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
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Navarro-Sánchez, E., Desprès, P., & Cedillo‐Barrón, L. (2005) · Archives of Medical Research · doi:10.1016/j.arcmed.2005.04.007 · Cited by 140
Duits, L. A., Nibbering, P. H., Strijen, E., Vos, J. B., Mannesse-Lazeroms, S. P. G., Sterkenburg, M. A. J. A., & Hiemstra, P. S. (2003) · FEMS Immunology & Medical Microbiology · doi:10.1016/s0928-8244(03)00106-8 · Cited by 135
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Long, L., Deng, Y., Yao, F., Guan, D., Feng, Y., Jiang, H., Li, X., Hu, P., Lu, X., Wang, H., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.01.015 · Cited by 127
Carvalho, A., De Luca, A., Bozza, S., Cunha, C., D'Angelo, C., Moretti, S., Perruccio, K., Iannitti, R. G., Fallarino, F., Pierini, A., et al. (2012) · Blood · doi:10.1182/blood-2011-06-362582 · Cited by 131
Matsumoto, M., Tatematsu, M., Nishikawa, F., Azuma, M., Ishii, N., Morii-Sakai, A., Shime, H., & Seya, T. (2015) · Nature Communications · doi:10.1038/ncomms7280 · Cited by 130
Toll‐like receptors and pregnancy: Trophoblast as modulators of the immune response
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Reinert, L. S., Rashidi, A. S., Tran, D. N., Katzilieris-Petras, G., Hvidt, A. K., Gohr, M., Fruhwürth, S., Bodda, C., Thomsen, M. K., Vendelbo, M. H., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci136824 · Cited by 118
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Development of Therapeutic-Grade Small Interfering RNAs by Chemical Engineering
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Finberg, R. W., Wang, J. P., & Kurt‐Jones, E. A. (2007) · Reviews in Medical Virology · doi:10.1002/rmv.525 · Cited by 90
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Collado-Hidalgo, A., Sung, C., & Cole, S. (2006) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2006.01.005 · Cited by 69
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Luo, Z., Liu, L.-F., Jiang, Y.-N., Tang, L.-P., Li, W., Ouyang, S.-H., Tu, L.-F., Wu, Y.-P., Gong, H.-B., Yan, C.-Y., et al. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00238-z · Cited by 34
Wilson, C. L., Mann, J., Walsh, M., Perrugoria, M. J., Oakley, F., Wright, M. C., Brignole, C., Di Paolo, D., Perri, P., Ponzoni, M., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0083391 · Cited by 31
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Mitchell, W. M., Nicodemus, C. F., Carter, W. A., Horvath, J. C., & Strayer, D. R. (2014) · The American Journal of Pathology · doi:10.1016/j.ajpath.2013.12.006 · Cited by 27
Deng, T., Feng, X., Liu, P., Yan, K., Chen, Y., & Han, D. (2013) · Immunology & Cell Biology · doi:10.1038/icb.2012.45 · Cited by 25
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Kanmani, P., & Kim, H. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01536 · Cited by 21
Short, K. R., Vissers, M., de Kleijn, S., Zomer, A. L., Kedzierska, K., Grant, E., Reading, P. C., Hermans, P. W. M., Ferwerda, G., & Diavatopoulos, D. A. (2014) · Journal of Innate Immunity · doi:10.1159/000353905 · Cited by 20
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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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