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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]
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“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]
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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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