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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.

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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.

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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.

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Correspondence to Shizuo Akira.

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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

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