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

Masahiro Yamamoto, Shintaro Sato, Hiroaki Hemmi, Hideki Sanjo, Satoshi Uematsu, Tsuneyasu Kaisho, Katsuaki Hoshino, Osamu Takeuchi, Masaya Kobayashi, Takashi Fujita, Kiyoshi Takeda and Shizuo Akira ()
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Masahiro Yamamoto: Osaka University, Japan Science and Technology Corporation
Shintaro Sato: Osaka University, Japan Science and Technology Corporation
Hiroaki Hemmi: Osaka University, Japan Science and Technology Corporation
Hideki Sanjo: Osaka University, Japan Science and Technology Corporation
Satoshi Uematsu: Osaka University, Japan Science and Technology Corporation
Tsuneyasu Kaisho: Osaka University, Japan Science and Technology Corporation
Katsuaki Hoshino: Osaka University, Japan Science and Technology Corporation
Osamu Takeuchi: Osaka University, Japan Science and Technology Corporation
Masaya Kobayashi: Osaka University, Japan Science and Technology Corporation
Takashi Fujita: The Tokyo Metropolitan Institute of Medical Science
Kiyoshi Takeda: Osaka University, Japan Science and Technology Corporation
Shizuo Akira: Osaka University, Japan Science and Technology Corporation

Nature, 2002, vol. 420, issue 6913, 324-329

Abstract: 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.

Date: 2002
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DOI: 10.1038/nature01182

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