Escherichia coli Braun lipoprotein induces a lipopolysaccharide-like endotoxic response from primary human endothelial cells
Escherichia coli Braun lipoprotein induces a lipopolysaccharide-like endotoxic response from primary human endothelial cells
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DOI：
10.4049/jimmunol.167.9.5231
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发表时间：
2001-11-01
影响因子：
4.4
通讯作者：
McIntyre, TM
中科院分区：
文献类型：
--
作者：
Neilsen, PO;Zimmerman, GA;McIntyre, TM
所有细菌都含有氨基末端半胱氨酸残基被 N-酰基 S-二酰基甘油功能修饰的蛋白质，带有这种修饰的肽和蛋白质具有免疫调节作用。大肠杆菌的主要外膜脂蛋白布劳恩脂蛋白 (BLP) 是典型的三酰化半胱氨酰修饰蛋白。我们发现它在刺激人内皮细胞产生炎症表型方面与 LPS 一样活跃，并且大肠杆菌的 BLP 阴性突变体比其亲本菌株的炎症性更小。虽然脂质修饰是必要的，但脂质化蛋白质比脂质修饰肽更有效。 BLP 与 CD14 相关，但与 LPS 不同，这种相互作用不需要引发内皮细胞激活。 BLP 刺激内皮细胞 E-选择素表面表达、IL-6 分泌以及由 LPS 诱导的相同细胞因子 mRNA 组的上调。对 4400 个基因的定量微阵列分析表明，BLP 和 LPS 诱导了相同的 30 个基因，并且基因诱导水平几乎完全一致。我们得出的结论是，至少一种丰富的革兰氏阴性蛋白的脂质修饰对于内毒素活性至关重要，但蛋白质成分也会影响活性。 BLP 和 LPS 的等效效力以及它们在内皮细胞激活的性质和程度方面的完全一致性表明，大肠杆菌的内毒素活性不仅仅归因于 LPS。大肠杆菌的主要外膜蛋白是内皮细胞的完全活性内毒素激动剂。
All bacteria contain proteins in which their amino-terminal cysteine residue is modified with N-acyl S-diacylglycerol functions, and peptides and proteins bearing this modification are immunomodulatory. The major outer membrane lipoprotein of Escherichia coli, the Braun lipoprotein (BLP), is the prototypical triacylated cysteinyl-modified protein. We find it is as active as LPS in stimulating human endothelial cells to an inflammatory phenotype, and a BLP-negative mutant of E. coli was less inflammatory than its parental strain. While the lipid modification was essential, the lipidated protein was more potent than a lipid-modified peptide. BLP associates with CD14, but this interaction, unlike that with LPS, was not required to elicit endothelial cell activation. BLP stimulated endothelial cell E-selectin surface expression, IL-6 secretion, and up-regulation of the same battery of cytokine mRNAs induced by LPS. Quantitative microarray analysis of 4400 genes showed the same 30 genes were induced by BLP and LPS, and that there was near complete concordance in the level of gene induction. We conclude that the lipid modification of at least one abundant Gram-negative protein is essential for endotoxic activity, but that the protein component also influences activity. The equivalent potency of BLP and LPS, and their complete concordance in the nature and extent of endothelial cell activation show that E. coli endotoxic activity is not due to just LPS. The major outer membrane protein of E. coli is a fully active endotoxic agonist for endothelial cells.