CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation
CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation
复制标题
DOI：
10.1093/emboj/17.21.6230
复制
发表时间：
1998-11-02
期刊：
影响因子：
11.4
通讯作者：
Wagner, H
中科院分区：
文献类型：
--
作者：
Häcker, H;Mischak, H;Wagner, H
细菌DNA、质粒DNA和合成寡脱氧核苷酸（CpG ODN）中的未甲基化CpG蛾以CD40-CD40配体独立的方式激活树突状细胞（DC）和巨噬细胞。为了理解其中的分子机制，我们重点研究了CpG ODN的细胞摄取、内体成熟的必要性以及应激激酶途径的作用。本研究表明，CpG-DNA诱导小鼠巨噬细胞和树突状细胞中Jun n -末端激酶1 （JNKK1/SEK/MKK4）磷酸化，随后激活应激激酶JNK1/2和p38。这导致转录因子激活蛋白1 （ap -1）通过其成分c-Jun和ATF2的磷酸化而激活。此外，应激激酶激活对于cpg - dna诱导的肿瘤坏死因子α (TNF α)和白细胞介素-12 （IL-12）的细胞因子释放至关重要，因为p38的抑制会导致这种生物反应的严重损害。我们进一步证明，通过内吞作用和随后的内体成熟的细胞摄取对于信号钉钉至关重要，因为非CpG- dna或阻断内体成熟的化合物（如氯喹或巴菲霉素A）的竞争阻止了细胞激活的所有方面。数据表明，内体成熟是内体CpG- ODN序列通过应激激酶途径转化为信号通路所必需的。其中p38激酶激活是cpg - odn触发抗原呈递细胞激活的重要步骤。
Unmethylated CpG moths in bacterial DNA, plasmid DNA and synthetic oligodeoxynucleotides (CpG ODN) activate dendritic cells (DC) and macrophages in a CD40-CD40 ligand-independent fashion. To understand the molecular mechanisms involved we focused on the cellular uptake of CpG ODN, the need for endosomal maturation and the role of the stress kinase pathway. Here we demonstrate that CpG-DNA induces phosphorylation of Jun N-terminal kinase kinase 1 (JNKK1/SEK/MKK4) and subsequent activation of the stress kinases JNK1/2 and p38 in murine macrophages and dendritic cells. This Leads to activation of the transcription factor activating protein-1 (AP-I) via phosphorylation of its constituents c-Jun and ATF2, Moreover, stress kinase activation is essential for CpG-DNA-induced cytokine release of tumor necrosis factor alpha (TNF alpha) and interleukin-12 (IL-12), as inhibition of p38 results in severe impairment of this biological response. We further demonstrate that cellular uptake via endocytosis and subsequent endosomal maturation is essential for sig-nailing, since competition by non-CpG-DNA or compounds blocking endosomal maturation such as chloroquine or bafilomycin A prevent all aspects of cellular activation, The data suggest that endosomal maturation is required for translation of intraendosomal CpG ODN sequences into signalling via the stress kinase pathway, where p38 kinase activation represents an essential step in CpG-ODN-triggered activation of antigen-presenting cells.