Vogel S N, Kaufman E N, Tate M D, Neta R
Department of Microbiology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Infect Immun. 1988 Oct;56(10):2650-7. doi: 10.1128/iai.56.10.2650-2657.1988.
Endotoxin, the lipopolysaccharide (LPS) derived from gram-negative bacteria, invokes a wide range of responses in susceptible hosts. It is known that virtually all responses to LPS are mediated by the action of macrophage-derived cytokines (such as interleukin-1 [IL-1], tumor necrosis factor [TNF], and others) which are produced principally by macrophages and maximally within several hours of LPS administration. One manifestation of LPS administration which is not well understood is the phenomenon of "early endotoxin tolerance." In response to a single sublethal injection of LPS, experimental animals become refractory to challenge with a homologous or heterologous LPS preparation 3 to 4 days later. Animals rendered tolerant exhibit mitigated toxicity and a reduced capacity to produce circulating cytokines (i.e., colony-stimulating factor or interferon) in response to the challenge LPS injection. Previous studies have also shown that this state of transient, acquired hyporesponsiveness to LPS is accompanied by a marked increase in the size of cells in the bone marrow which are enriched in numbers of macrophage progenitors. In this study, we examined the capacity of recombinant IL-1 or recombinant TNF or both to induce early endotoxin tolerance and its associated hematopoietic changes. Neither cytokine alone was able to mimic LPS for induction of tolerance. Combined administration of recombinant IL-1 and recombinant TNF doses which were not toxic when administered individually led to synergistic toxicity (as assessed by death or weight loss). However, within a nontoxic range, the two cytokines synergized to induce a significant reduction in the capacity to produce colony-stimulating factor in response to LPS, as well as the characteristic increase in bone marrow cell size and macrophage progenitors shown previously to be associated with LPS-induced tolerance.
内毒素是革兰氏阴性菌产生的脂多糖（LPS），可在易感宿主中引发多种反应。众所周知，几乎所有对LPS的反应都是由巨噬细胞衍生的细胞因子（如白细胞介素-1 [IL-1]、肿瘤坏死因子 [TNF] 等）介导的，这些细胞因子主要由巨噬细胞产生，并在给予LPS后的数小时内达到最大量。LPS给药的一种尚未得到充分理解的表现是“早期内毒素耐受”现象。在单次注射亚致死剂量的LPS后，实验动物在3至4天后对同源或异源LPS制剂的攻击变得耐受。产生耐受的动物表现出毒性减轻，并且在受到LPS攻击注射后产生循环细胞因子（即集落刺激因子或干扰素）的能力降低。先前的研究还表明，这种对LPS的短暂获得性低反应状态伴随着骨髓中富含巨噬细胞祖细胞数量的细胞大小显著增加。在本研究中，我们研究了重组IL-1或重组TNF或两者诱导早期内毒素耐受及其相关造血变化的能力。单独一种细胞因子都不能模拟LPS诱导耐受。单独给药时无毒的重组IL-1和重组TNF联合给药导致协同毒性（通过死亡或体重减轻评估）。然而，在无毒范围内，这两种细胞因子协同作用，导致对LPS产生集落刺激因子的能力显著降低，以及先前显示与LPS诱导的耐受相关的骨髓细胞大小和巨噬细胞祖细胞特征性增加。
