O'Neill L
Department of Biochemistry, Trinity College Dublin, Ireland.
Biochem Soc Trans. 2000 Oct;28(5):557-63. doi: 10.1042/bst0280557.
The pro-inflammatory cytokine interleukin-1 (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-kappa B 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 non-receptor 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.
促炎细胞因子白细胞介素-1（IL-1）通过I型IL-1受体（IL-1RI）发出信号，诱导许多在免疫和炎症中起作用的基因表达增加。信号通路涉及两种衔接蛋白，髓样分化因子88（MyD88）和Toll相互作用蛋白（Tollip），它们通过两种IL-1受体相关激酶（IRAK和IRAK-2）激活转录因子，如核因子-κB，以及蛋白激酶，如p38丝裂原活化蛋白激酶。低分子量G蛋白Rac、Ras和Rap在这些过程中的作用也已得到证实。IL-1RI是一个多样的受体超家族的创始成员，所有这些受体都共享一个胞质结构域，称为Toll/IL-1受体（TIR）结构域。该超家族大致可分为三个亚组。其中第一个亚组与IL-1RI最为相似，包括IL-18受体和Th2细胞调节因子T1/ST2。第二个亚组与果蝇蛋白Toll最为相似，包括对宿主抵御革兰氏阳性菌和真菌至关重要的Toll样受体2（TLR2），以及对脂多糖反应性至关重要、因此参与宿主抵御革兰氏阴性菌的TLR4。植物和昆虫中也有许多TLR，都参与宿主防御。第三个亚组包含具有TIR结构域的非受体蛋白，这些蛋白位于胞质中。MyD88是其中一员，它可能通过TIR-TIR相互作用与IL-1RI形成复合物。另外两个成员是由痘苗病毒编码的蛋白A46R和A52R，它们阻断TIR依赖性信号传导。因此，这个受体超家族似乎在炎症和宿主抗感染防御中发挥核心作用，表明TIR结构域是先天免疫反应中的关键分子参与者。
