Yang R B, Mark M R, Gray A, Huang A, Xie M H, Zhang M, Goddard A, Wood W I, Gurney A L, Godowski P J
Department of Molecular Biology, Genentech, South San Francisco, California 94080-4990, USA.
Nature. 1998 Sep 17;395(6699):284-8. doi: 10.1038/26239.
Vertebrates and invertebrates initiate a series of defence mechanisms following infection by Gram-negative bacteria by sensing the presence of lipopolysaccharide (LPS), a major component of the cell wall of the invading pathogen. In humans, monocytes and macrophages respond to LPS by inducing the expression of cytokines, cell-adhesion proteins, and enzymes involved in the production of small proinflammatory mediators. Under pathophysiological conditions, LPS exposure can lead to an often fatal syndrome known as septic shock. Sensitive responses of myeloid cells to LPS require a plasma protein called LPS-binding protein and the glycosylphosphatidylinositol-anchored membrane protein CD14. However, the mechanism by which the LPS signal is transduced across the plasma membrane remains unknown. Here we show that Toll-like receptor 2 (TLR2) is a signalling receptor that is activated by LPS in a response that depends on LPS-binding protein and is enhanced by CD14. A region in the intracellular domain of TLR2 with homology to a portion of the interleukin (IL)-1 receptor that is implicated in the activation of the IL-1-receptor-associated kinase is required for this response. Our results indicate that TLR2 is a direct mediator of signalling by LPS.
脊椎动物和无脊椎动物在受到革兰氏阴性菌感染后，会通过感知脂多糖（LPS）（入侵病原体细胞壁的主要成分）的存在来启动一系列防御机制。在人类中，单核细胞和巨噬细胞通过诱导细胞因子、细胞黏附蛋白以及参与小促炎介质产生的酶的表达来对LPS作出反应。在病理生理条件下，接触LPS可导致一种通常致命的综合征，称为脓毒性休克。髓样细胞对LPS的敏感反应需要一种名为LPS结合蛋白的血浆蛋白和糖基磷脂酰肌醇锚定膜蛋白CD14。然而，LPS信号跨质膜转导的机制仍不清楚。在这里，我们表明Toll样受体2（TLR2）是一种信号受体，它在一种依赖于LPS结合蛋白且被CD14增强的反应中被LPS激活。TLR2胞内结构域中与白细胞介素（IL）-1受体的一部分具有同源性的区域（该区域与IL-1受体相关激酶的激活有关）是此反应所必需的。我们的结果表明TLR2是LPS信号传导的直接介质。
