Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide
Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide
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DOI：
10.1172/jci8541
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发表时间：
2000-02-01
影响因子：
15.9
通讯作者：
Golenbock, DT
中科院分区：
文献类型：
--
作者：
Lien, E;Means, TK;Golenbock, DT
脂多糖（LPS）是革兰阴性菌脓毒症休克和死亡的主要诱导物。最近的证据表明，LPS诱导的信号转导始于CD 14介导的1种或多种Toll样受体（TLR）的激活。脂质A类似物脂质IVa和类球红细菌脂质A（RSLA）表现出不常见的物种特异性药理学。这两种化合物在人细胞中抑制LPS的作用，但在仓鼠细胞中显示LPS模拟活性。我们将人TLR 4或人TLR 2转染到仓鼠成纤维细胞中，以确定这些LPS信号转导子中的任一种是否负责种特异性药理学RSLA和脂质IVa在表达CD 14的中国仓鼠卵巢成纤维细胞（CHO/CD 14）中强烈诱导NF-κ B活性和IL-6释放，但这些化合物拮抗过表达人TLR 4的CHO/CD 14成纤维细胞中的LPS拮抗剂。在过表达人TLR 2的细胞中没有发生这种拮抗作用。我们从仓鼠巨噬细胞中克隆了TLR 4，发现表达仓鼠TLR 4的人THP-1细胞对作为LPS模拟物的脂质IVa有反应，就好像它们是仓鼠来源的一样。因此，异源过表达来自不同物种的TLR 4的细胞获得了关于识别对应于TLR 4转基因起源的物种的脂质A亚结构的药理学表型。这些数据表明TLR 4是LPS受体复合物中的中心脂质A识别蛋白。
Lipopolysaccharide (LPS) is the main inducer of shock and death in Gram-negative sepsis. Recent evidence suggests that LPS-induced signal transduction begins with CD14-mediated activation of 1 or more Toll-like receptors (TLRs). The lipid A analogues lipid IVa and Rhodobacter sphaeroides lipid A (RSLA) exhibit an uncommon species-specific pharmacology Both compounds inhibit the effects of LPS in human cells but display LPS-mimetic activity in hamster cells. We transfected human TLR4 or human TLR2 into hamster fibroblasts to determine if either of these LPS signal transducers is responsible for the species-specific pharmacology RSLA and lipid IVa strongly induced NF-KB activity and IL-6 release in Chinese hamster ovary fibroblasts expressing CD14 (CHO/CD14), but these compounds antagonized LPS antagonists in CHO/CD14 fibroblasts that overexpressed human TLR4. No such antagonism occurred in cells overexpressing human TLR2. We cloned TLR4 from hamster macrophages and found that human THP-1 cells expressing the hamster TLR4 responded to Lipid IVa as an LPS mimetic, as if they were hamster in origin. Hence, cells heterologously overexpressing TLR4 from different species acquired a pharmacological phenotype with respect to recognition of lipid A substructures that corresponded to the species from which the TLR4 transgene originated. These data suggest that TLR4 is the central lipid A-recognition protein in the LPS receptor complex.