ER stress and its regulator X-box-binding protein-1 enhance polyIC-induced innate immune response in dendritic cells.
ER stress and its regulator X-box-binding protein-1 enhance polyIC-induced innate immune response in dendritic cells.
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DOI：
10.1002/eji.201040831
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发表时间：
2011-04
影响因子：
5.4
通讯作者：
Wang, Xiang-Yang
中科院分区：
文献类型：
--
作者：
Hu, Fanlei;Yu, Xiaofei;Wang, Hongxia;Zuo, Daming;Guo, Chunqing;Yi, Huanfa;Tirosh, Boaz;Subjeck, John R.;Qiu, Xiaoyan;Wang, Xiang-Yang
多种生理和病理条件干扰内质网（ER）的功能。然而，关于ER应激对树突状细胞（DC）识别病原体分子后的炎症反应的影响仍然未知。我们发现，ER应激大大增强了多聚IC（一种病毒dsRNA的合成模拟物）刺激的小鼠DC中炎性细胞因子和IFN-β的表达。Toll样受体3和黑色素瘤分化相关基因5都参与了IFN-β的产生，这与NF-κB和IRF 3信号的激活以及X-box结合蛋白1（XBP-1）的剪接有关，XBP-1是参与ER应激反应的重要调节因子。令人惊讶的是，在ER应激存在或不存在的情况下，XBP-1的沉默降低了聚IC刺激的IFN-β表达，表明XBP-1可能是聚IC信号传导和ER应激扩增的IFN-β产生所必需的。剪接形式的XBP-1（XBP-1 s）的过表达协同增强polyIC诱导的炎症反应。我们首次发现，XBP-1 s过表达增强了DC中IFN-β的产生，显著抑制了水疱性口炎病毒感染，揭示了XBP-1在抗病毒反应中以前未被认识的作用。我们的研究结果表明，进化上保守的ER应激反应和XBP-1可能与先天免疫在维持细胞内稳态中协同发挥作用。
Multiple physiological and pathological conditions interfere with the function of Endoplasmic Reticulum (ER). However, much remains unknown regarding the impact of ER stress on inflammatory responses in dendritic cells (DCs) upon the recognition of pathogen molecules. We show that ER stress greatly potentiates the expression of inflammatory cytokines and IFN-β in murine DCs stimulated by polyIC, a synthetic mimic of virus dsRNA. Both toll-like receptor 3 and melanoma differentiation-associated gene-5 are involved in the enhanced IFN-β production, which is associated with increased activation of NF-κB and IRF3 signaling as well as the splicing of X-box binding protein-1 (XBP-1), an important regulator involved in ER stress response. Surprisingly, silencing of XBP-1 reduces polyIC-stimulated IFN-β expression in the presence or absence of ER stress, indicating that XBP-1 may be essential for polyIC signaling and ER stress-amplified IFN-β production. Overexpression of a spliced form of XBP-1(XBP-1s) synergistically augments polyIC-induced inflammatory response. For the first time we show that XBP-1s overexpression-enhanced IFN-β production in DCs markedly suppresses vesicular stomatitis virus infection, revealing a previously unrecognized role of XBP-1 in an antiviral response. Our findings suggest that evolutionarily conserved ER stress response and XBP-1 may function collaboratively with the innate immunity in maintaining cellular homeostasis.
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影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
16
作者：
Harding, HP;Novoa, I;Ron, D
通讯作者：
Ron, D
影响因子：
4.4
作者：
Renn, Claudia N.;Sanchez, David Jesse;Modlin, Robert L.
通讯作者：
Modlin, Robert L.
影响因子：
15.3
作者：
Iwakoshi, Neal N.;Pypaert, Marc;Glimcher, Laurie H.
通讯作者：
Glimcher, Laurie H.
DOI：
10.1196/annals.1443.020
发表时间：
2008-01-01
期刊：
YEAR IN IMMUNOLOGY 2008
影响因子：
--
作者：
Kawai, Taro;Akira, Shizuo
通讯作者：
Akira, Shizuo