Mouse toll-like receptor 4•MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by taxol
Mouse toll-like receptor 4•MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by taxol
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DOI：
10.1074/jbc.275.4.2251
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发表时间：
2000-01-28
影响因子：
4.8
通讯作者：
Nishijima, M
中科院分区：
文献类型：
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作者：
Kawasaki, K;Akashi, S;Nishijima, M
紫杉醇是一种从植物中提取的抗肿瘤药物，它在小鼠体内模拟脂多糖(LPS)的作用，但在人类中不模拟，尽管紫杉醇在结构上与脂多糖无关，紫杉醇和脂多糖被认为共享一个受体或信号分子，但在脂多糖反应低下的C3H/HeJ小鼠中没有观察到紫杉醇的类脂多糖活性，因为Toll样受体4(TLR4)存在点突变，因此TLR4似乎同时参与紫杉醇和脂多糖信号转导。此外，TLR4最近被证明与MD-2物理上相关，MD-2是一种赋予TLR4上的内毒素反应性的分子。为了确定TLR4 MD-2复合体是否介导了紫杉醇诱导的信号转导，我们构建了单独表达小鼠TLR4的小鼠Pro-B细胞系BA/F3，小鼠TLR4和小鼠MD-2以及小鼠MD-2和小鼠TLR4都缺乏胞浆部分，然后检测紫杉醇是否诱导这些转染体中的NF-kappa B活化，紫杉醇在表达小鼠TLR4和小鼠MD-2的BaB/F3中检测到显著的NF-kappa B活化，而在其他转染体中检测不到。人TLR4和人MD-2的共表达不能赋予BA/F3细胞紫杉醇的反应性，提示TLR4 MD-2复合体是紫杉醇反应性的物种特异性的原因。此外，紫杉醇通过TLR4 MD-2诱导的核因子kappaB的激活可被一种内毒素拮抗剂阻断。这些结果表明，小鼠TLR4和小鼠MD-2的共表达是紫杉醇反应所必需的，TLR4-MD-2复合体是小鼠紫杉醇和内毒素信号转导的共同分子。
Taxol, an antitumor agent derived from a plant, mimics the action of lipopolysaccharide (LPS) in mice but not in humans, Although Taxol is structurally unrelated to LPS, Taxol and LPS are presumed to share a receptor or signaling molecule, The LPS-mimetic activity of Taxol is not observed in LPS-hyporesponsive C3H/HeJ mice, which possess a point mutation in Toll-like receptor 4 (TLR4); therefore, TLR4 appears to be involved in both Taxol and LPS signaling. In addition, TLR4 was recently shown to physically associate with MD-2, a molecule that confers LPS responsiveness on TLR4. To determine whether TLR4 MD-2 complex mediates a Taxol-induced signal, we constructed transformants of the mouse pro-B cell line, Ba/F3, expressing mouse TLR4 alone, both mouse TLR4 and mouse MD-2, and both mouse MD-2 and mouse TLR4 lacking the cytoplasmic portion, and then examined whether Taxol induced NF kappa B activation in these transfectants, Noticeable NF kappa B activation by Taxol was detected in Ba/F3 expressing mouse TLR4 and mouse MD-2 but not in the other transfectants. Coexpression of human TLR4 and human MD-2 did not confer Taxol responsiveness on Ba/F3 cells, suggesting that the TLR4 MD-2 complex is responsible for the species specificity with respect to Taxol responsiveness. Furthermore, Taxol-induced NF kappa B activation via TLR4 MD-2 was blocked by an LPS antagonist that blocks LPS-induced NF kappa B activation via TLR4 MD-2. These results demonstrated that coexpression of mouse TLR4 and mouse MD-2 is required for Taxol responsiveness and that the TLR4.MD-2 complex is the shared molecule in Taxol and LPS signal transduction in mice.