Interleukin-1 receptor-associated kinase 2- and protein kinase D1-dependent regulation of IRAK-monocyte expression by CpG DNA.
Interleukin-1 receptor-associated kinase 2- and protein kinase D1-dependent regulation of IRAK-monocyte expression by CpG DNA.
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DOI：
10.1371/journal.pone.0043970
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Yi AK
中科院分区：
文献类型：
--
作者：
Kim YI;Park JE;Kwon KH;Hong CY;Yi AK
作为负反馈机制的一部分，CpG DNA诱导单核细胞中IRAK - M的表达。在本研究中，我们研究了一种生化信号通路以及负责CpG DNA介导的Irak - m基因表达的转录因子。CpG DNA诱导的Irak - m表达不需要新的蛋白质合成，并且是通过一种内体pH敏感的TLR9/MyD88信号通路在转录水平上进行调控的。在TLR9通路中过表达显性负性（DN）形式的信号调节剂或对其进行基因特异性敲低表明，CpG DNA诱导的Irak - m转录需要IRAK4、IRAK1、IRAK2和PKD1。DN - IRAK1的过表达仅部分但显著地抑制了CpG DNA诱导的Irak - m启动子活性。虽然IRAK1对初始阶段至关重要，但IRAK2通过维持PKD1的激活（从而导致NF - κB和MAPKs的激活）对TLR9信号传导的后期阶段是必需的。对Irak - m启动子中预测的顺式作用转录调控元件进行改变的Irak - m启动子 - 荧光素酶报告基因显示，Irak - m启动子区域中的NF - κB共有位点对Irak - m基因表达是绝对必需的。AP - 1和CREB结合位点也有助于CpG DNA诱导的Irak - m的最佳表达。总之，我们的结果表明，IRAK2通过维持PKD1和NF - κB的激活在TLR9介导的Irak - m表达的转录调控中起关键作用。
As a part of the negative feedback mechanism, CpG DNA induces IRAK-M expression in monocytic cells. In the present study we investigated a biochemical signaling pathway and the transcription factors responsible for CpG DNA-mediated Irak-m gene expression. CpG DNA-induced Irak-m expression did not require new protein synthesis and was regulated at the transcriptional level through an endosomal pH-sensitive TLR9/MyD88 signaling pathway. Over-expression of the dominant negative (DN) form of or gene-specific knockdown of signaling modulators in the TLR9 pathway demonstrated that IRAK4, IRAK1, IRAK2, and PKD1 are required for Irak-m transcription induced by CpG DNA. Over-expression of DN-IRAK1 only partially, but significantly, inhibited CpG DNA-induced Irak-m promoter activity. While IRAK1 was critical for the initial phase, IRAK2 was required for the late phase of TLR9 signaling by sustaining activation of PKD1 that leads to activation of NF-κB and MAPKs. Irak-m promoter-luciferase reporters with alterations in the predicted cis-acting transcriptional regulatory elements revealed that the NF-κB consensus site in the Irak-m promoter region is absolutely required for Irak-m gene expression. AP-1 and CREB binding sites also contributed to the optimal Irak-m expression by CpG DNA. Collectively, our results demonstrate that IRAK2 plays a key role in the TLR9-mediated transcriptional regulation of Irak-m expression by sustaining activation of PKD1 and NF-κB.
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影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
DOI：
10.1084/jem.192.4.595
发表时间：
2000-08-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Häcker H;Vabulas RM;Takeuchi O;Hoshino K;Akira S;Wagner H
通讯作者：
Wagner H
影响因子：
15.3
作者：
Kanakaraj, P;Schafer, PH;Fung-Leung, WP
通讯作者：
Fung-Leung, WP
影响因子：
4.4
作者：
Dalpke, AH;Opper, S;Heeg, K
通讯作者：
Heeg, K
影响因子：
5.5
作者：
Li, Chong Hui;Wang, Jiang Huai;Redmond, H. Paul
通讯作者：
Redmond, H. Paul