Kiener P A, Marek F, Rodgers G, Lin P F, Warr G, Desiderio J
Department of Immunology, Bristol-Myers Company, Wallingford, CT 06492.
J Immunol. 1988 Aug 1;141(3):870-4.
The effect of the i.v. administration of endotoxin (LPS), diphosphoryl lipid A, and the non-toxic derivative monophosphoryl lipid A (MPL), on the production of serum cachectin (TNF), IFN-gamma, and the appearance of endotoxin shock have been measured in mice primed with Listeria monocytogenes. All three of the lipid A varieties induced the production of TNF in a dose-dependent manner. Although comparable peak levels of TNF were produced (5 X 10(5) to 1 X 10(6) U/ml), treatments with LPS or diphosphoryl lipid A were lethal whereas those with MPL were not. A study following TNF in the mouse sera for up to 24 h after treatment with the lipid A types showed that serum levels of TNF peaked 90 min after the treatment, and that TNF levels induced by LPS treatment were maintained for several hours longer than those induced by lipid A or MPL. All three molecules also resulted in the production of IFN-gamma in the serum, which peaked at 4 to 5 h after treatment. After 90 min there were no significant differences in the levels of serum IFN-gamma in any of the groups of treated animals. However, as was observed with the TNF, the levels of IFN in animals treated with LPS persisted longer than those induced by MPL or lipid A. These results suggest that the non-toxic MPL as well as the toxic forms of lipid A can induce the production of TNF by macrophages. Furthermore, although it is essential, TNF alone is not necessarily sufficient to induce septic shock in mice.
在经单核细胞增多性李斯特菌致敏的小鼠中，已检测了静脉注射内毒素（LPS）、二磷酸脂质A和无毒衍生物单磷酸脂质A（MPL）对血清恶病质素（TNF）、干扰素-γ产生以及内毒素休克出现情况的影响。所有这三种脂质A变体均以剂量依赖方式诱导TNF产生。尽管产生了相当的TNF峰值水平（5×10⁵至1×10⁶U/ml），但LPS或二磷酸脂质A处理是致死性的，而MPL处理则不然。一项在小鼠血清中追踪脂质A类型处理后长达24小时TNF情况的研究表明，TNF血清水平在处理后90分钟达到峰值，且LPS处理诱导的TNF水平维持时间比脂质A或MPL诱导的长数小时。所有这三种分子还导致血清中干扰素-γ产生，在处理后4至5小时达到峰值。90分钟后，任何处理组动物的血清干扰素-γ水平均无显著差异。然而，正如对TNF所观察到的那样，LPS处理动物中的干扰素水平比MPL或脂质A诱导的持续时间更长。这些结果表明，无毒的MPL以及有毒形式的脂质A均可诱导巨噬细胞产生TNF。此外，尽管TNF是必不可少的，但仅TNF不一定足以在小鼠中诱导败血性休克。
