Evidence of a specific interaction between new synthetic antisepsis agents and CD14.
Evidence of a specific interaction between new synthetic antisepsis agents and CD14.
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DOI：
10.1021/bi901601b
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发表时间：
2009-12-29
期刊：
影响因子：
2.9
通讯作者：
Peri, Francesco
中科院分区：
文献类型：
--
作者：
Piazza, Matteo;Yu, Liping;Teghanemt, Athmane;Gioannini, Theresa;Weiss, Jerrold;Peri, Francesco
衍生自天然糖的具有带正电荷的氨基或铵盐和两个亲脂性链的合成分子已显示在体外和体内抑制TLR 4活化。为了表征这类分子的作用机制，我们研究了与结合并穿梭内毒素（脂多糖，LPS）至TLR 4（即LBP、CD 14和MD-2）的细胞外组分的可能相互作用。抑制TLR 4活化的分子可抑制脑膜炎奈瑟氏球菌氚化脂寡糖（[3 H]LOS）聚集体衍生的内毒素单体向MD-2·TLR 4的LBP·CD 14依赖性转移，导致[[3 H]LOS·MD-2·TLR 4 ECD]2（Mr ~ 190，000）复合物的形成减少。这种效应是由于抑制了[3 H]LOS从溶液中的聚集体转移到sCD 14，而对[3 H]LOS从[3 H]LOS·sCD 14到MD-2的穿梭几乎没有影响。这些化合物还抑制[3 H]LOS单体从全长CD 14转移至截短的多组氨酸标记的CD 14。用抑制TLR 4活化的三种不同合成化合物中的每一种观察到两种形式的CD 14之间的[3 H]LOS转移的剂量依赖性抑制，但不通过缺乏TLR 4拮抗活性的另一种结构相关的类似物。饱和转移差（STD）NMR数据显示合成TLR 4拮抗剂主要通过合成化合物的脂质链介导与CD 14直接结合。综上所述，我们的研究结果强烈表明，这些化合物通过竞争性占据CD 14抑制内毒素对TLR 4的活化，从而减少活化内毒素向MD-2·TLR 4的递送。
Synthetic molecules derived from natural sugars with a positively charged amino group or ammonium salt and two lipophilic chains have been shown to inhibit TLR4 activation in vitro and in vivo. In order to characterize the mechanism of action of this class of molecules, we investigated possible interactions with the extracellular components that bind and shuttle endotoxin (lipopolysaccharide, LPS) to TLR4, namely LBP, CD14, and MD-2. Molecules that inhibited TLR4 activation inhibited LBP·CD14-dependent transfer of endotoxin monomers derived from aggregates of tritiated lipooligosaccharide ([3H]LOS) from Neisseria meninigitidis to MD-2·TLR4, resulting in reduced formation of a [[3H]LOS·MD-2·TLR4ECD]2 (Mr ~190,000) complex. This effect was due to inhibition of the transfer of [3H]LOS from aggregates in solution to sCD14 with little or no effect on [3H]LOS shuttling from [3H]LOS·sCD14 to MD-2. These compounds also inhibited transfer of [3H]LOS monomer from full length CD14 to a truncated, polyhistidine tagged CD14. Dose-dependent inhibition of [3H]LOS transfer between the two forms of CD14 was observed with each of three different synthetic compounds that inhibited TLR4 activation but not by another structurally related analog that lacked TLR4 antagonistic activity. Saturation transfer difference (STD) NMR data showed direct binding to CD14 by the synthetic TLR4 antagonist mediated principally through the lipid chains of the synthetic compound. Taken together, our findings strongly suggest that these compounds inhibit TLR4 activation by endotoxin by competitively occupying CD14 and thereby reducing the delivery of activating endotoxin to MD-2·TLR4.
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影响因子：
4.8
作者：
Post, DMB;Zhang, DS;Weiss, JP
通讯作者：
Weiss, JP
影响因子：
6.2
作者：
Bettoni, Isabella;Comelli, Francesca;Costa, Barbara
通讯作者：
Costa, Barbara
影响因子：
7.3
作者：
Miller, KA;Kumar, EVKS;David, SA
通讯作者：
David, SA
影响因子：
4.1
作者：
Jerala, Roman
通讯作者：
Jerala, Roman
影响因子：
7.3
作者：
Meinecke, R;Meyer, B
通讯作者：
Meyer, B