The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3
Abstract
Toll-like receptors (TLRs) are a family of innate immune-recognition receptors that recognize molecular patterns associated with microbial pathogens, and induce antimicrobial immune responses. Double-stranded RNA (dsRNA) is a molecular pattern associated with viral infection, because it is produced by most viruses at some point during their replication. Here we show that mammalian TLR3 recognizes dsRNA, and that activation of the receptor induces the activation of NF-kappaB and the production of type I interferons (IFNs). TLR3-deficient (TLR3-/-) mice showed reduced responses to polyinosine-polycytidylic acid (poly(I:C)), resistance to the lethal effect of poly(I:C) when sensitized with d-galactosamine (d-GalN), and reduced production of inflammatory cytokines. MyD88 is an adaptor protein that is shared by all the known TLRs. When activated by poly(I:C), TLR3 induces cytokine production through a signalling pathway dependent on MyD88. Moreover, poly(I:C) can induce activation of NF-kappaB and mitogen-activated protein (MAP) kinases independently of MyD88, and cause dendritic cells to mature.
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“However, several RNA structural features have been described as immunostimulatory due to interactions with various RNA sensors such as Toll-like receptors, RIG-I, and PKR.”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [7]
In the citing paper
“Activation of TLR3 signaling by its agonists can induce apoptosis in human cancer cells [29, 33].”
From Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells (2016) · cites this paper as [33]
In the citing paper
“Through recognition of TLR3 in endosomes or retinoic acid-inducible gene I, melanoma differentiation-associated protein 5, and inflammasomes in the cytoplasm,96, 97, 98, 99 depending on the amount, dsRNAs might overactivate innate immunity and lead to adverse events.”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [96]
In the citing paper
“90.7% efficacy in participants 5 to 11 years of age96”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [96]
Citations
Cites
Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene
Poltorak, A., He, X., Smirnova, I., Liu, M.-Y., Huffel, C. V., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., et al. (1998) · Science · doi:10.1126/science.282.5396.2085 · Cited by 7,631
A Toll-like receptor recognizes bacterial DNA
Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., Matsumoto, M., Hoshino, K., Wagner, H., Takeda, K., et al. (2000) · Nature · doi:10.1038/35047123 · Cited by 6,491
A human homologue of the Drosophila Toll protein signals activation of adaptive immunity
Medzhitov, R., Preston-Hurlburt, P., & Janeway, C. A. J. (1997) · Nature · doi:10.1038/41131 · Cited by 6,137
HOW CELLS RESPOND TO INTERFERONS
Stark, G. R., Kerr, I. M., Williams, B. R. G., Silverman, R. H., & Schreiber, R. D. (1998) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.67.1.227 · Cited by 3,932
Inaba, K., Inaba, M., Romani, N., Aya, H., Deguchi, M., Ikehara, S., Muramatsu, S., & Steinman, R. M. (1992) · The Journal of Experimental Medicine · doi:10.1084/jem.176.6.1693 · Cited by 3,741
Takeuchi, O., Hoshino, K., Kawai, T., Sanjo, H., Takada, H., Ogawa, T., Takeda, K., & Akira, S. (1999) · Immunity · doi:10.1016/s1074-7613(00)80119-3 · Cited by 3,680
The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5
Hayashi, F., Smith, K. D., Ozinsky, A., Hawn, T. R., Yi, E. C., Goodlett, D. R., Eng, J. K., Akira, S., Underhill, D. M., & Aderem, A. A. (2001) · Nature · doi:10.1038/35074106 · Cited by 3,605
Hoshino, K., Takeuchi, O., Kawai, T., Sanjo, H., Ogawa, T., Takeda, Y., Takeda, K., & Akira, S. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.7.3749 · Cited by 3,374
Unresponsiveness of MyD88-deficient mice to endotoxin.
Kawai, T., Adachi, O., Ogawa, T., Takeda, K., & Akira, S. (1999) · Immunity · doi:10.1016/s1074-7613(00)80086-2 · Cited by 2,367
MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways.
Medzhitov, R., Preston-Hurlburt, P., Kopp, E., Stadlen, A., Chen, C.-Q., Ghosh, S., & Janeway, C. (1998) · Molecules and Cells · doi:10.1016/s1097-2765(00)80136-7 · Cited by 1,783
Innate immune recognition: mechanisms and pathways
Medzhitov, R., & Janeway, C. (2000) · Immunological Reviews · doi:10.1034/j.1600-065x.2000.917309.x · Cited by 1,589
Noncytolytic Control of Viral Infections by the Innate and Adaptive ImmuneResponse
Guidotti, L. G., & Chisari, F. V. (2001) · Annual Review of Immunology · doi:10.1146/annurev.immunol.19.1.65 · Cited by 1,003
The Toll-receptor family and control of innate immunity.
Kopp, E., & Medzhitov, R. (1999) · Current Opinion in Immunology · doi:10.1016/s0952-7915(99)80003-x · Cited by 734
Deficient signaling in mice devoid of double‐stranded RNA‐dependent protein kinase.
Yang, Y. L., Reis, L. F. L., Pavlovic, J., Aguzzi, A., Schäfer, R., Kumar, A., Williams, B. R. G., Aguet, M., & Weissmann, C. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb00300.x · Cited by 632
The Double-Stranded RNA-Dependent Protein Kinase PKR: Structure and Function
Clemens, M. J., & Elia, A. (1997) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.1997.17.503 · Cited by 605
Jacobs, B. L., & Langland, J. (1996) · Virology · doi:10.1006/viro.1996.0259 · Cited by 588
Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor
Burns, K., Clatworthy, J., Martin, L., Martinon, F., Plumpton, C., Maschera, B., Lewis, A., Ray, K. P., Tschopp, J., & Volpe, F. (2000) · Nature Cell Biology · doi:10.1038/35014038 · Cited by 554
Toll-like Receptors and Innate Immunity
Akira, S. (2001) · Advances in immunology · doi:10.1016/s0065-2776(01)78001-7 · Cited by 511
Häcker, H., Vabulas, R. M., Takeuchi, O., Hoshino, K., Akira, S., & Wagner, H. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.4.595 · Cited by 466
TLR6: A novel member of an expanding Toll-like receptor family
Takeuchi, O., Kawai, T., Sanjo, H., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Takeda, K., & Akira, S. (1999) · Gene · doi:10.1016/s0378-1119(99)00098-0 · Cited by 429
JNK2 and IKKβ Are Required for Activating the Innate Response to Viral Infection
Chu, W., Ostertag, D. G., Li, Z.-W., Chang, L., Chen, Y., Hu, Y., Williams, B. R. G., Perrault, J., & Karin, M. (1999) · Immunity · doi:10.1016/s1074-7613(00)80146-6 · Cited by 389
Antisense RNA: Function and Fate of Duplex RNA in Cells of Higher Eukaryotes
Kumar, M., & Carmichael, G. (1998) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.62.4.1415-1434.1998 · Cited by 320
Goh, K. C., deVeer, M. J., & Williams, B. R. G. (2000) · The EMBO Journal · doi:10.1093/emboj/19.16.4292 · Cited by 285
Recognition of CpG DNA is mediated by signaling pathways dependent on the adaptor protein MyD88
Schnare, M., Czopik, A. K., Takeda, K., Akira, S., & Medzhitov, R. M. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00700-4 · Cited by 249
Interferon Action in Triply Deficient Mice Reveals the Existence of Alternative Antiviral Pathways
Zhou, A., Paranjape, J. M., Der, S. D., Williams, B. R. G., & Silverman, R. H. (1999) · Virology · doi:10.1006/viro.1999.9738 · Cited by 244
Abraham, N. B., Stojdl, D. F., Duncan, P. I., Méthot, N., Ishii, T. M., Dubé, M., Vanderhyden, B. C., Atkins, H. L., Gray, D. A., McBurney, M. W., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.9.5953 · Cited by 232
Toll-like receptors: lessons from knockout mice
Akira, S. (2000) · Biochemical Society Transactions · doi:10.1042/bst0280551 · Cited by 119
Comparison of acute phase responses induced in rabbits by lipopolysaccharide and double-stranded RNA
Kimura, M., Toth, L. A., Agostini, H. T., Cady, A. B., Majde, J. A., & Krueger, J. M. (1994) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1994.267.6.r1596 · Cited by 102
Potential role of PKR in double‐stranded RNA‐induced macrophage activation
Maggi, L. B., Heitmeier, M. R., Scheuner, D. L., Kaufman, R. J., Buller, R. M. L., & Corbett, J. A. (2000) · The EMBO Journal · doi:10.1093/emboj/19.14.3630 · Cited by 88
Role of external Na+ and cytosolic pH in agonist-evoked cytosolic Ca2+ response in human platelets
Kimura, M., Nakamura, K., Fenton, J. W., Andersen, T. T., Reeves, J. P., & Aviv, A. (1994) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1994.267.6.c1543 · Cited by 34
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Pathogen Recognition and Innate Immunity
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Janeway, C. A., & Medzhitov, R. (2002) · Annual Review of Immunology · doi:10.1146/annurev.immunol.20.083001.084359 · Cited by 8,394
Akira, S., & Takeda, K. (2004) · Nature reviews. Immunology · doi:10.1038/nri1391 · Cited by 8,312
Takeda, K., Kaisho, T., & Akira, S. (2003) · Annual Review of Immunology · doi:10.1146/annurev.immunol.21.120601.141126 · Cited by 6,143
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Metadata
- Authors
- Alexopoulou, L., Holt, A. C., Medzhitov, R., & Flavell, R. A.
- Affiliations
- Yale University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Medzhitov, Ruslan
- Flavell, Richard A.
- Venue
- Nature
- Published
- 2001-10
- Volume
- 413
- Issue
- 6857
- Pages
- 732-738
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2076361525
- Cited by
- 6,129
- References
- 30
- Citations by year
- 2026: 134 · 2025: 156 · 2024: 161 · 2023: 174 · 2022: 203 · 2021: 270 · 2020: 216 · 2019: 203 · 2018: 209 · 2017: 209 · 2016: 219 · 2015: 237 · 2014: 258 · 2013: 279 · 2012: 303
- FWCI
- 66.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- TLR3, double-stranded RNA, NF-κB activation, type I interferon, MyD88, poly(I:C), innate immunity, viral infection, MAPK signaling, dendritic cell maturation, inflammatory cytokines
- MeSH terms
- Amino Acid Sequence, Animals, Antigens, Differentiation, B-Lymphocytes, Cell Line, Cells, Cultured, Galactosamine, Humans, Interferon Type I, Lymphocyte Activation, Macrophages, Membrane Glycoproteins, Molecular Sequence Data, Poly I-C, Receptors, Cell Surface, Receptors, Immunologic, RNA, Double-Stranded, Virus Diseases, Signal Transduction, Cytokines, NF-kappa B, Sequence Homology, Amino Acid, Mitogen-Activated Protein Kinases, Drosophila Proteins, Adaptor Proteins, Signal Transducing, Toll-Like Receptors, Toll-Like Receptor 3, Mice, Myeloid Differentiation Factor 88
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