Toll-like receptor 9 signaling activates NF-kappaB through IFN regulatory factor-8/IFN consensus sequence binding protein in dendritic cells

J Immunol. 2004 Jun 1;172(11):6820-7. doi: 10.4049/jimmunol.172.11.6820.

Abstract

Unmethylated CpG DNA binds to the Toll-like receptor 9 (TLR9) and activates NF-kappaB to induce cytokine genes in dendritic cells (DCs). IFN regulatory factor (IRF)-8/IFN consensus sequence binding protein is a transcription factor important for development and activation of DCs. We found that DCs from IRF-8(-/-) mice were unresponsive to CpG and failed to induce TNF-alpha and IL-6, targets of NF-kappaB. Revealing a signaling defect selective for CpG, these cytokines were robustly induced in IRF-8(-/-) DCs in response to LPS that signals through TLR4. IRF-8(-/-) DCs expressed TLR9, adaptor myeloid differentiation factor 88, and other signaling molecules, but CpG failed to activate NF-kappaB in -/- cells. This was due to the selective inability of -/- DCs to activate I-kappaB kinase alphabeta, the kinases required for NF-kappaB in response to CpG. IRF-8 reintroduction fully restored CpG activation of NF-kappaB and cytokine induction in -/- DCs. Together, TLR signals that activate NF-kappaB are diverse among different TLRs, and TLR9 signaling uniquely depends on IRF-8 in DCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dendritic Cells / physiology*
  • Gene Transfer, Horizontal
  • Humans
  • I-kappa B Kinase
  • Interferon Regulatory Factors
  • Interleukin-6 / biosynthesis
  • Membrane Glycoproteins / physiology*
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / metabolism*
  • Oligodeoxyribonucleotides / pharmacology
  • Phosphorylation
  • Protein Serine-Threonine Kinases / metabolism
  • Receptors, Cell Surface / physiology*
  • Repressor Proteins / genetics
  • Repressor Proteins / physiology*
  • Signal Transduction
  • Toll-Like Receptor 4
  • Toll-Like Receptor 9
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha / biosynthesis
  • p38 Mitogen-Activated Protein Kinases

Substances

  • CPG-oligonucleotide
  • Interferon Regulatory Factors
  • Interleukin-6
  • Membrane Glycoproteins
  • NF-kappa B
  • Oligodeoxyribonucleotides
  • Receptors, Cell Surface
  • Repressor Proteins
  • TLR4 protein, human
  • TLR9 protein, human
  • Toll-Like Receptor 4
  • Toll-Like Receptor 9
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • interferon regulatory factor-8
  • Protein Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases