The Toll/interleukin-1 receptor domain: a molecular switch for inflammation and host defence
The Toll/interleukin-1 receptor domain: a molecular switch for inflammation and host defence
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DOI：
10.1042/bst0280557
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发表时间：
2000-10-01
影响因子：
3.9
通讯作者：
O'Neill, L
中科院分区：
文献类型：
--
作者：
O'Neill, L
促炎细胞因子白细胞介素-I（IL-1）通过I型IL-1受体（IL-1 RI）发出信号，诱导许多在免疫和炎症中起作用的基因的表达增加。信号通路涉及两种衔接蛋白MyD 88和Tollip，其通过两种IL-1受体相关激酶（IRAK和IRAK-2）激活转录因子如核因子-KB和蛋白激酶如p38促分裂原活化蛋白激酶。低分子量G蛋白Rac、Ras和Rap在这些过程中的作用也已被指出。IL-1 RI是多种受体超家族的创始者，其都共享称为Toll/IL-1受体（TIR）结构域的胞质结构域。该超家族可大致分为三个亚族。其中第一个与IL-1 RI最相似，包括IL-18受体和Th 2细胞调节因子T1/ST 2。第二个亚组与果蝇蛋白质Toll最相似，包括Toll样受体2（TLR 2）和TLR 4，Toll样受体2是宿主防御革兰氏阳性细菌和真菌所必需的，TLR 4是脂多糖反应所必需的，因此参与宿主防御革兰氏阴性细菌。在植物和昆虫中也有许多TLR，它们都参与宿主的防御。第三个亚组包含非受体蛋白，其具有TIR结构域并且是胞质的。MyD 88是一个成员，它可能通过TIR-TIR相互作用与IL-1 RI复合。另外两个成员是由牛痘病毒编码的蛋白质，A46 R和A52 R，它们阻断TIR依赖性信号传导。因此，该受体超家族似乎在炎症和宿主对感染的防御中发挥核心作用，指出TIR结构域是先天免疫应答中的关键分子参与者。
The pro-inflammatory cytokine interleukin-l (IL-1) signals via the Type-I IL-1 receptor (IL-1RI), inducing an increase in the expression of many genes with roles in immunity and inflammation. The signalling pathways involve two adapter proteins, MyD88 and Tollip, which via two IL-1 receptor-associated kinases (IRAK and IRAK-2) activate transcription factors such as nuclear factor-KB and protein kinases such as p38 mitogen-activated protein kinase. A role for the low-molecular-mass G-proteins Rac, Ras and Rap in these processes has also been indicated. IL-1RI is the founder of a diverse superfamily of receptors, which all share a cytosolic domain, termed the Toll/IL-1 receptor (TIR) domain. The superfamily can be divided broadly into three subgroups. The first of these is most similar to IL-1RI and includes the receptor for IL-18 and the Th2 cell regulator T1/ST2. The second subgroup is most similar to the Drosophila melanagaster protein Toll and includes Toll-like receptor 2 (TLR2), which is required for host defence against Gram-positive bacteria and fungi, and TLR4, which is required for lipopolysaccharide responsiveness, and thus is involved in host defence against: Gram-negative bacteria. There are also a number of TLRs in plants and insects, all involved in host: defence. The third subgroup contains nonreceptor proteins which possess a TIR domain and are cytosolic. MyD88 is a member, and it presumably complexes with IL-1RI via a TIR-TIR interaction. The other two members are proteins encoded by the vaccinia virus, A46R and A52R, which block TIR-dependent signalling. This receptor superfamily therefore appears to play a central role in inflammation and host defence against infection, pointing to the TIR domain as a critical molecular player in the innate immune response.