Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway

• DOI: 10.1126/science.1087262
• Publication Date: 2003-07-15T00:21:04Z
• Authors: Masahiro Yamamoto; Shintaro Sato; Hiroaki Hemmi; Katsuaki Hoshino; Tsuneyasu Kaisho; Hideki Sanjo; Osamu Takeuchi; Masanaka Sugiyama; Masaru Okabe; Kiyoshi Takeda; Shizuo Akira
• Keywords: Lipopolysaccharides; Membrane Glycoproteins; JNK Mitogen-Activated Protein Kinases; Interferon-beta; Fibroblasts; Embryo, Mammalian; Ligands; Antigens, Differentiation; DNA-Binding Proteins; Adaptor Proteins, Vesicular Transport; Mice; 03 medical and health sciences; 0302 clinical medicine; Gene Expression Regulation; Gene Targeting; Macrophages, Peritoneal; Animals; Cytokines; Interferon Regulatory Factor-3; Dimerization; Cells, Cultured; Adaptor Proteins, Signal Transducing

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)-β 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-β 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.