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| Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4 |
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| Author(s): Yamamoto M, Sato S, Hemmi H, Sanjo H, Uematsu S, Kaisho T, Hoshino K, Takeuchi O, Kobayashi M, Fujita T, Takeda K, Akira S |
| Source: NATURE Volume: 420 Issue: 6913 Pages: 324-329 Published: NOV 21 2002 |
| Times Cited: 399 References: 19 |
| 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 domain(1-4). 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 observed(5-7). 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 response(8,9). 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-kappaB and mitogen-activated protein kinases is induced with delayed kinetics in TIRAP-deficient mice(5). 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Akira, S (reprint author), Osaka Univ, Res Inst Microbial Dis, Dept Host Def, 2-2 Yamadaoka, Suita, Osaka 5650871 Japan |
Addresses:
1. Osaka Univ, Res Inst Microbial Dis, Dept Host Def, Suita, Osaka 5650871 Japan
2. Japan Sci & Technol Corp, Solut Oriented Res Sci & Technol, Suita, Osaka 5650871 Japan
3. RIKEN, Res Ctr Allergy & Immunol, Tsurumi Ku, Kanagawa 2300045, Japan
4. Tokyo Metropolitan Inst Med Sci, Dept Tumor Cell Biol, Bunkyo Ku, Tokyo 1138613, Japan |
| Publisher: NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND |
| Subject Category: Multidisciplinary Sciences |
| IDS Number: 617BM |
| ISSN: 0028-0836 |
| DOI: 10.1038/nature01182 |
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