Studies on regulatory mechanisms of LPS signal transductions in human cells.

细菌LPS的脂质A部分在内毒素介质的产生中起着核心作用。人类和小鼠巨噬细胞对脂质a样结构的反应不同。我们研究了一系列结构相关的单糖脂质a类似物，与小鼠巨噬细胞RAW264.7细胞相比，它们能激活人巨噬细胞U937细胞和外周血单核细胞产生tnf - α和IL-6。结果表明，脂质A类似物被人体细胞识别为LPS激动剂，其结构由d -葡萄糖胺、碳链长度为C14和C12的磷酸基和酰基组成，其比例为1:1:3；这些成分是单糖和双糖分子所共有的，识别所需的元素比小鼠细胞所需要的更严格。相反，广泛的脂质a样结构，被小鼠细胞识别为LPS激动剂和拮抗剂，被人类细胞识别为LPS拮抗剂。寻找和表征一种能将LPS信号转导到细胞中的推定的LPS受体是目前LPS研究的一个重要课题。有人提出，该蛋白在信号转导中以生产性或非生产性方式识别脂质a样结构，并且该蛋白在动物物种之间的差异导致细胞对脂质a样结构的反应具有物种特异性。在本研究中，这种蛋白可以被认为是脂质a类似物作为LPS激动剂或拮抗剂转导其信号的靶分子。基于本研究获得的信息，进一步应用单糖脂质A类似物和双糖类似物有望寻找有价值的新信息来阐明这些问题。

The lipid A portion of bacterial LPS plays a central role in the production of endotoxic mediators. Different responses between human and murine macrophages to lipid A-like structures have been indicated. We investigated a series of structurally related monosaccharide lipid A analogues for their potency to activate human macrophage U937 cells and peripheral blood mononuclear cells for production of TNF-alpha and IL-6 compared with that of murine macrophage RAW264.7 cells. As the results, it was reveal that the structure of lipid A analogues recognized as LPS agonist by human cells comprises D-glucosamine, phosphoryl groups and acyl groups with defined carbon chain lengths of C14 and C12 in a ratio proportional to 1 : 1 : 3 ; these constituents are common to monosaccharide and disaccharide molecules and the elements necessary for recognition are more strict than those required by murine cells. In contrast, broad lipid A-like structures, which are recognized by the murine cells as LPS agonist and antagonist, are recognized as being LPS antagonist by human cells. It is now an important subject in LPS studies to find and characterize a putative LPS-receptor which transduces LPS-signals into cells. It is proposed that the protein recognizes lipid A-like structures in a productive or nonproductive manner for signal transduction and that the difference in this protein between animal species causes species specificity in the response of the cells to lipid A-like structures. In the present study, such a protein can be assumed to play a role as the target molecule for lipid A analogues to transduce their signals as LPS agonist or antagonist. Based on the information obtained in this study, further application of monosaccharide lipid A analogues as well as disaccharide analogues is promising in the search for valuable new information to elucidate of such problems.