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Originally published in Science Express on 10 July 2003
Science 1 August 2003:
Vol. 301. no. 5633, pp. 640 - 643
DOI: 10.1126/science.1087262
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Reports

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

Masahiro Yamamoto,1 Shintaro Sato,1,2 Hiroaki Hemmi,1 Katsuaki Hoshino,1,4 Tsuneyasu Kaisho,1,4 Hideki Sanjo,1 Osamu Takeuchi,1 Masanaka Sugiyama,1 Masaru Okabe,3 Kiyoshi Takeda,1,2 Shizuo Akira1,2*

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)-ß 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-ß 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.

1 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita Osaka 565-0871, Japan.
2 ERATO, Japan Science and Technology Corporation, 3-1 Yamada-oka, Suita Osaka 565-0871, Japan.
3 Genome Information Research Center, 3-1 Yamada-oka, Suita Osaka 565-0871, Japan.
4 RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumiku, Yokohama, Kanagawa 230-0045, Japan

* To whom correspondence should be addressed. E-mail: sakira{at}biken.osaka-u.ac.jp

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Varying Importance of Soluble and Membrane CD14 in Endothelial Detection of Lipopolysaccharide.
K. L. Lloyd-Jones, M. M. Kelly, and P. Kubes (2008)
J. Immunol. 181, 1446-1453
   Abstract »    Full Text »    PDF »
Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5.
H. Kato, O. Takeuchi, E. Mikamo-Satoh, R. Hirai, T. Kawai, K. Matsushita, A. Hiiragi, T. S. Dermody, T. Fujita, and S. Akira (2008)
J. Exp. Med. 205, 1601-1610
   Abstract »    Full Text »    PDF »
Viral Double-Stranded RNA Triggers Ig Class Switching by Activating Upper Respiratory Mucosa B Cells through an Innate TLR3 Pathway Involving BAFF.
W. Xu, P. A. Santini, A. J. Matthews, A. Chiu, A. Plebani, B. He, K. Chen, and A. Cerutti (2008)
J. Immunol. 181, 276-287
   Abstract »    Full Text »    PDF »
Homo-oligomerization Is Essential for Toll/Interleukin-1 Receptor Domain-containing Adaptor Molecule-1-mediated NF-{kappa}B and Interferon Regulatory Factor-3 Activation.
K. Funami, M. Sasai, H. Oshiumi, T. Seya, and M. Matsumoto (2008)
J. Biol. Chem. 283, 18283-18291
   Abstract »    Full Text »    PDF »
Cytomegalovirus M45 Cell Death Suppression Requires Receptor-interacting Protein (RIP) Homotypic Interaction Motif (RHIM)-dependent Interaction with RIP1.
J. W. Upton, W. J. Kaiser, and E. S. Mocarski (2008)
J. Biol. Chem. 283, 16966-16970
   Abstract »    Full Text »    PDF »
CD45 Regulates TLR-Induced Proinflammatory Cytokine and IFN-{beta} Secretion in Dendritic Cells.
J. L. Cross, K. Kott, T. Miletic, and P. Johnson (2008)
J. Immunol. 180, 8020-8029
   Abstract »    Full Text »    PDF »
Dendritic Cells Differentiated in the Presence of a Single-Stranded Viral RNA Sequence Conserve Their Ability To Activate CD4 T Lymphocytes but Lose Their Capacity for Th1 Polarization.
V. Marin-Esteban, M. Abdul, D. Charron, A. Haziot, and N. Mooney (2008)
Clin. Vaccine Immunol. 15, 954-962
   Abstract »    Full Text »    PDF »
Upregulation of the TLR3 Pathway by Kaposi's Sarcoma-Associated Herpesvirus during Primary Infection.
J. West and B. Damania (2008)
J. Virol. 82, 5440-5449
   Abstract »    Full Text »    PDF »
Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system.
Y. Kondo, T. Yoshimoto, K. Yasuda, S. Futatsugi-Yumikura, M. Morimoto, N. Hayashi, T. Hoshino, J. Fujimoto, and K. Nakanishi (2008)
Int. Immunol. 20, 791-800
   Abstract »    Full Text »    PDF »
Class-specific Regulation of Pro-inflammatory Genes by MyD88 Pathways and I{kappa}B{zeta}.
H. Kayama, V. R. Ramirez-Carrozzi, M. Yamamoto, T. Mizutani, H. Kuwata, H. Iba, M. Matsumoto, K. Honda, S. T. Smale, and K. Takeda (2008)
J. Biol. Chem. 283, 12468-12477
   Abstract »    Full Text »    PDF »
Zebrafish TRIF, a Golgi-Localized Protein, Participates in IFN Induction and NF-{kappa}B Activation.
S. Fan, S. Chen, Y. Liu, Y. Lin, H. Liu, L. Guo, B. Lin, S. Huang, and A. Xu (2008)
J. Immunol. 180, 5373-5383
   Abstract »    Full Text »    PDF »
Deletion of MyD88 markedly attenuates sepsis-induced T and B lymphocyte apoptosis but worsens survival.
O. M. Peck-Palmer, J. Unsinger, K. C. Chang, C. G. Davis, J. E. McDunn, and R. S. Hotchkiss (2008)
J. Leukoc. Biol. 83, 1009-1018
   Abstract »    Full Text »    PDF »
MDA5 Participates in the Detection of Paramyxovirus Infection and Is Essential for the Early Activation of Dendritic Cells in Response to Sendai Virus Defective Interfering Particles.
J. S. Yount, L. Gitlin, T. M. Moran, and C. B. Lopez (2008)
J. Immunol. 180, 4910-4918
   Abstract »    Full Text »    PDF »
Phagocytosis of Picornavirus-Infected Cells Induces an RNA-Dependent Antiviral State in Human Dendritic Cells.
M. Kramer, B. M. Schulte, L. W. J. Toonen, P. M. Barral, P. B. Fisher, K. H. W. Lanke, J. M. D. Galama, F. J. M. van Kuppeveld, and G. J. Adema (2008)
J. Virol. 82, 2930-2937
   Abstract »    Full Text »    PDF »
Deoxynucleic Acids from Cryptococcus neoformans Activate Myeloid Dendritic Cells via a TLR9-Dependent Pathway.
K. Nakamura, A. Miyazato, G. Xiao, M. Hatta, K. Inden, T. Aoyagi, K. Shiratori, K. Takeda, S. Akira, S. Saijo, et al. (2008)
J. Immunol. 180, 4067-4074
   Abstract »    Full Text »    PDF »


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