Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway.
Journal:
Science 2003 AugAuthors:
Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, Takeuchi O, Sugiyama M, Okabe M, Takeda K, Akira S
Abstract
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
...[more]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.[less]
Mesh Headings:
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