R-form LPS, the master key to the activation of TLR4/MD-2-positive cells
R-form LPS, the master key to the activation of TLR4/MD-2-positive cells
复制标题
DOI：
10.1002/eji.200535593
复制
发表时间：
2006-03-01
影响因子：
5.4
通讯作者：
Freudenberg, MA
中科院分区：
文献类型：
--
作者：
Huber, M;Kalis, C;Freudenberg, MA
内毒素是宿主检测革兰氏阴性菌的主要识别标记物，也是感染后炎症反应的有力启动者。用来自沙门氏菌和大肠杆菌野生型和R突变体的S型和R型内毒素，我们发现R型内毒素很容易激活表达信号受体Toll样受体4/髓系分化蛋白2(TLR4/MD2)的小鼠细胞，而S型内毒素进一步需要内毒素结合蛋白CD14和LBP的帮助，从而限制了其激活能力。因此，在生理条件下，R型内毒素比S型内毒素能招募更多的细胞参与内毒素反应。我们还发现，高浓度的可溶性CD_(14)使CD_(14)阴性的细胞能够对S形式的内毒素产生应答。所给出的体外数据得到了一项体内研究的证实，该研究测量了小鼠注射R型和S型脂多糖后肿瘤坏死因子-α的水平。由于R型内毒素广泛存在于所有野生型细菌中，它对先天免疫反应和感染的病理生理的贡献远高于过去半个世纪的预期。
Lipopolysaccharide (endotoxin, LPS) is a major recognition marker for the detection of gram-negative bacteria by the host and a powerful initiator of the inflammatory response to infection. Using S- and R-form LPS from wild-type and R-mutants of Salmonella and E. coli, we show that R-form LPS readily activates mouse cells expressing the signaling receptor Toll-like receptor 4/myeloid differentiation protein 2 (TLR4/MD2), while the S-form requires further the help of the LPS-binding proteins CD14 and LBP, which limits its activating capacity. Therefore, the R-form LPS under physiological conditions recruits a larger spectrum of cells in endotoxic reactions than S-form LPS. We also show that soluble CD14 at high concentrations enables CD14-negative cells to respond to S-form LPS. The presented in vitro data are corroborated by an in vivo study measuring TNF-alpha levels in response to injection of R- and S-form LPS in mice. Since the R-form LPS constitutes ubiquitously part of the total LPS present in all wild-type bacteria its contribution to the innate immune response and pathophysiology of infection is much higher than anticipated during the last half century.