Selective TRIF-dependent signaling by a synthetic toll-like receptor 4 agonist.
Selective TRIF-dependent signaling by a synthetic toll-like receptor 4 agonist.
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DOI：
10.1126/scisignal.2001963
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发表时间：
2012-02-14
影响因子：
7.3
通讯作者：
Evans JT
中科院分区：
文献类型：
--
作者：
Bowen WS;Minns LA;Johnson DA;Mitchell TC;Hutton MM;Evans JT
响应于配体与Toll样受体4（TLR 4）和髓样分化-2（MD-2）受体复合物的结合，涉及不同衔接蛋白的两个主要信号传导途径被激活。一种途径依赖于髓样分化标志物88（MyD 88），其促进促炎反应，而另一种途径依赖于含有Toll-IL-1受体（TIR）结构域的衔接子诱导干扰素-β（TRIF），其促进I型干扰素的产生。在这里，我们表明，TLR 4激动剂和疫苗佐剂CRX-547，合成脂质A模拟物的氨基烷基氨基葡糖苷4-磷酸（AGP）类的成员，在人类细胞中显示TRIF选择性信号传导，这取决于对羧基生物电子等排体的微小结构修饰，对应于大多数脂质A类型上的1-磷酸基团。CRX-547刺激很少或没有激活MyD 88依赖性信号分子或细胞因子，而其激活TRIF依赖性途径的能力与结构相关的炎性AGP和来自沙门氏菌的脂多糖相似。这种TRIF选择性信号传导应答导致产生实质上更少的与MyD 88信号传导相关的促炎介质，从而潜在地降低毒性并改善这种合成TLR 4激动剂和疫苗佐剂的治疗指数。
In response to ligand binding to the Toll-like receptor 4 (TLR4) and myeloid differentiation-2 (MD-2) receptor complex, two major signaling pathways are activated that involve different adaptor proteins. One pathway depends on myeloid differentiation marker 88 (MyD88), which elicits proinflammatory responses, whereas the other depends on Toll–IL-1 receptor (TIR) domain–containing adaptor inducing interferon-β (TRIF), which elicits type I interferon production. Here, we showed that the TLR4 agonist and vaccine adjuvant CRX-547, a member of the aminoalkyl glucosaminide 4-phosphate (AGP) class of synthetic lipid A mimetics, displayed TRIF-selective signaling in human cells, which was dependent on a minor structural modification to the carboxyl bioisostere corresponding to the 1-phosphate group on most lipid A types. CRX-547 stimulated little or no activation of MyD88-dependent signaling molecules or cytokines, whereas its ability to activate the TRIF-dependent pathway was similar to that of a structurally related inflammatory AGP and of lipopolysaccharide from Salmonella minnesota. This TRIF-selective signaling response resulted in the production of substantially less of the proinflammatory mediators that are associated with MyD88 signaling, thereby potentially reducing toxicity and improving the therapeutic index of this synthetic TLR4 agonist and vaccine adjuvant.
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影响因子：
32.4
作者：
Kawai, T;Adachi, O;Akira, S
通讯作者：
Akira, S
影响因子：
56.9
作者：
Mata-Haro, Veronica;Cekic, Caglar;Mitchell, Thomas C.
通讯作者：
Mitchell, Thomas C.
影响因子：
5.5
作者：
Baldridge, JR;Yorgensen, Y;Ulrich, JT
通讯作者：
Ulrich, JT
DOI：
10.1016/j.bbrc.2007.01.104
发表时间：
2007-03-23
影响因子：
3.1
作者：
Neumann, Detlef;Kollewe, Christian;Martin, Michael U.
通讯作者：
Martin, Michael U.
影响因子：
5.3
作者：
Conze, Dietrich B.;Wu, Chuan-Jin;Ashwell, Jonathan D.
通讯作者：
Ashwell, Jonathan D.