The role of TLR4 in endotoxin responsiveness in humans
The role of TLR4 in endotoxin responsiveness in humans
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DOI：
10.1179/096805101101532972
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发表时间：
2001-01-01
期刊：
影响因子：
--
通讯作者：
Schwartz, DA
中科院分区：
文献类型：
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作者：
Schwartz, DA
尽管个体间对吸入毒素的反应存在巨大差异，但我们根本不明白为什么某些人在受到环境因素的挑战时会患上疾病，而其他人却保持健康。为了解决这个问题，我们研究了 Toll-4 (TLR4) 基因（已被证明会影响小鼠的脂多糖 (LPS) 反应性）是否是人类吸入 LPS 气道反应性变异的基础。在这里，我们证明了 TLR4 受体胞外域中常见的共分离错义突变（Asp299Gly 和 Thr399Ile）与 83 名人类对吸入 LPS 的反应显着减弱有关。 THP-1 细胞的转染表明 Asp299Gly 突变（但不是 Thr399Ile 突变）会中断 TLR4 介导的 LPS 信号传导。此外，TLR4 的野生型等位基因可以挽救从具有 TLR4 突变的个体获得的原代气道上皮细胞或肺泡巨噬细胞中的 LPS 低反应表型。我们的研究结果提供了第一个遗传证据，证明 TLR4 的常见突变与人类 LPS 反应性差异相关，并证明基因序列变化可以改变宿主对环境压力的反应能力。
Despite the tremendous inter-individual variability in the response to inhaled toxins, we simply do not understand why certain people develop disease when challenged with environmental agents and others remain healthy. To address this concern, we investigated whether the Toll-4 (TLR4) gene, that has been shown to affect lipopolysaccharide (LPS) responsiveness in mice, underlies the variability in airway responsiveness to inhaled LPS in humans. Here we show that common, co-segregating missense mutations (Asp299Gly and Thr399Ile) in the extracellular domain of the TLR4 receptor are associated with a significantly blunted response to inhaled LPS in 83 humans. Transfection of THP-1 cells demonstrates that the Asp299Gly mutation (but not the Thr399Ile mutation) interrupts TLR4-mediated LPS signaling. Moreover, the wild-type allele of TLR4 rescues the LPS hyporesponsive phenotype in either primary airway epithelial cells or alveolar macrophages obtained from individuals with the TLR4 mutations. Our findings provide the first genetic evidence that common mutations in TLR4 are associated with differences in LPS responsiveness in humans, and demonstrate that gene sequence changes can alter the ability of the host to respond to environmental stress.