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 RIS Download
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