：
Chen L;Peng Z;Meng Q;Mongan M;Wang J;Sartor M;Chen J;Niu L;Medvedovic M;Kao W;Xia Y
利用正向、反向遗传学和全局基因表达分析，我们探索了i - κ b激酶β (IKKβ)和转化生长因子β (TGFβ)信号通路之间的串扰。我们发现体外消融成纤维细胞中的Ikkβ可导致ROS积累和TGFβ活化，最终加速细胞迁移、成纤维细胞向肌成纤维细胞转化和衰老。从机制上讲，IKKβ的基础活性是抗氧化基因表达和氧化还原稳态所必需的。缺乏这种活性，IKKβ-null细胞显示ROS积累和应激敏感转录因子AP-1/c-Jun的激活。AP-1/c-Jun激活导致Tgfβ2启动子上调，进而通过诱导NADPH氧化酶（NOX）进一步增强细胞内ROS。这些数据表明，通过阻断ROS-TGFβ环的自分泌扩增，IKKβ在预防成纤维细胞-肌成纤维细胞转化和衰老中起着至关重要的作用。本文的在线版本（doi:10.1007/s13238-015-0241-6）包含补充材料，仅供授权用户使用。
Using forward and reverse genetics and global gene expression analyses, we explored the crosstalk between the IκB kinase β (IKKβ) and the transforming growth factor β (TGFβ) signaling pathways. We show that in vitro ablation of Ikkβ in fibroblasts led to progressive ROS accumulation and TGFβ activation, and ultimately accelerated cell migration, fibroblast-myofibroblast transformation and senescence. Mechanistically, the basal IKKβ activity was required for anti-oxidant gene expression and redox homeostasis. Lacking this activity, IKKβ-null cells showed ROS accumulation and activation of stress-sensitive transcription factor AP-1/c-Jun. AP-1/c-Jun activation led to up-regulation of the Tgfβ2 promoter, which in turn further potentiated intracellular ROS through the induction of NADPH oxidase (NOX). These data suggest that by blocking the autocrine amplification of a ROS-TGFβ loop IKKβ plays a crucial role in the prevention of fibroblast-myofibroblast transformation and senescence. The online version of this article (doi:10.1007/s13238-015-0241-6) contains supplementary material, which is available to authorized users.