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

细菌内毒素的脂类A部分在内毒素介质的产生中起着核心作用。人和小鼠巨噬细胞对类脂A结构的反应不同。我们研究了一系列结构相关的单糖类脂A类似物激活人巨噬细胞U937细胞和外周血单核细胞产生肿瘤坏死因子-α和白介素6的能力，并与小鼠巨噬细胞RAW264.7细胞的活性进行了比较。结果表明，被人类细胞识别为脂多糖激动剂的类脂A类似物的结构由D-氨基、磷酸基和酰基组成，其碳链长度为C14和C12，比例为1：1：3，这些成分是单糖和双糖分子所共有的，识别所需的元件比小鼠细胞所需的元件更严格。相反，广泛的类脂A结构被小鼠细胞识别为内毒素激动剂和拮抗剂，而被人类细胞识别为内毒素拮抗剂。寻找和鉴定一种可能的内毒素受体，将内毒素信号传导到细胞内，是目前内毒素研究中的一个重要课题。有人认为，该蛋白以一种生产性或非生产性的方式识别类脂A结构进行信号转导，这种蛋白质在动物物种之间的差异导致了细胞对类脂A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蛋白A类似物的靶分子，作为内毒素激动剂或拮抗剂来传递其信号。基于本研究获得的信息，单糖类脂A类似物和双糖类似物在寻找有价值的新信息以阐明这类问题方面具有很大的应用前景。

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.