Horng Tiffany, Barton Gregory M, Flavell Richard A, Medzhitov Ruslan
Howard Hughes Medical Institute, Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Nature. 2002 Nov 21;420(6913):329-33. doi: 10.1038/nature01180.
Mammalian Toll-like receptors (TLRs) function as sensors of infection and induce the activation of innate and adaptive immune responses. Upon recognizing conserved pathogen-associated molecular products, TLRs activate host defence responses through their intracellular signalling domain, the Toll/interleukin-1 receptor (TIR) domain, and the downstream adaptor protein MyD88 (refs 1-3). Although members of the TLR and the interleukin-1 (IL-1) receptor families all signal through MyD88, the signalling pathways induced by individual receptors differ. TIRAP, an adaptor protein in the TLR signalling pathway, has been identified and shown to function downstream of TLR4 (refs 4, 5). Here we report the generation of mice deficient in the Tirap gene. TIRAP-deficient mice respond normally to the TLR5, TLR7 and TLR9 ligands, as well as to IL-1 and IL-18, but have defects in cytokine production and in activation of the nuclear factor NF-kappaB and mitogen-activated protein kinases in response to lipopolysaccharide, a ligand for TLR4. In addition, TIRAP-deficient mice are also impaired in their responses to ligands for TLR2, TLR1 and TLR6. Thus, TIRAP is differentially involved in signalling by members of the TLR family and may account for specificity in the downstream signalling of individual TLRs.
哺乳动物的Toll样受体（TLRs）作为感染的传感器，可诱导先天性和适应性免疫反应的激活。在识别保守的病原体相关分子产物后，TLRs通过其细胞内信号结构域、Toll/白细胞介素-1受体（TIR）结构域以及下游衔接蛋白MyD88激活宿主防御反应（参考文献1-3）。尽管TLR家族和白细胞介素-1（IL-1）受体家族的成员均通过MyD88进行信号传导，但各个受体诱导的信号通路有所不同。TIRAP是TLR信号通路中的一种衔接蛋白，已被鉴定并证明在TLR4下游发挥作用（参考文献4,5）。在此，我们报告了Tirap基因缺失小鼠的产生。TIRAP缺陷小鼠对TLR5、TLR7和TLR9配体以及IL-1和IL-18的反应正常，但在细胞因子产生以及对脂多糖（一种TLR4配体）的反应中，核因子NF-κB和丝裂原活化蛋白激酶的激活存在缺陷。此外，TIRAP缺陷小鼠对TLR2、TLR1和TLR6配体的反应也受损。因此，TIRAP以不同方式参与TLR家族成员的信号传导，可能是各个TLR下游信号特异性的原因。
