Gangloff Sophie C, Zähringer Ulrich, Blondin Catherine, Guenounou Moncef, Silver Jack, Goyert Sanna M
North Shore-LIJ Research Institute/New York University School of Medicine, Manhasset, NY 11030, USA.
J Immunol. 2005 Sep 15;175(6):3940-5. doi: 10.4049/jimmunol.175.6.3940.
The interaction of LPS (endotoxin) with the CD14-TLR4 receptor complex modulates the host innate immune response. Several studies using partial structures of LPS have suggested that TLR4 determines the ligand specificity of this complex, and that CD14 indiscriminately serves to deliver the ligand to TLR4. This conclusion has been made despite observations that the response of TLR4(+/+),CD14(-/-) macrophages to LPS is very weak. To determine whether CD14 itself plays a role in specific ligand recognition, the influences of various partial structures of LPS on induction of the proinflammatory cytokine, TNF, by CD14(+/+) and CD14(-/-) macrophages were compared. These studies show that the ligand specificities of CD14(+/+) and CD14(-/-) macrophages are very different. When CD14 is present, the receptor complex shows exquisite specificity for smooth LPS, the major form expressed by Gram-negative bacteria; however, as increasing amounts of carbohydrate are removed from smooth LPS, the sensitivity of CD14(+/+) macrophages decreases as much as 500-fold. In contrast, CD14(-/-) macrophages are unable to distinguish between smooth LPS and its various partial structures. Furthermore, CD14(-/-) macrophages are 150,000-fold less sensitive than CD14(+/+) macrophages to smooth LPS. A similar ability to distinguish the differing LPS structures of various bacteria such as Bacteroides fragilis and Salmonella abortus are observed for CD14(+/+), but not CD14(-/-), macrophages. Thus, CD14(+/+), but not CD14(-/-), macrophages are highly sensitive to stimulation by natural forms of LPS and show the ability to distinguish between various LPS ligands, consistent with CD14 being a highly specific receptor.
脂多糖（内毒素）与CD14 - TLR4受体复合物的相互作用调节宿主的固有免疫反应。几项使用脂多糖部分结构的研究表明，TLR4决定了该复合物的配体特异性，而CD14则不加区分地将配体递送至TLR4。尽管有观察结果显示TLR4(+/+)、CD14(-/-)巨噬细胞对脂多糖的反应非常微弱，但仍得出了这一结论。为了确定CD14自身是否在特异性配体识别中发挥作用，比较了脂多糖的各种部分结构对CD14(+/+)和CD14(-/-)巨噬细胞诱导促炎细胞因子TNF的影响。这些研究表明，CD14(+/+)和CD14(-/-)巨噬细胞的配体特异性非常不同。当存在CD14时，受体复合物对光滑型脂多糖表现出极高的特异性，光滑型脂多糖是革兰氏阴性菌表达的主要形式；然而，随着从光滑型脂多糖中去除的碳水化合物量增加，CD14(+/+)巨噬细胞的敏感性降低多达500倍。相比之下，CD14(-/-)巨噬细胞无法区分光滑型脂多糖及其各种部分结构。此外，CD14(-/-)巨噬细胞对光滑型脂多糖的敏感性比CD14(+/+)巨噬细胞低150,000倍。在CD14(+/+)巨噬细胞中观察到了区分不同细菌（如脆弱拟杆菌和流产沙门氏菌）不同脂多糖结构的类似能力，但在CD14(-/-)巨噬细胞中未观察到。因此，CD14(+/+)巨噬细胞而非CD14(-/-)巨噬细胞对天然形式的脂多糖刺激高度敏感，并表现出区分各种脂多糖配体的能力，这与CD14是一种高度特异性受体一致。
