Transfer of monomeric endotoxin from MD-2 to CD14
Transfer of monomeric endotoxin from MD-2 to CD14
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DOI：
10.1074/jbc.m705995200
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发表时间：
2007-12-14
影响因子：
4.8
通讯作者：
Weiss, Jerrold P.
中科院分区：
文献类型：
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作者：
Teghanemt, Athmane;Prohinar, Polonca;Weiss, Jerrold P.
内毒素对Toll样受体4（TLR 4）依赖性细胞的有效激活依赖于内毒素单体从聚集形式通过脂多糖结合蛋白依次转移至CD 14，然后转移至MD-2。我们现在表明，单体内毒素可以从MD-2反向转移到CD 14，但不能转移到脂多糖结合蛋白。反向转移需要类似于内毒素-MD-2的1000倍摩尔过量的CD 14。内毒素从MD-2转移到细胞外可溶性CD 14减少了表达TLR 4的细胞的活化，而没有MD-2。然而，内毒素从MD-2转移到膜CD 14（mCD 14）使得表达MD-2中心点TLR 4的细胞对内毒素-MD-2复合物的活化敏感。不能单独激活表达TLR 4的细胞的内毒素-突变体（F126 A）MD-2复合物通过将内毒素转移至mCD 14，然后将内毒素转移至内源性野生型MD-2中心点TLR 4，从而有效激活表达mCD 14、MD-2和TLR 4的细胞。这些发现描述了一种新的内毒素转移途径，该途径提供了内毒素对细胞活化的额外调节层。
Potent Toll-like receptor 4 (TLR4)-dependent cell activation by endotoxin depends on sequential transfer of monomers of endotoxin from an aggregated form to CD14 via the lipopolysaccharide-binding protein and then to MD-2. We now show that monomeric endotoxin can be transferred in reverse from MD-2 to CD14 but not to lipopolysaccharide-binding protein. Reverse transfer requires a similar to 1000-fold molar excess of CD14 to endotoxin-MD-2. Transfer of endotoxin from MD-2 to extracellular soluble CD14 reduces activation of cells expressing TLR4 without MD-2. However, transfer of endotoxin from MD-2 to membrane CD14 (mCD14) makes cells expressing MD-2 center dot TLR4 sensitive to activation by the endotoxin-MD-2 complex. An endotoxin-mutant (F126A) MD-2 complex that does not activate cells expressing TLR4 alone potently activates cells expressing mCD14, MD-2, and TLR4 by transferring endotoxin to mCD14, which then transfers endotoxin to endogenous wildtype MD-2 center dot TLR4. These findings describe a novel pathway of endotoxin transfer that provides an additional layer of regulation of cell activation by endotoxin.