Kremer J P, Jarrar D, Steckholzer U, Ertel W
GSF-Forschungszentrum für Umwelt und Gesundheit, Institut für Experimentelle Hämatologie, München, Germany.
Acta Haematol. 1996;95(3-4):268-73. doi: 10.1159/000203895.
Proinflammatory cytokines are important mediators during endotoxemia. In experimental models, injection of lipopolysaccharide (LPS) activates macrophages leading to excessive secretion of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and IL-6; infusion of high dose of these mediators results in organ failure and death. Natural infection may be different, because it persists over days or even weeks, with repeated endotoxin challenge to macrophages. Little is known about the capacity of peripheral blood mononuclear cells (PBMCs) to release proinflammatory cytokines under these conditions. Therefore, as an ex vivo model of sepsis, the expression of proinflammatory cytokines after stimulation of whole blood with LPS was studied. A high LPS dose (1 microgram/ml) maximally increased TNF-alpha, IL-1 beta and IL-6 secretion in controls, but a marked depression was observed in septic patients (p < 0.01; 15 patients with severe sepsis versus 20 control patients without infection). This reduction persisted for up to 10 days after diagnosis of sepsis. The release of TNF-alpha, IL-1 beta and IL-6 was markedly decreased in the septic group even when a lower and physiologically more relevant LPS concentration (1 ng/ml) was used. IL-1 beta mRNA was similar to controls, but a down-regulation was observed in TNF-alpha and IL-6 transcript levels in PBMCs from the blood of septic patients. This was at least in part due to a marked reduction in TNF and IL-6 mRNA half-life. These results indicate that different mechanisms down-regulate proinflammatory cytokine release in the whole blood of septic patients. Although excessive secretion is known to be deleterious, low concentrations of these cytokines are involved in regulating essential cellular and humoral immune functions. Thus, the reduced capacity to express and release adequate amounts of proinflammatory cytokines after exposure to endotoxin, as observed in whole-blood PBMCs from septic patients, may contribute to the development of immunodeficiency.
促炎细胞因子是内毒素血症期间的重要介质。在实验模型中，注射脂多糖（LPS）可激活巨噬细胞，导致肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1β和IL-6的过度分泌；注入高剂量的这些介质会导致器官衰竭和死亡。自然感染可能有所不同，因为它会持续数天甚至数周，巨噬细胞会反复受到内毒素刺激。关于外周血单个核细胞（PBMC）在这些条件下释放促炎细胞因子的能力知之甚少。因此，作为脓毒症的体外模型，研究了用LPS刺激全血后促炎细胞因子的表达。高剂量LPS（1微克/毫升）可使对照组中的TNF-α、IL-1β和IL-6分泌最大化，但在脓毒症患者中观察到明显降低（p<0.01；15例严重脓毒症患者与20例无感染的对照患者）。这种降低在脓毒症诊断后持续长达10天。即使使用较低且生理上更相关的LPS浓度（1纳克/毫升），脓毒症组中TNF-α、IL-1β和IL-6的释放也明显减少。IL-1βmRNA与对照组相似，但在脓毒症患者血液中的PBMC中观察到TNF-α和IL-6转录水平下调。这至少部分是由于TNF和IL-6 mRNA半衰期的显著缩短。这些结果表明，不同机制下调了脓毒症患者全血中促炎细胞因子的释放。尽管已知过度分泌是有害的，但这些细胞因子的低浓度参与调节基本的细胞和体液免疫功能。因此，正如在脓毒症患者的全血PBMC中观察到的那样，暴露于内毒素后表达和释放足够量促炎细胞因子的能力降低可能导致免疫缺陷的发生。
