The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.
A Toll-like receptor recognizes bacterial DNA
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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“all of the AAV-induced cytokines and chemokines can be upregulated by activation of TLR9 in the periphery using synthetic CpG-rich oligonucleotides.8,9,10,11,12,52,53,54,55,56,57,58”
From An innate immune response to adeno-associated virus genomes decreases cortical dendritic complexity and disrupts synaptic transmission (2024) · cites this paper as [52]
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 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
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
Self-citationCpG motifs in bacterial DNA trigger direct B-cell activation
Krieg, A. M., Yi, A.-K., Matson, S., Waldschmidt, T. J., Bishop, G. A., Teasdale, R., Koretzky, G. A., & Klinman, D. M. (1995) · Nature · doi:10.1038/374546a0 · Cited by 3,508
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
Self-citationInnate Immunity: The Virtues of a Nonclonal System of Recognition
Medzhitov, R., & Janeway, C. A. (1997) · Cell · doi:10.1016/s0092-8674(00)80412-2 · Cited by 2,434
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
Self-citationA family of human receptors structurally related to Drosophila Toll.
Rock, F., Hardiman, G., Timans, J., Kastelein, R., & Bazan, J. (1998) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.95.2.588 · Cited by 2,009
Host Defense Mechanisms Triggered by Microbial Lipoproteins Through Toll-Like Receptors
Brightbill, H. D., Libraty, D. H., Krutzik, S. R., Yang, R., Belisle, J. T., Bleharski, J. R., Maitland, M. L., Norgard, M. V., Plevy, S. E., Smale, S. T., et al. (1999) · Science · doi:10.1126/science.285.5428.732 · Cited by 1,659
Cell Activation and Apoptosis by Bacterial Lipoproteins Through Toll-like Receptor-2
Aliprantis, A. O., Yang, R., Mark, M. R., Suggett, S., Devaux, B., Radolf, J. D., Klimpel, G. R., Godowski, P. J., & Zychlinsky, A. (1999) · Science · doi:10.1126/science.285.5428.736 · Cited by 1,463
The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens
Underhill, D. M., Ozinsky, A., Hajjar, A. M., Stevens, A. M., Wilson, C. B., Bassetti, M., & Aderem, A. A. (1999) · Nature · doi:10.1038/44605 · Cited by 1,370
Häcker, H., Mischak, H., Miethke, T., Liptay, S., Schmid, R. M., Sparwasser, T. D., Heeg, K. M., Lipford, G. B., & Wagner, H. (1998) · The EMBO Journal · doi:10.1093/emboj/17.21.6230 · Cited by 670
Self-citationCpG DNA: A potent signal for growth, activation, and maturation of human dendritic cells
Hartmann, G., Weiner, G. J., & KRIEG, A. M. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.16.9305 · Cited by 623
Takeuchi, O., Kaufmann, A. M., Grote, K., Kawai, T., Hoshino, K., Morr, M., Mühlradt, P. F., & Akira, S. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.2.554 · Cited by 569
Self-citationJakob, T., Walker, P., Krieg, A. Μ., Udey, M. C., & Vogel, J. C. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.6.3042 · Cited by 535
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
Self-citationTLR6: 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
Self-citationMacrophages sense pathogens via DNA motifs: induction of tumor necrosis factor‐α‐mediated shock
Sparwasser, T. D., Miethke, T., Lipford, G. B., Erdmann, A. A., Häcker, H., Heeg, K. M., & Wagner, H. (1997) · European Journal of Immunology · doi:10.1002/eji.1830270712 · Cited by 412
Self-citationThe role of CpG motifs in innate immunity
Krieg, A. Μ. (2000) · Current Opinion in Immunology · doi:10.1016/s0952-7915(99)00048-5 · Cited by 342
Bacterial CpG DNA Activates Immune Cells to Signal Infectious Danger
Wagner, H. (1999) · Advances in immunology · doi:10.1016/s0065-2776(08)60790-7 · Cited by 313
Self-citationMacfarlane, D. E., & Manzel, L. J. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.3.1122 · Cited by 257
Cutting Edge: Rapid Induction of Mitogen-Activated Protein Kinases by Immune Stimulatory CpG DNA
Yi, A., & Krieg, A. Μ. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.9.4493 · Cited by 214
Rapid induction of mitogen-activated protein kinases by immune stimulatory CpG DNA.
Yi, A., & KRIEG, A. M. (1998) · PubMed · Cited by 208
Lipford, G. B., Sparwasser, T. D., Zimmermann, S., Heeg, K. M., & Wagner, H. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.3.1228 · Cited by 137
Self-citationLymphocyte activation by CpG dinucleotide motifs in prokaryotic DNA
Krieg, A. Μ. (1996) · Trends in Microbiology · doi:10.1016/0966-842x(96)81515-0 · Cited by 128
Häcker, H., Mischak, H., Häcker, G., Eser, S., Prenzel, N., Ullrich, A., & Wagner, H. (1999) · The EMBO Journal · doi:10.1093/emboj/18.24.6973 · Cited by 122
Self-citationBacterial DNA as immune cell activator
Lipford, G. B. (1998) · Trends in Microbiology · doi:10.1016/s0966-842x(98)01408-5 · Cited by 120
Immune Recognition of Foreign DNA
Klinman, D. M., Verthelyi, D. I., Takeshita, F., & Ishii, K. J. (1999) · Immunity · doi:10.1016/s1074-7613(00)80087-4 · Cited by 116
Crompton, T., Outram, S. V., Buckland, J., & Owen, M. J. (1998) · European Journal of Immunology · doi:10.1002/(sici)1521-4141(199806)28:06 · Cited by 49
Self-citationLiang, H., Reich, C. F., Pisetsky, D. S., & Lipsky, P. E. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.3.1438 · Cited by 40
The discovery of immunostimulatory DNA sequence
Yamamoto, S., Yamamoto, T., & Tokunaga, T. (2001) · Springer eBooks · doi:10.1007/978-3-642-56866-4_2 · Cited by 39
The discovery of immunostimulatory DNA sequence
Yamamoto, S., Yamamoto, T., & Tokunaga, T. (2000) · Springer Seminars in Immunopathology · doi:10.1007/s002810000019 · Cited by 33
Yoshimura, A., Lien, E., Ingalls, R., Tuomanen, E., Dziarski, R., & Golenbock, D. (1999) · Journal of Immunology · doi:10.4049/jimmunol.163.1.1 · Cited by 2
Flagged first, then by citations
Cited by
Sorted by citations
Pathogen Recognition and Innate Immunity
Akira, S., Uematsu, S., & Takeuchi, O. (2006) · Cell · doi:10.1016/j.cell.2006.02.015 · Cited by 11,976
“Bacterial DNA Bacterial genomic DNA is also an immunostimulant and is recognized by TLR9 (Hemmi et al., 2000; Krieg, 2002).”
Self-citationJaneway, C. A., & Medzhitov, R. (2002) · Annual Review of Immunology · doi:10.1146/annurev.immunol.20.083001.084359 · Cited by 8,394
“It turns out that the two recombinase-activating genes are encoded in a short stretch of DNA, in opposite orientations and lacking exons.”
BackgroundInfluentialAkira, S., & Takeda, K. (2004) · Nature reviews. Immunology · doi:10.1038/nri1391 · Cited by 8,312
Self-citationRecognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3
Alexopoulou, L., Holt, A. C., Medzhitov, R., & Flavell, R. A. (2001) · Nature · doi:10.1038/35099560 · Cited by 6,129
Toll-like receptors: critical proteins linking innate and acquired immunity
Akira, S., Takeda, K., & Kaisho, T. (2001) · Nature Immunology · doi:10.1038/90609 · Cited by 4,777
Self-citation
Metadata
- 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
- Venue
- Nature
- Published
- 2000-12-07
- Volume
- 408
- Issue
- 6813
- Pages
- 740-745
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
