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Abstract：
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.
摘要：
未甲基化的CpGDNA结合Toll样受体9(TLR9)并激活NF-κB以诱导树突状细胞(DC)中的细胞因子基因。IFN调节因子(IRF)-8/IFN共有序列结合蛋白是对DC的发育和活化重要的转录因子。我们发现来自IRF-8(-/-)小鼠的DC对CpG无反应并且不能诱导TNF-α和IL-6(NF-κB的靶标)。显示对CpG有选择性的信令缺陷，这些细胞因子在IRF-8(-/-)DC中被强力诱导,以响应通过TLR4发出信号的LPS。IRF-8(-/-)DCs表达TLR9、适配髓样分化因子88等信号分子,但CpG未能激活-/-细胞中的NF-κB。这是由于-/-DCs选择性地不能激活I-kappaB激酶alphabeta，NF-κB响应CpG所需的激酶。IRF-8再导入完全恢复了-/-DC中NF-κB的CpG活化和细胞因子诱导。一起,激活NF-κB的TLR信号在不同的TLR之间是不同的，和TLR9信号唯一地依赖于DC中的IRF-8。
