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Science 301 (5633): 640-643

Copyright © 2003 by the American Association for the Advancement of Science

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*

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)-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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R. Xiong, L. Nie, L.-x. Xiang, and J.-z. Shao (2012)
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Into the Eye of the Cytokine Storm.
J. R. Tisoncik, M. J. Korth, C. P. Simmons, J. Farrar, T. R. Martin, and M. G. Katze (2012)
Microbiol. Mol. Biol. Rev. 76, 16-32
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Selective TRIF-Dependent Signaling by a Synthetic Toll-Like Receptor 4 Agonist.
W. S. Bowen, L. A. Minns, D. A. Johnson, T. C. Mitchell, M. M. Hutton, and J. T. Evans (2012)
Science Signaling 5, ra13
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Cholera toxin activates nonconventional adjuvant pathways that induce protective CD8 T-cell responses after epicutaneous vaccination.
I. Olvera-Gomez, S. E. Hamilton, Z. Xiao, C. P. Guimaraes, H. L. Ploegh, K. A. Hogquist, L. Wang, and S. C. Jameson (2012)
PNAS 109, 2072-2077
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Phospholipase C{gamma}-2 and Intracellular Calcium Are Required for Lipopolysaccharide-induced Toll-like Receptor 4 (TLR4) Endocytosis and Interferon Regulatory Factor 3 (IRF3) Activation.
C.-Y. Chiang, V. Veckman, K. Limmer, and M. David (2012)
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Expression of type I interferon by splenic macrophages suppresses adaptive immunity during sepsis.
T. Schwandt, B. Schumak, G. H. Gielen, F. Jungerkes, P. Schmidbauer, K. Klocke, A. Staratschek-Jox, N. van Rooijen, G. Kraal, I. Ludwig-Portugall, et al. (2012)
EMBO J. 31, 201-213
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The Toll-Like Receptor 3-Mediated Antiviral Response Is Important for Protection against Poliovirus Infection in Poliovirus Receptor Transgenic Mice.
Y. Abe, K. Fujii, N. Nagata, O. Takeuchi, S. Akira, H. Oshiumi, M. Matsumoto, T. Seya, and S. Koike (2012)
J. Virol. 86, 185-194
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Exogenous Ceramide-1-phosphate Reduces Lipopolysaccharide (LPS)-mediated Cytokine Expression.
J. L. Hankins, T. E. Fox, B. M. Barth, K. A. Unrath, and M. Kester (2011)
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Host innate recognition of an intestinal bacterial pathogen induces TRIF-dependent protective immunity.
J. Sotolongo, C. Espana, A. Echeverry, D. Siefker, N. Altman, J. Zaias, R. Santaolalla, J. Ruiz, K. Schesser, B. Adkins, et al. (2011)
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Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway.
S. He, Y. Liang, F. Shao, and X. Wang (2011)
PNAS 108, 20054-20059
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Ehrlichia chaffeensis Induces Monocyte Inflammatory Responses through MyD88, ERK, and NF-{kappa}B but Not through TRIF, Interleukin-1 Receptor 1 (IL-1R1)/IL-18R1, or Toll-Like Receptors.
K. Miura, J. Matsuo, M. A. Rahman, Y. Kumagai, X. Li, and Y. Rikihisa (2011)
Infect. Immun. 79, 4947-4956
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Characterization of dsRNA-induced pancreatitis model reveals the regulatory role of IFN regulatory factor 2 (Irf2) in trypsinogen5 gene transcription.
H. Hayashi, T. Kohno, K. Yasui, H. Murota, T. Kimura, G. S. Duncan, T. Nakashima, K. Yamamoto, I. Katayama, Y. Ma, et al. (2011)
PNAS 108, 18766-18771
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The TLR3/TICAM-1 Pathway Is Mandatory for Innate Immune Responses to Poliovirus Infection.
H. Oshiumi, M. Okamoto, K. Fujii, T. Kawanishi, M. Matsumoto, S. Koike, and T. Seya (2011)
J. Immunol. 187, 5320-5327
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Evasion and Subversion of Interferon-Mediated Antiviral Immunity by Kaposi's Sarcoma-Associated Herpesvirus: an Overview.
N. Sathish and Y. Yuan (2011)
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Prmt2 Regulates the Lipopolysaccharide-Induced Responses in Lungs and Macrophages.
E. Dalloneau, P. Lopes Pereira, V. Brault, E. G. Nabel, and Y. Herault (2011)
J. Immunol. 187, 4826-4834
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Delineation of the Role of Toll-like Receptor Signaling during Peritonitis by a Gradually Growing Pathogenic Escherichia coli.
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Myxoma Virus Induces Type I Interferon Production in Murine Plasmacytoid Dendritic Cells via a TLR9/MyD88-, IRF5/IRF7-, and IFNAR-Dependent Pathway.
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J. Virol. 85, 10814-10825
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Innate immunity and adjuvants.
S. Akira (2011)
Phil Trans R Soc B 366, 2748-2755
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TLR Regulation of SPSB1 Controls Inducible Nitric Oxide Synthase Induction.
R. S. Lewis, T. B. Kolesnik, Z. Kuang, A. A. D'Cruz, M. E. Blewitt, S. L. Masters, A. Low, T. Willson, R. S. Norton, and S. E. Nicholson (2011)
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A subclass of acylated anti-inflammatory mediators usurp Toll-like receptor 2 to inhibit neutrophil recruitment through peroxisome proliferator-activated receptor {gamma}.
E. M. Long, A. C. Klimowicz, H. A. Paula-Neto, B. Millen, D.-M. McCafferty, P. Kubes, and S. M. Robbins (2011)
PNAS 108, 16357-16362
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Myocardial Ischemia Activates an Injurious Innate Immune Signaling via Cardiac Heat Shock Protein 60 and Toll-like Receptor 4.
Y. Li, R. Si, Y. Feng, H. H. Chen, L. Zou, E. Wang, M. Zhang, H. S. Warren, D. E. Sosnovik, and W. Chao (2011)
J. Biol. Chem. 286, 31308-31319
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Mycobacterial hypersensitivity pneumonitis requires TLR9-MyD88 in lung CD11b+ CD11c+ cells.
H. Daito, T. Kikuchi, T. Sakakibara, K. Gomi, T. Damayanti, J. Zaini, N. Tode, M. Kanehira, S. Koyama, S. Fujimura, et al. (2011)
Eur. Respir. J. 38, 688-701
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Contribution of a Streptococcus mutans Antigen Expressed by a Salmonella Vector Vaccine in Dendritic Cell Activation.
Q. Xu, J. Katz, P. Zhang, A. R. Ashtekar, D. E. Gaddis, M. Fan, and S. M. Michalek (2011)
Infect. Immun. 79, 3792-3800
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