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

被引:770
作者
Yamamoto, M
Sato, S
Hemmi, H
Sanjo, H
Uematsu, S
Kaisho, T
Hoshino, K
Takeuchi, O
Kobayashi, M
Fujita, T
Takeda, K
Akira, S
机构
[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
基金
日本学术振兴会; 美国国家科学基金会;
关键词
D O I
10.1038/nature01182
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:324 / 329
页数:7
相关论文
共 19 条
[1]   Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function [J].
Adachi, O ;
Kawai, T ;
Takeda, K ;
Matsumoto, M ;
Tsutsui, H ;
Sakagami, M ;
Nakanishi, K ;
Akira, S .
IMMUNITY, 1998, 9 (01) :143-150
[2]   Toll-like receptors: critical proteins linking innate and acquired immunity [J].
Akira, S ;
Takeda, K ;
Kaisho, T .
NATURE IMMUNOLOGY, 2001, 2 (08) :675-680
[3]   Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3 [J].
Alexopoulou, L ;
Holt, AC ;
Medzhitov, R ;
Flavell, RA .
NATURE, 2001, 413 (6857) :732-738
[4]   Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction [J].
Fitzgerald, KA ;
Palsson-McDermott, EM ;
Bowie, AG ;
Jefferies, CA ;
Mansell, AS ;
Brady, G ;
Brint, E ;
Dunne, A ;
Gray, P ;
Harte, MT ;
McMurray, D ;
Smith, DE ;
Sims, JE ;
Bird, TA ;
O'Neill, LAJ .
NATURE, 2001, 413 (6851) :78-83
[5]   Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway [J].
Hemmi, H ;
Kaisho, T ;
Takeuchi, O ;
Sato, S ;
Sanjo, H ;
Hoshino, K ;
Horiuchi, T ;
Tomizawa, H ;
Takeda, K ;
Akira, S .
NATURE IMMUNOLOGY, 2002, 3 (02) :196-200
[6]   A Toll-like receptor recognizes bacterial DNA [J].
Hemmi, H ;
Takeuchi, O ;
Kawai, T ;
Kaisho, T ;
Sato, S ;
Sanjo, H ;
Matsumoto, M ;
Hoshino, K ;
Wagner, H ;
Takeda, K ;
Akira, S .
NATURE, 2000, 408 (6813) :740-745
[7]   TIRAP: an adapter molecule in the Toll signaling pathway [J].
Horng, T ;
Barton, GM ;
Medzhitov, R .
NATURE IMMUNOLOGY, 2001, 2 (09) :835-841
[8]  
IMER JL, 2001, TRENDS CELL BIOL, V11, P304
[9]   Induction of IRF-3/-7 kinase and NF-κB in response to double-stranded RNA and virus infection:: common and unique pathways [J].
Iwamura, T ;
Yoneyama, M ;
Yamaguchi, K ;
Suhara, W ;
Mori, W ;
Shiota, K ;
Okabe, Y ;
Namiki, H ;
Fujita, T .
GENES TO CELLS, 2001, 6 (04) :375-388
[10]   Innate immune recognition [J].
Janeway, CA ;
Medzhitov, R .
ANNUAL REVIEW OF IMMUNOLOGY, 2002, 20 :197-216