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.
Yamamoto
Masahiro
M
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita Osaka 565-0871, Japan.
Sato
Shintaro
S
Hemmi
Hiroaki
H
Hoshino
Katsuaki
K
Kaisho
Tsuneyasu
T
Sanjo
Hideki
H
Takeuchi
Osamu
O
Sugiyama
Masanaka
M
Okabe
Masaru
M
Takeda
Kiyoshi
K
Akira
Shizuo
S
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D018390:Gene Targeting; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D008024:Ligands; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000502:physiology*; D015398:Signal Transduction; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014157:Transcription Factors / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000943:Antigens, Differentiation; D016207:Cytokines; D004268:DNA-Binding Proteins; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D048031:JNK Mitogen-Activated Protein Kinases; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D020928:Mitogen-Activated Protein Kinases; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011070:Poly I-C; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014157:Transcription Factors; C494233:Irf3 protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse