Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF)6.
Transition of immature antigen presenting cells (APCs) to the state of professional APCs is essential for initiation of cell-mediated immune responses to pathogens. Signal transduction via molecules of the Toll-like receptor (TLR)/interleukin 1 receptor (IL-1R) pathway is critical for activation of APCs either by pathogen-derived pattern ligands like lipopolysaccharides (LPS) or by CD40 ligation through T helper cells. The capacity of bacterial DNA (CpG-DNA) to induce APCs to differentiate into professional APCs represents an interesting discovery. However, the signaling pathways involved are poorly understood. Here we show that CpG-DNA activates the TLR/IL-1R signaling pathway via the molecules myeloid differentiation marker 88 (MyD88) and tumor necrosis factor receptor-associated factor 6 (TRAF6), leading to activation of kinases of the IkappaB kinase complex and the c-jun NH(2)-terminal kinases. Moreover, cells of TLR2- and TLR4-deficient mice are activated by CpG-DNA, whereas cells of MyD88-deficient mice do not respond. The data suggest that CpG-DNA initiates signaling via the TLR/IL-1R pathway in APCs in a manner similar to LPS and to T helper cell-mediated CD40 ligation. Activation of the TLR/IL-1R signaling pathway by foreign bacterial DNA may be one way to initiate innate defense mechanisms against infectious pathogens in vivo.
Häcker
H
H
Institute of Medical Microbiology, Immunology and Hygiene, Technische Universität München, D-81675 Munich, Germany. hans.haecker@lrz.tum.de
Vabulas
R M
RM
Takeuchi
O
O
Hoshino
K
K
Akira
S
S
Wagner
H
H
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D004269:DNA, Bacterial / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D029721:Drosophila Proteins; D017930:Genes, Reporter; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D053594:Myeloid Differentiation Factor 88; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D048029:TNF Receptor-Associated Factor 6; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; C408982:CPG-oligonucleotide; D004269:DNA, Bacterial; D029721:Drosophila Proteins; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D009838:Oligodeoxyribonucleotides; D011506:Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D011993:Recombinant Fusion Proteins; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D048029:TNF Receptor-Associated Factor 6; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors