Toll-like receptor 9 signaling activates NF-κB through IFN regulatory Factor-8/IFN consensus sequence binding protein in dendritic cells
Toll-like receptor 9 signaling activates NF-κB through IFN regulatory Factor-8/IFN consensus sequence binding protein in dendritic cells
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DOI：
10.4049/jimmunol.172.11.6820
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发表时间：
2004-06-01
影响因子：
4.4
通讯作者：
Ozato, K
中科院分区：
文献类型：
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作者：
Tsujimura, H;Tamura, T;Ozato, K
未甲基化的CpG DNA与Toll样受体9(TLR9)结合，激活核因子-kappaB，在树突状细胞(DC)中诱导细胞因子基因。干扰素调节因子(IRF)-8/干扰素共有序列结合蛋白是一种对DC的发育和激活起重要作用的转录因子。我们发现来自IRF-8(-/-)小鼠的DC对CpG无反应，并且不能诱导作为核因子-kappaB靶点的肿瘤坏死因子-α和白介素6。这些细胞因子在IRF-8(-/-)DC中被强烈地诱导，以响应通过TLR4信号的内毒素，揭示了CpG选择性的信号缺陷。IRF-8(-/-)树突状细胞表达TLR9、髓系分化因子88等信号分子，但CpG不能激活-/-细胞中的核因子-kappaB。这是由于-/-DC选择性地不能激活核因子-kappaB对CpG的应答所需的I-kappaB激酶Alphabeta。IRF-8可完全恢复-/-DC中CpG对核因子-kappaB的激活和细胞因子的诱导。总之，激活NF-kappaB的TLR信号在不同的TLR中是不同的，而TLR9信号唯一地依赖于DC中的IRF-8。
Unmethylated CpG DNA binds to the Toll-like receptor 9 (TLR9) and activates NF-kappaB to induce cytokine genes in dendritic cells (DCs). IFN regulatory factor (IRF)-8/IFN consensus sequence binding protein is a transcription factor important for development and activation of DCs. We found that DCs from IRF-8(-/-) mice were unresponsive to CpG and failed to induce TNF-alpha and IL-6, targets of NF-kappaB. Revealing a signaling defect selective for CpG, these cytokines were robustly induced in IRF-8(-/-) DCs in response to LPS that signals through TLR4. IRF-8(-/-) DCs expressed TLR9, adaptor myeloid differentiation factor 88, and other signaling molecules, but CpG failed to activate NF-kappaB in -/- cells. This was due to the selective inability of -/- DCs to activate I-kappaB kinase alphabeta the kinases required for NF-kappaB in response to CpG. IRF-8 reintroduction fully restored CpG activation of NF-kappaB and cytokine induction in -/- DCs. Together, TLR signals that activate NF-kappaB are diverse among different TLRs, and TLR9 signaling uniquely depends on IRF-8 in DCs.