Influence of CD14 on ligand interactions between lipopolysaccharide and its receptor complex
Influence of CD14 on ligand interactions between lipopolysaccharide and its receptor complex
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DOI：
10.4049/jimmunol.175.6.3940
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发表时间：
2005-09-15
影响因子：
4.4
通讯作者：
Goyert, SM
中科院分区：
文献类型：
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作者：
Gangloff, SC;Zähringer, U;Goyert, SM
内毒素与CD14-TLR4受体复合体的相互作用调节宿主的先天免疫反应。几项利用脂多糖部分结构的研究表明，TLR4决定了该复合体的配体特异性，而CD14不分青红皂白地将配体输送到TLR4。尽管观察到TLR4(+/+)、CD14(-/-)巨噬细胞对内毒素的反应很弱，但仍得出了这一结论。为了确定CD14本身是否在特异性配体识别中起作用，比较了不同结构的内毒素对CD14(+/+)和CD14(-/-)巨噬细胞诱生促炎细胞因子TNF的影响。这些研究表明，CD14(+/+)和CD14(-/-)巨噬细胞的配体特异性有很大不同。当CD14存在时，受体复合体对光滑的内毒素(革兰氏阴性菌表达的主要形式)显示出极高的特异性；然而，随着从光滑的内毒素中去除越来越多的碳水化合物，CD14(+/+)巨噬细胞的敏感性降低。减少多达500倍。相反，CD14(-/-)巨噬细胞不能区分光滑的内毒素及其不同的部分结构。此外，CD14(-/-)巨噬细胞对平稳内毒素的敏感性比CD14(+/+)巨噬细胞低15万倍。在CD14(+/+)巨噬细胞中观察到类似的区分不同细菌如脆弱类杆菌和流产沙门氏菌的不同内毒素结构的能力，但不能观察到CD14(-/-)巨噬细胞。因此，CD14(+/+)，而不是CD14(-/-)，巨噬细胞对自然形式的内毒素刺激高度敏感，并显示出区分各种内毒素配体的能力，这与CD14是一个高度特异的受体是一致的。
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.