Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF)6

J Exp Med. 2000 Aug 21;192(4):595-600. doi: 10.1084/jem.192.4.595.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antigen-Presenting Cells / immunology*
  • Antigen-Presenting Cells / metabolism
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / metabolism*
  • Blotting, Western
  • Cells, Cultured
  • DNA, Bacterial / genetics
  • DNA, Bacterial / immunology
  • DNA, Bacterial / metabolism
  • Drosophila Proteins*
  • Genes, Reporter
  • Humans
  • Lipopolysaccharides / pharmacology
  • Macrophages, Peritoneal / metabolism
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Myeloid Differentiation Factor 88
  • Oligodeoxyribonucleotides / genetics
  • Oligodeoxyribonucleotides / immunology*
  • Oligodeoxyribonucleotides / metabolism
  • Proteins / genetics
  • Proteins / metabolism*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Receptors, Immunologic*
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / metabolism*
  • Recombinant Fusion Proteins
  • Signal Transduction*
  • Spleen / cytology
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • CPG-oligonucleotide
  • DNA, Bacterial
  • Drosophila Proteins
  • Lipopolysaccharides
  • MYD88 protein, human
  • Membrane Glycoproteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Oligodeoxyribonucleotides
  • Proteins
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Receptors, Interleukin-1
  • Recombinant Fusion Proteins
  • TLR2 protein, human
  • TLR4 protein, human
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors