Yamamoto Masahiro, Sato Shintaro, Hemmi Hiroaki, Sanjo Hideki, Uematsu Satoshi, Kaisho Tsuneyasu, Hoshino Katsuaki, Takeuchi Osamu, Kobayashi Masaya, Fujita Takashi, Takeda Kiyoshi, Akira Shizuo
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Japan Science and Technology Corporation, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Nature. 2002 Nov 21;420(6913):324-9. doi: 10.1038/nature01182.
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. 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. 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. 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. 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.
通过Toll样受体（TLR）进行的信号转导起源于其细胞内的Toll/白细胞介素-1受体（TIR）结构域，该结构域与MyD88结合，MyD88是一种含有TIR结构域的常见接头蛋白。虽然在MyD88缺陷小鼠中细胞因子的产生完全被消除，但仍可观察到对脂多糖（LPS）的一些反应，包括干扰素诱导基因的诱导和树突状细胞的成熟。另一种接头蛋白TIRAP（也称为Mal）已被克隆为一种与TLR4特异性结合的分子，因此可能负责不依赖MyD88的反应。在此我们报告，在缺乏TIRAP的小鼠中，LPS诱导的脾细胞增殖和细胞因子产生被消除。与MyD88缺陷小鼠一样，在缺乏TIRAP的小鼠中，核因子NF-κB和丝裂原活化蛋白激酶的LPS激活以延迟的动力学诱导。在这些小鼠中观察到干扰素诱导基因的表达和树突状细胞的成熟；它们对TLR2配体也表现出缺陷反应，但对激活TLR3、TLR7或TLR9的刺激没有缺陷反应。与先前的观点相反，我们的结果表明TIRAP并非TLR4信号传导所特有，也不参与不依赖MyD88的途径。相反，TIRAP在TLR2和TLR4共有的依赖MyD88的信号传导途径中起关键作用。
