Cited by 6,491Immune Response and InflammationImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

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A Toll-like receptor recognizes bacterial DNA

Hemmi, Hiroaki, Takeuchi, Osamu, Kawai, Taro, Kaisho, Tsuneyasu, Sato, Shintaro, Sanjo, Hideki, Matsumoto, Makoto, Hoshino, Katsuaki, Wagner, Hermann, Takeda, Kiyoshi, Akira, Shizuo·2000·Nature

DOI 10.1038/35047123

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Abstract

DNA from bacteria has stimulatory effects on mammalian immune cells, which depend on the presence of unmethylated CpG dinucleotides in the bacterial DNA. In contrast, mammalian DNA has a low frequency of CpG dinucleotides, and these are mostly methylated; therefore, mammalian DNA does not have immuno-stimulatory activity. CpG DNA induces a strong T-helper-1-like inflammatory response. Accumulating evidence has revealed the therapeutic potential of CpG DNA as adjuvants for vaccination strategies for cancer, allergy and infectious diseases. Despite its promising clinical use, the molecular mechanism by which CpG DNA activates immune cells remains unclear. Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. TLR9-deficient (TLR9-/-) mice did not show any response to CpG DNA, including proliferation of splenocytes, inflammatory cytokine production from macrophages and maturation of dendritic cells. TLR9-/- mice showed resistance to the lethal effect of CpG DNA without any elevation of serum pro-inflammatory cytokine levels. The in vivo CpG-DNA-mediated T-helper type-1 response was also abolished in TLR9-/- mice. Thus, vertebrate immune systems appear to have evolved a specific Toll-like receptor that distinguishes bacterial DNA from self-DNA.

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Background
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Self-citation
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Background
Exercise and Toll-like receptors
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Influential
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Background
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BackgroundInfluential
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BackgroundSelf-citation
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BackgroundInfluentialSelf-citation
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Background
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BackgroundInfluential
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“…the Toll-like receptors (TLRs) (Alexopoulou et al., 2001; Diebold et al., 2004; Gantner et al., 2003; Godaly and Young, 2005; Hayashi et al., 2001; Hemmi et al., 2000, 2002; Jurk et al., 2002; Liu-Bryan et al., 2005; Takeuchi et al., 1999; Zhao et al., 2007), nucleotide-binding domain and…”
Background
APC-Independent Activation of NK Cells by the Toll-Like Receptor 3 Agonist Double-Stranded RNA
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BackgroundInfluential
Repetitive Elements in Mammalian Telomeres Suppress Bacterial DNA-Induced Immune Activation
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Murine Plasmacytoid Pre-Dendritic Cells Generated from Flt3 Ligand-Supplemented Bone Marrow Cultures Are Immature APCs
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Apoptosis and Necroptosis as Host Defense Strategies to Prevent Viral Infection
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“It has been shown that many toll-like receptor (TLR) ligands, including LPS, CpG motifs in bacterial DNA, viral dsRNA or its synthetic equivalent poly(I:C) can promote IL-12 production, and activate DC that promote the differentiation of Th1 cells [18,19].”
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Prenatal Maternal Stress and Cord Blood Innate and Adaptive Cytokine Responses in an Inner-City Cohort
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“How is the IFN-β gene activated in DNase II −/− and CAD −/− DNase II −/− ? Non-methylated, CpG-rich bacterial DNA is known to activate the innate immunity through Toll-like receptor 9 (TLR-9”
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Response to Neisseria gonorrhoeae by Cervicovaginal Epithelial Cells Occurs in the Absence of Toll-Like Receptor 4-Mediated Signaling
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Background

Authors: Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., Matsumoto, M., Hoshino, K., Wagner, H., Takeda, K., & Akira, S.
Affiliations: Research Institute for Microbial Diseases, The University of Osaka (JP)
Japan Science and Technology Agency (JP)
Technical University of Munich (DE)
Corresponding author: Akira, Shizuo
ORCID: Hemmi, Hiroaki
Takeuchi, Osamu
Kawai, Taro
Kaisho, Tsuneyasu
Sato, Shintaro
Sanjo, Hideki
Hoshino, Katsuaki
Takeda, Kiyoshi
Akira, Shizuo
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2000-12-07
Volume: 408
Issue: 6813
Pages: 740-745
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/35047123
OpenAlex: W1514540900
Cited by: 6,491
References: 33
Citations by year: 2026: 85 · 2025: 115 · 2024: 136 · 2023: 167 · 2022: 156 · 2021: 191 · 2020: 180 · 2019: 164 · 2018: 187 · 2017: 219 · 2016: 201 · 2015: 226 · 2014: 276 · 2013: 281 · 2012: 235
FWCI: 102.08
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: Japan Society for the Promotion of Science
Topics: Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords: TLR9, CpG, innate immunity, T helper 1 response, adjuvants, vaccination, dendritic cell maturation, macrophage cytokine production, self-DNA, TLR9-deficient mice
MeSH terms: Amino Acid Sequence, Animals, Antigens, Differentiation, Base Sequence, Cells, Cultured, Cloning, Molecular, Dendritic Cells, DNA-Binding Proteins, DNA, Bacterial, T-Lymphocytes, Helper-Inducer, Humans, Membrane Glycoproteins, Mice, Inbred C57BL, Molecular Sequence Data, Receptors, Cell Surface, Receptors, Immunologic, Dinucleoside Phosphates, Signal Transduction, Cytokines, Mutagenesis, Sequence Homology, Amino Acid, Drosophila Proteins, Adaptor Proteins, Signal Transducing, Toll-Like Receptors, Toll-Like Receptor 9, Mice, Myeloid Differentiation Factor 88

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A Toll-like receptor recognizes bacterial DNA

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