Lipid A-like molecules that antagonize the effects of endotoxins on human monocytes.
Lipid A-like molecules that antagonize the effects of endotoxins on human monocytes.
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DOI：
10.1016/s0021-9258(18)55023-7
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发表时间：
1991-10
期刊：
影响因子：
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通讯作者：
Douglas T. GolenbockSQll;Randolph;HamptonIIQ;N. Qureshi;K. Takayama;Christian R. H. RaetzQ
中科院分区：
文献类型：
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作者：
Douglas T. GolenbockSQll;Randolph;HamptonIIQ;N. Qureshi;K. Takayama;Christian R. H. RaetzQ
内毒素是导致革兰氏阴性败血症临床综合征的细菌产物。尽管内毒素的脂类A结构域似乎与内毒素的毒性有关，但光合作用细菌球形红杆菌(RSLA)的类脂A和肠道细菌的类脂A的双糖前体脂质IVA对人类细胞几乎没有活性。利用人原单核细胞系THP-1和人单核细胞，我们现在证明脂质IVA和RSLA都是内毒素的拮抗剂。通过测量细胞因子和前列腺素E_2的释放来判断，当拮抗剂过量10-100倍时，完全的、显然是竞争性的抑制内毒素活性是可能的。这两种拮抗剂都可以防止从各种革兰氏阴性细菌中提取的内毒素对单核细胞的刺激。用任何一种抑制剂处理过的细胞，在随后的洗涤过程中，对内毒素的反应仍然减弱。整个革兰氏阴性菌对单核细胞的刺激也以剂量依赖的方式被拮抗。在与脂类IVA和RSLA相同的剂量范围内，脂类X没有抑制作用。这些发现排除了将内毒素隔离作为观察到的拮抗作用的解释。这两种抑制剂都不能改变佛波酯、金黄色葡萄球菌或纯化蛋白衍生物对单核细胞的刺激作用，显示出对内毒素的特异性。虽然RSLA在用人和小鼠的巨噬细胞进行测试时似乎抑制了内毒素，但脂类IVA具有独特的能力，对人来源的细胞具有内毒素拮抗剂的作用，但对小鼠来源的细胞则表现出类似内毒素的作用。与脂多糖一样，脂质IVA可刺激小鼠RAW 264.7巨噬细胞瘤细胞释放肿瘤坏死因子α和花生四烯酸。脂质IVA在小鼠细胞中诱导内毒素样效应所需的浓度范围与在人单核细胞中拮抗内毒素作用所需的浓度范围相似。RSLA可完全抑制脂质IVA的激动剂活性。用脂质IVA观察到的这种独特的物种依赖药理学可能反映了人和鼠脂多糖受体之间的差异。RSLA和脂质IVA可能有助于确定内毒素在革兰氏阴性细菌感染中的作用，并可能被证明是治疗革兰氏阴性败血症的典型药物。
Lipopolysaccharide (LPS) endotoxin is implicated as the bacterial product responsible for the clinical syndrome of Gram-negative septicemia. Although the lipid A domain of LPS appears to be responsible for the toxicity of endotoxin, lipid A from the photosynthetic bacterium Rhodobacter sphaeroides (RSLA) and a disaccharide precursor of lipid A from enteric bacteria, termed lipid IVA, have little activity on human cells. Using the human promonomyelocytic cell line THP-1 and human monocytic cells, we now show that both lipid IVA and RSLA are antagonists of LPS. Complete, apparently competitive, inhibition of LPS activity is possible at a 10-100-fold excess of antagonist, as judged by measuring the release of cytokines and prostaglandin E2. Both antagonists prevent monocyte stimulation by endotoxin extracted from a variety of Gram-negative bacteria. Cells pretreated with either inhibitor and subsequently washed still show attenuated responses to LPS. Stimulation of monocytes by whole Gram-negative bacteria is also antagonized in a dose-dependent manner. Lipid X has no inhibitory effect in the same dose range as lipid IVA and RSLA. These findings rule out LPS sequestration as the explanation for the observed antagonism. Neither inhibitor alters monocyte stimulation by phorbol 12-myristate 13-acetate, Staphylococcus aureus, or purified protein derivative, demonstrating specificity for LPS. Although RSLA appears to inhibit LPS when tested with macrophages from both humans and mice, lipid IVA had the unique ability to act as an LPS antagonist with human-derived cells but to exhibit LPS-like effects with murine-derived cells. Like LPS, lipid IVA stimulated the release of both tumor necrosis factor alpha and arachidonic acid from murine-derived RAW 264.7 macrophage tumor cells. The range of concentrations necessary for lipid IVA to induce LPS-like effects in murine cells was similar to that necessary to antagonize the actions of LPS in human monocytes. The agonist activities of lipid IVA were completely inhibitable by RSLA. This unique species-dependent pharmacology observed with lipid IVA may reflect differences between human and murine LPS receptors. RSLA and lipid IVA may be useful in defining the role of LPS in Gram-negative bacterial infections and may prove to be prototypical therapeutic agents for the treatment of Gram-negative septicemia.