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Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway.

Stimulation of Toll-like receptors (TLRs) triggers activation of a common MyD88-dependent signaling pathway as well as a MyD88-independent pathway that is unique to TLR3 and TLR4 signaling pathways leading to interferon (IFN)-beta production. Here we disrupted the gene encoding a Toll/IL-1 receptor (TIR) domain-containing adaptor, TRIF. TRIF-deficient mice were defective in both TLR3- and TLR4-mediated expression of IFN-beta and activation of IRF-3. Furthermore, inflammatory cytokine production in response to the TLR4 ligand, but not to other TLR ligands, was severely impaired in TRIF-deficient macrophages. Mice deficient in both MyD88 and TRIF showed complete loss of nuclear factor kappa B activation in response to TLR4 stimulation. These findings demonstrate that TRIF is essential for TLR3- and TLR4-mediated signaling pathways facilitating mammalian antiviral host defense.

Pubmed ID: 12855817

Authors

  • Yamamoto M
  • Sato S
  • Hemmi H
  • Hoshino K
  • Kaisho T
  • Sanjo H
  • Takeuchi O
  • Sugiyama M
  • Okabe M
  • Takeda K
  • Akira S

Journal

Science (New York, N.Y.)

Publication Data

August 1, 2003

Associated Grants

None

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Animals
  • Antigens, Differentiation
  • Cells, Cultured
  • Cytokines
  • DNA-Binding Proteins
  • Dimerization
  • Embryo, Mammalian
  • Fibroblasts
  • Gene Expression Regulation
  • Gene Targeting
  • Interferon Regulatory Factor-3
  • Interferon-beta
  • JNK Mitogen-Activated Protein Kinases
  • Ligands
  • Lipopolysaccharides
  • Macrophages, Peritoneal
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinases
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Poly I-C
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Signal Transduction
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Transcription Factors