The CD14 ligands lipoarabinomannan and lipopolysaccharide differ in their requirement for Toll-like receptors.
The CD14 ligands lipoarabinomannan and lipopolysaccharide differ in their requirement for Toll-like receptors.
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DOI：
10.4049/jimmunol.163.12.6748
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发表时间：
1999-12
影响因子：
4.4
通讯作者：
T. Means;E. Lien;A. Yoshimura;Shuyan Wang;D. Golenbock;M. Fenton
中科院分区：
文献类型：
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作者：
T. Means;E. Lien;A. Yoshimura;Shuyan Wang;D. Golenbock;M. Fenton
哺乳动物Toll样受体（TLR）蛋白是IL-1受体家族的新成员，其参与细菌和细菌产物对细胞的活化。最近的一些报道表明，TLR蛋白介导的细胞活化细菌LPS通过信号转导途径，主要是共享的I型IL-1受体。我们先前表明，中国仓鼠卵巢（CHO）成纤维细胞工程表达CD 14（CHO/CD 14）的LPS，但不响应一个独特的CD 14配体，分枝杆菌脂阿拉伯甘露聚糖（LAM）。随后发现这些CHO/CD 14细胞在TLR 2基因内具有移码突变，这导致它们不能表达功能性TLR 2蛋白。因此，我们假设TLR 2而不是TLR 4是LAM信号传导所必需的。在本文中，我们表明CHO/CD 14细胞工程化表达功能性TLR 2蛋白获得的能力被激活的LAM。类似地，小鼠巨噬细胞中TLR 2的过表达赋予增强的LAM响应性。总之，我们的数据表明，不同的CD 14配体LAM和LPS利用不同的TLR蛋白来启动细胞内信号。这些发现表明一种新的受体信号传导模式，其中不同配体的结合是由一个共同的受体链介导的，但细胞激活是通过不同的信号转导链，赋予配体特异性。这种模式与许多细胞因子受体复合物形成对比，在这些复合物中，受体特异性由独特的配体结合链赋予，但细胞活化通过共享的信号转导链启动。
Mammalian Toll-like receptor (TLR) proteins are new members of the IL-1 receptor family that participate in activation of cells by bacteria and bacterial products. Several recent reports indicate that TLR proteins mediate cellular activation by bacterial LPS via a signaling pathway that is largely shared by the type I IL-1 receptor. We previously showed that Chinese hamster ovary (CHO) fibroblasts engineered to express CD14 (CHO/CD14) were responsive to LPS, but not to a distinct CD14 ligand, mycobacterial lipoarabinomannan (LAM). These CHO/CD14 cells were subsequently found to possess a frame-shift mutation within the TLR2 gene which resulted in their inability to express functional TLR2 protein. Thus, we hypothesized that TLR2, but not TLR4, was necessary for LAM signaling. In this paper we show that CHO/CD14 cells engineered to express functional TLR2 protein acquired the ability to be activated by LAM. Similarly, overexpression of TLR2 in murine macrophages conferred enhanced LAM responsiveness. Together, our data demonstrate that the distinct CD14 ligands LAM and LPS utilize different TLR proteins to initiate intracellular signals. These findings suggest a novel receptor signaling paradigm in which the binding of distinct ligands is mediated by a common receptor chain, but cellular activation is initiated via distinct signal-transducing chains that confer ligand specificity. This paradigm contrasts with many cytokine receptor complexes in which receptor specificity is conferred by a unique ligand-binding chain but cellular activation is initiated via shared signal-transducing chains.