[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3

Nature volume 413, pages 732–738 (2001)Cite this article

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 responses1,2. Double-stranded RNA (dsRNA) is a molecular pattern associated with viral infection, because it is produced by most viruses at some point during their replication3. Here we show that mammalian TLR3 recognizes dsRNA, and that activation of the receptor induces the activation of NF-κB 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 TLRs1. 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-κB and mitogen-activated protein (MAP) kinases independently of MyD88, and cause dendritic cells to mature.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: TLR3 specifically signals for NF-κB activation in response to poly(I:C).
Figure 2: Amino-acid sequence and expression pattern of TLR3, and generation of TLR3-/- mice.
Figure 3: Impaired responses to poly(I:C) from TLR3-/- cells.
Figure 4: Measurement of poly(I:C)-induced shock in TLR3-/- mice.
Figure 5: Responses to poly(I:C) in MyD88-/- and TLR3-transfected 293T cells.
Figure 6: Cellular responses independent of MyD88.

Similar content being viewed by others

References

  1. Akira, S. Toll-like receptors and innate immunity. Adv. Immunol. 78, 1–56 (2001).

    Article  CAS  Google Scholar 

  2. Medzhitov, R. M. & Janeway, C. A. Innate immune recognition: Mechanisms and pathways. Immunol. Rev. 173, 89–97 (2000).

    Article  CAS  Google Scholar 

  3. Jacobs, B. L. & Langland, J. O. When two strands are better than one: the mediators and modulators of the cellular responses to double-stranded RNA. Virology 219, 339–349 (1996).

    Article  CAS  Google Scholar 

  4. Guidotti, L. G. & Chisari, F. V. Noncytolytic control of viral infections by the innate and adaptive immune response. Annu. Rev. Immunol. 19, 65–91 (2001).

    Article  CAS  Google Scholar 

  5. Stark, G. R., Kerr, I. M., Williams, B. R., Silverman, R. H. & Schreiber, R. D. How cells respond to interferons. Annu. Rev. Biochem. 67, 227–264 (1998).

    Article  CAS  Google Scholar 

  6. Hayashi, F. et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410, 1099–1103 (2001).

    Article  CAS  ADS  Google Scholar 

  7. Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000).

    Article  CAS  ADS  Google Scholar 

  8. Hoshino, K. et al. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J. Immunol. 162, 3749–3752 (1999).

    CAS  PubMed  Google Scholar 

  9. Takeuchi, O. et al. Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cell wall components. Immunity 11, 443–451 (1999).

    Article  CAS  Google Scholar 

  10. Takeuchi, O. et al. TLR6: A novel member of an expanding toll-like receptor family. Gene 231, 59–65 (1999).

    Article  CAS  Google Scholar 

  11. Clemens, M. J. & Elia, A. The double-stranded RNA-dependent protein kinase PKR: structure and function. J. Interferon Cytokine Res. 17, 503–524 (1997).

    Article  CAS  Google Scholar 

  12. Chu, W. M. et al. JNK2 and IKKβ are required for activating the innate response to viral infection. Immunity 11, 721–731 (1999).

    Article  CAS  Google Scholar 

  13. Maggi, L. B. Jr et al. Potential role of PKR in double-stranded RNA-induced macrophage activation. EMBO J. 19, 3630–3638 (2000).

    Article  CAS  Google Scholar 

  14. Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).

    Article  CAS  ADS  Google Scholar 

  15. Kimura, M. et al. Comparison of acute phase responses induced in rabbits by lipopolysaccharide and double-stranded RNA. Am. J. Physiol. 267, R1596–R1605 (1994).

    Article  CAS  Google Scholar 

  16. Kopp, E. B. & Medzhitov, R. The Toll-receptor family and control of innate immunity. Curr. Opin. Immunol. 11, 13–18 (1999).

    Article  CAS  Google Scholar 

  17. Kawai, T., Adachi, O., Ogawa, T., Takeda, K. & Akira, S. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11, 115–122 (1999).

    Article  CAS  Google Scholar 

  18. Burns, K. et al. Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nature Cell Biol. 2, 346–351 (2000).

    Article  CAS  Google Scholar 

  19. Medzhitov, R., Preston-Hurlburt, P. & Janeway, C. A. Jr A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394–397 (1997).

    Article  CAS  ADS  Google Scholar 

  20. Goh, K. C., deVeer, M. J. & Williams, B. R. The protein kinase PKR is required for p38 MAPK activation and the innate immune response to bacterial endotoxin. EMBO J. 19, 4292–4297 (2000).

    Article  CAS  Google Scholar 

  21. Hacker, H. et al. Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF)6. J. Exp. Med. 192, 595–600 (2000).

    Article  CAS  Google Scholar 

  22. Schnare, M., Holt, A. C., Takeda, K., Akira, S. & Medzhitov, R. Recognition of CpG DNA is mediated by signaling pathways dependent on the adaptor protein MyD88. Curr. Biol. 10, 1139–1142 (2000).

    Article  CAS  Google Scholar 

  23. Akira, S. Toll-like receptors: lessons from knockout mice. Biochem. Soc. Trans. 28, 551–556 (2000).

    Article  CAS  Google Scholar 

  24. Kumar, M. & Carmichael, G. G. Antisense RNA: function and fate of duplex RNA in cells of higher eukaryotes. Microbiol. Mol. Biol. Rev. 62, 1415–1434 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Abraham, N. et al. Characterization of transgenic mice with targeted disruption of the catalytic domain of the double-stranded RNA-dependent protein kinase, PKR. J. Biol. Chem. 274, 5953–5962 (1999).

    Article  CAS  Google Scholar 

  26. Yang, Y. L. et al. Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase. EMBO J. 14, 6095–6106 (1995).

    Article  CAS  Google Scholar 

  27. Zhou, A., Paranjape, J. M., Der, S. D., Williams, B. R. & Silverman, R. H. Interferon action in triply deficient mice reveals the existence of alternative antiviral pathways. Virology 258, 435–440 (1999).

    Article  CAS  Google Scholar 

  28. Medzhitov, R. et al. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol. Cell 2, 253–258 (1998).

    Article  CAS  Google Scholar 

  29. Inaba, K. et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J. Exp. Med. 176, 1693–1702 (1992).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Nibert for providing viral dsRNA; S. Akira for providing the TLR2-/- and MyD88-/-mice; L. Evangelisti, D. Butkus, C. Hughes and J. Stein for technical assistance; and F. Manzo for secretarial work. This work was supported by the Howard Hughes Medical Institute and grants from the National Institutes of Health (NIH). L.A. was the recipient of a Human Frontier Science Program Postdoctoral Fellowship. R.M. is a Searle Scholar, R.A.F. is an Investigator and R.M. is an Assistant Investigator of the Howard Hughes Medical Institute.

Author information

Author notes

  1. Ruslan Medzhitov and Richard A. Flavell: These authors contributed equally to the work

Authors and Affiliations

  1. Section of Immunobiology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Lena Alexopoulou, Agnieszka Czopik Holt, Ruslan Medzhitov & Richard A. Flavell

  2. Department of Molecular, Cellular and Developmental Biology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Agnieszka Czopik Holt

  3. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Ruslan Medzhitov & Richard A. Flavell

Authors
  1. Lena Alexopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Agnieszka Czopik Holt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ruslan Medzhitov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard A. Flavell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ruslan Medzhitov or Richard A. Flavell.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Alexopoulou, L., Holt, A., Medzhitov, R. et al. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738 (2001). https://doi.org/10.1038/35099560

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35099560

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing