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:

Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4

Abstract

Signal transduction through Toll-like receptors (TLRs) originates from their intracellular Toll/interleukin-1 receptor (TIR) domain, which binds to MyD88, a common adaptor protein containing a TIR domain1,2,3,4. Although cytokine production is completely abolished in MyD88-deficient mice, some responses to lipopolysaccharide (LPS), including the induction of interferon-inducible genes and the maturation of dendritic cells, are still observed5,6,7. Another adaptor, TIRAP (also known as Mal), has been cloned as a molecule that specifically associates with TLR4 and thus may be responsible for the MyD88-independent response8,9. Here we report that LPS-induced splenocyte proliferation and cytokine production are abolished in mice lacking TIRAP. As in MyD88-deficient mice, LPS activation of the nuclear factor NF-κB and mitogen-activated protein kinases is induced with delayed kinetics in TIRAP-deficient mice5. Expression of interferon-inducible genes and the maturation of dendritic cells is observed in these mice; they also show defective response to TLR2 ligands, but not to stimuli that activate TLR3, TLR7 or TLR9. In contrast to previous suggestions, our results show that TIRAP is not specific to TLR4 signalling and does not participate in the MyD88-independent pathway. Instead, TIRAP has a crucial role in the MyD88-dependent signalling pathway shared by TLR2 and TLR4.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Targeted disruption of the murine Tirap gene.
Figure 2: Impaired response to LPS in TIRAP-deficient splenocytes.
Figure 3: Cytokine production in peritoneal macrophages in response to TLR ligands.
Figure 4: Activation of signalling cascades in response to TLR2, TLR4 and TLR7 ligands in peritoneal macrophages.
Figure 5: LPS-induced activation of the MyD88-independent signalling pathway in TIRAP-deficient mice.

Similar content being viewed by others

References

  1. Akira, S., Takeda, K. & Kaisho, T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nature Immunol. 2, 675–680 (2001)

    Article  CAS  Google Scholar 

  2. Imer, J. L. & Hoffmann, J. A. Toll-like receptors in innate immunity. Trends Cell Biol. 11, 304–311 (2001)

    Article  Google Scholar 

  3. Medzhitov, R. Toll-like receptors and innate immunity. Nature Rev. Immunol. 1, 135–145 (2002)

    Article  Google Scholar 

  4. Janeway, C. A. Jr & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002)

    Article  CAS  Google Scholar 

  5. 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 

  6. Kaisho, T., Takeuchi, O., Kawai, T., Hoshino, K. & Akira, S. Endotoxin-induced maturation of MyD88-deficient dendritic cells. J. Immunol. 166, 5688–5694 (2001)

    Article  CAS  Google Scholar 

  7. Kawai, T. et al. Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IRF-3 and the expression of a subset of LPS-inducible genes. J. Immunol. 167, 5887–5894 (2001)

    Article  CAS  Google Scholar 

  8. Horng, T., Barton, G. M. & Medzhitov, R. TIRAP: an adapter molecule in the Toll signaling pathway. Nature Immunol. 2, 835–841 (2001)

    Article  CAS  Google Scholar 

  9. Fitzgerald, K. A. et al. Mal (MyD88-adaptor-like) is required for Toll-like receptor-4 signal transduction. Nature 413, 78–83 (2001)

    Article  ADS  CAS  Google Scholar 

  10. Adachi, O. et al. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9, 143–150 (1998)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  12. Hemmi, H. et al. Small anti-viral compounds activate immune cells via the TLR7-MyD88-dependent signaling pathway. Nature Immunol. 3, 196–200 (2002)

    Article  CAS  Google Scholar 

  13. Alexopoulou, L., Holt, A. C., Medzhitov, R. & Flavell, R. A. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738 (2001)

    Article  ADS  CAS  Google Scholar 

  14. Takeuchi, O. et al. Cutting edge: preferentially the R-stereoisomer of the mycoplasmal lipopeptide macrophage-activating lipopeptide-2 activates immune cells through a toll-like receptor 2- and MyD88-dependent signaling pathway. J. Immunol. 164, 554–557 (2000)

    Article  CAS  Google Scholar 

  15. 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 

  16. Toshchakov, V. et al. TLR4, but not TLR2, mediates IFN-β-induced STAT1α/β-dependent gene expression in macrophages. Nature Immunol. 3, 392–398 (2002)

    Article  CAS  Google Scholar 

  17. O'Neill, L. A. Toll-like receptor signal transduction and the tailoring of innate immunity: a role for Mal? Trends Immunol. 23, 296–300 (2002)

    Article  CAS  Google Scholar 

  18. Sato, S. et al. A variety of microbial components induce tolerance to lipopolysaccharide by differentially affecting MyD88-dependent and -independent pathways. Int. Immunol. 14, 783–791 (2002)

    Article  CAS  Google Scholar 

  19. Iwamura, T. et al. Induction of IRF-3/-7 kinase and NF-κB in response to double-stranded RNA and virus infection: common and unique pathways. Genes Cells 6, 375–388 (2001)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank P. F. Mühlradt and H. Tomizawa for MALP-2 and R-848, respectively; E. Horita for secretarial assistance; and N. Okita and N. Iwami for technical assistance. This work was supported by grants from Special Coordination Funds, the Ministry of Education, Culture, Sports, Science and Technology, and Research Fellowships from the Japan Society for the Promotion of Science for Young Scientists.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shizuo Akira.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yamamoto, M., Sato, S., Hemmi, H. et al. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420, 324–329 (2002). https://doi.org/10.1038/nature01182

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01182

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

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