Collaborative action of NF-κB and p38 MAPK is involved in CpG DNA-Induced IFN-α and chemokine production in human plasmacytoid dendritic cells
Collaborative action of NF-κB and p38 MAPK is involved in CpG DNA-Induced IFN-α and chemokine production in human plasmacytoid dendritic cells
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DOI：
10.4049/jimmunol.177.7.4841
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发表时间：
2006-10-01
影响因子：
4.4
通讯作者：
Fujieda, Shigeharu
中科院分区：
文献类型：
--
作者：
Osawa, Youko;Iho, Sumiko;Fujieda, Shigeharu
CpG DNA诱导浆细胞样树突状细胞（pDC）产生I型IFN和趋化因子。然而，还没有完全阐明TLR 9信号通路如何与这些基因表达相关联。我们研究了涉及TLR 9和I型IFN信号通路的机制，与CpG DNA诱导的IFN-α、IFN调节因子（IRF）-7和趋化因子有关。人pDC中的pCXCL 10和CCL 3。在pDC中，NF-κ B亚基p65和p50被组成性激活。pDC还组成性表达IRF-7和CCL 3，并且基因表达似乎受NF-κ B调节。CpG DNA可增强NF-κ B B p65/p50的活性，并与p38 MAPK协同上调IRF-7、CXCL 10和CCL 3的表达，其作用方式与I型IFN信号无关。然后，我们研究了IFN-α表达的途径。I型干扰素诱导的。p以NF-κ B非依赖性方式表达IRF-7，但不表达IFN-α。在NF-κ B/p38 MAPK抑制剂存在下，CpG DNA使I型IFN处理的pDC能够表达IFN-α，氯喹消除了这种作用。对于CpG DNA，组成型和新表达的IRF-7独立于NF-κ B/p38 MAPK移动到细胞核。这些发现表明，在CpG DNA刺激的人pDC中，IRF-7、CXCL 10和CCL 3的诱导由NF-κ B/p38 MAPK通路介导，并且IRF-7在氯喹敏感性调节机制中的NF-κ B/p38 MAPK激活的上游被激活，从而导致IFN-α的表达。
CpG DNA induces plasmacytoid dendritic cells (pDC) to produce type I IFN and chemokines. However, it has not been fully elucidated how the TLR9 signaling pathway is linked to these gene expressions. We examined the mechanisms involving the TLR9 and type I IFN signaling pathways, in relation to CpG DNA-induced IFN-alpha, IFN regulatory factor (IRF)-7, and chemokines. p CXCL10 and CCL3 in human pDC. In pDC, NF-kappa B subunits p65 and p50 were constitutively activated. pDC also constitutively expressed IRF-7 and CCL3, and the gene expressions seemed to be regulated by NF-kappa B. CpG DNA enhanced the NF-kappa B p65/p50 activity, which collaborated with p38 MAPK to up-regulate the expressions of IRF-7, CXCL10, and CCL3 in a manner independent of type I IFN signaling. We then examined the pathway through which IFN-alpha is expressed. Type I IFN induced the. p expression of IRF-7, but not of IFN-alpha, in a NF-kappa B-independent way. CpG DNA enabled the type I IFN-treated pDC to express IFN-alpha in the presence of NF-kappa B/p38 MAPK inhibitor, and chloroquine abrogated this effect. With CpG DNA, IRF-7, both constitutively and newly expressed, moved to the nuclei independently of NF-kappa B/p38 MAPK. These findings suggest that, in CpG DNA-stimulated human pDC, the induction of IRF-7, CXCL10, and CCL3 is mediated by the NF-kappa B/p38 MAPK pathway, and that IRF-7 is activated upstream of the activation of NF-kappa B/p38 MAPK in chloroquine-sensitive regulatory machinery, thereby leading to the expression of IFN-alpha.