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CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation

Item Type:Article
Title:CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation
Creators Name:Hacker, H. and Mischak, H. and Miethke, T. and Liptay, S. and Schmid, R. and Sparwasser, T. and Heeg, K. and Lipford, G.B. and Wagner, H.
Abstract:Unmethylated CpG motifs 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-1) 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 (TNFalpha) 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 signalling, 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.
Keywords:Antigen-Presenting Cell, CpG-DNA, p38 MAP Kinase, SAPK, Animals, Mice
Source:EMBO Journal
ISSN:0261-4189
Publisher:Nature Publishing Group (U.S.A.)
Volume:17
Number:21
Page Range:6230-6240
Date:2 November 1998
Official Publication:https://doi.org/10.1093/emboj/17.21.6230
PubMed:View item in PubMed

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