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.

IκB kinase-α is critical for interferon-α production induced by Toll-like receptors 7 and 9

Nature volume 440, pages 949–953 (2006)Cite this article

Abstract

The Toll-like receptor (TLR) family has important roles in microbial recognition and dendritic cell activation1,2. TLRs 7 and 9 can recognize nucleic acids3,4,5,6 and trigger signalling cascades that activate plasmacytoid dendritic cells to produce interferon-α (IFN-α) (refs 7, 8). TLR7/9-mediated dendritic cell activation is critical for antiviral immunity but also contributes to the pathogenesis of systemic lupus erythematosus, a disease in which serum IFN-α levels are elevated owing to plasmacytoid dendritic cell activation8,9. TLR7/9-induced IFN-α induction depends on a molecular complex that contains a TLR adaptor, MyD88, and IFN regulatory factor 7 (IRF-7) (refs 10–14), but the underlying molecular mechanisms are as yet unknown. Here we show that IκB kinase-α (IKK-α) is critically involved in TLR7/9-induced IFN-α production. TLR7/9-induced IFN-α production was severely impaired in IKK-α-deficient plasmacytoid dendritic cells, whereas inflammatory cytokine induction was decreased but still occurred. Kinase-deficient IKK-α inhibited the ability of MyD88 to activate the Ifna promoter in synergy with IRF-7. Furthermore, IKK-α associated with and phosphorylated IRF-7. Our results identify a role for IKK-α in TLR7/9 signalling, and highlight IKK-α as a potential target for manipulating TLR-induced IFN-α production.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: Role for IKK-α in IFN-α production from TLR7/9-stimulated BMDCs in vitro.
Figure 2: Impairment of TLR7/9-induced IFN-α production in Ikka -/- PDCs.
Figure 3: Role for IKK-α in IRF-7-mediated signalling.
Figure 4: IRF-7 phosphorylation and activation by IKK-α.

References

  1. Medzhitov, R. Toll-like receptors and innate immunity. Nature Rev. Immunol. 1, 135–145 (2001)

    Article  CAS  Google Scholar 

  2. Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  4. Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S. & Reis, E. S. C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531 (2004)

    Article  ADS  CAS  Google Scholar 

  5. Heil, F. et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303, 1526–1529 (2004)

    Article  ADS  CAS  Google Scholar 

  6. Lund, J. M. et al. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc. Natl Acad. Sci. USA 101, 5598–5603 (2004)

    Article  ADS  CAS  Google Scholar 

  7. Wagner, H. The immunobiology of the TLR9 subfamily. Trends Immunol. 25, 381–386 (2004)

    Article  CAS  Google Scholar 

  8. Colonna, M., Trinchieri, G. & Liu, Y. J. Plasmacytoid dendritic cells in immunity. Nature Immunol. 5, 1219–1226 (2004)

    Article  CAS  Google Scholar 

  9. Blanco, P., Palucka, A. K., Gill, M., Pascual, V. & Banchereau, J. Induction of dendritic cell differentiation by IFN-α in systemic lupus erythematosus. Science 294, 1540–1543 (2001)

    Article  ADS  CAS  Google Scholar 

  10. Kawai, T. et al. Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nature Immunol. 5, 1061–1068 (2004)

    Article  CAS  Google Scholar 

  11. Honda, K. et al. Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc. Natl Acad. Sci. USA 101, 15416–15421 (2004)

    Article  ADS  CAS  Google Scholar 

  12. Uematsu, S. et al. Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-α induction. J. Exp. Med. 201, 915–923 (2005)

    Article  CAS  Google Scholar 

  13. Honda, K. et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434, 772–777 (2005)

    Article  ADS  CAS  Google Scholar 

  14. Honda, K. et al. Spatiotemporal regulation of MyD88–IRF-7 signalling for robust type-I interferon induction. Nature 434, 1035–1040 (2005)

    Article  ADS  CAS  Google Scholar 

  15. Hayden, M. S. & Ghosh, S. Signaling to NF-κB. Genes Dev. 18, 2195–2224 (2004)

    Article  CAS  Google Scholar 

  16. Bonizzi, G. & Karin, M. The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 25, 280–288 (2004)

    Article  CAS  Google Scholar 

  17. Hemmi, H. et al. The roles of two IκB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection. J. Exp. Med. 199, 1641–1650 (2004)

    Article  CAS  Google Scholar 

  18. Perry, A. K., Chow, E. K., Goodnough, J. B., Yeh, W. C. & Cheng, G. Differential requirement for TANK-binding kinase-1 in type I interferon responses to Toll-like receptor activation and viral infection. J. Exp. Med. 199, 1651–1658 (2004)

    Article  CAS  Google Scholar 

  19. Takeda, K. et al. Limb and skin abnormalities in mice lacking IKKα. Science 284, 313–316 (1999)

    Article  ADS  CAS  Google Scholar 

  20. Hu, Y. et al. Abnormal morphogenesis but intact IKK activation in mice lacking the IKKα subunit of IκB kinase. Science 284, 316–320 (1999)

    Article  ADS  CAS  Google Scholar 

  21. Li, Q. et al. IKK1-deficient mice exhibit abnormal development of skin and skeleton. Genes Dev. 13, 1322–1328 (1999)

    Article  CAS  Google Scholar 

  22. Kaisho, T. et al. IκB kinase α is essential for mature B cell development and function. J. Exp. Med. 193, 417–426 (2001)

    Article  CAS  Google Scholar 

  23. Senftleben, U. et al. Activation by IKKα of a second, evolutionary conserved, NF-κB signaling pathway. Science 293, 1495–1499 (2001)

    Article  ADS  CAS  Google Scholar 

  24. Matsushima, A. et al. Essential role of nuclear factor (NF)-κB-inducing kinase and inhibitor of κB (IκB) kinase α in NF-κB activation through lymphotoxin β receptor, but not through tumor necrosis factor receptor I. J. Exp. Med. 193, 631–636 (2001)

    Article  CAS  Google Scholar 

  25. Verthelyi, D., Ishii, K. J., Gursel, M., Takeshita, F. & Klinman, D. M. Human peripheral blood cells differentially recognize and respond to two distinct CPG motifs. J. Immunol. 166, 2372–2377 (2001)

    Article  CAS  Google Scholar 

  26. Krug, A. et al. Identification of CpG oligonucleotide sequences with high induction of IFN-α/β in plasmacytoid dendritic cells. Eur. J. Immunol. 31, 2154–2163 (2001)

    Article  CAS  Google Scholar 

  27. Hemmi, H., Kaisho, T., Takeda, K. & Akira, S. The roles of Toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets. J. Immunol. 170, 3059–3064 (2003)

    Article  CAS  Google Scholar 

  28. Kato, H. et al. Cell type-specific involvement of RIG-I in antiviral response. Immunity 23, 19–28 (2005)

    Article  CAS  Google Scholar 

  29. Hochrein, H. et al. Herpes simplex virus type-1 induces IFN-α production via Toll-like receptor 9-dependent and -independent pathways. Proc. Natl Acad. Sci. USA 101, 11416–11421 (2004)

    Article  ADS  CAS  Google Scholar 

  30. Sharma, S. et al. Triggering the interferon antiviral response through an IKK-related pathway. Science 300, 1148–1151 (2003)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank N. Iwami, Y. Fukuda, N. Okita and E. Haga for technical assistance; Y. Hachiman and H. Fujimoto for cell sorting; and S. Haraguchi and T. Oyanagi for secretarial assistance. We also thank R. Triendl for critical review of the manuscript. This work was supported by the Advanced and Innovational Research Program in Life Sciences, the Special Coordination Fund for Promoting Science and Technology of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and Grant-in-Aid for Scientific Research of MEXT and the Japan Society for the Promotion of Science, the Uehara Memorial Foundation, the Naito Foundation, the Novartis Foundation for the Promotion of Science, and RIKEN Strategic programs. T.S. is supported by a RIKEN Junior Research Associate grant.

Author information

Authors and Affiliations

  1. Laboratory for Host Defense,

    Katsuaki Hoshino, Takahiro Sugiyama, Takashi Tanaka, Masuyoshi Saito & Tsuneyasu Kaisho

  2. Laboratory for Immunogenomics, RIKEN Research Center for Allergy and Immunology, Suehiro-cho 1-7-22, Tsurumi-ku, 230-0045, Kanagawa, Yokohama, Japan

    Osamu Ohara

  3. Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Kuramoto-cho 3-18-15, 770-8503, Tokushima, Tokushima, Japan

    Mitsuru Matsumoto

  4. Department of Host Defense, Research Institute for Microbial Diseases and ERATO, Japan Science and Technology Agency, Yamadaoka 3-1, Suita, 565-0871, Osaka, Japan

    Hiroaki Hemmi & Shizuo Akira

  5. Kazusa DNA Research Institute, Kazusa-Kamatari 2-6-7, 292-0818, Kisarazu, Chiba, Japan

    Osamu Ohara

Authors
  1. Katsuaki Hoshino
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takahiro Sugiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mitsuru Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takashi Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masuyoshi Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroaki Hemmi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Osamu Ohara
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shizuo Akira
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tsuneyasu Kaisho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tsuneyasu Kaisho.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Notes

This file contains Supplementary Methods, Supplementary Figure Legends and Supplementary Figures 1–6. (PDF 360 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hoshino, K., Sugiyama, T., Matsumoto, M. et al. IκB kinase-α is critical for interferon-α production induced by Toll-like receptors 7 and 9. Nature 440, 949–953 (2006). https://doi.org/10.1038/nature04641

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04641

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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