Mackensen A, Galanos C, Wehr U, Engelhardt R
Department of Hematology/Oncology, University of Freiburg, Germany.
Eur Cytokine Netw. 1992 Nov-Dec;3(6):571-9.
Endotoxin (lipopolysaccharide, LPS) has the property of inducing tolerance to its own biological effects. This phenomenon has been extensively studied in animal models but only few studies exist on the regulation in humans. Here we describe experiments designed to determine the cytokine regulation and cellular changes in humans during induction of LPS tolerance after repeated LPS injections. Intravenous administration of purified LPS Salmonella abortus equi to cancer patients induces high amounts of circulating tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-8 (IL-8), granulocyte colony-stimulating factor (G-CSF), and macrophage colony-stimulating factor (M-CSF). Repeated injections of LPS at daily intervals resulted in a marked downregulation of the cytokine response and in the case of TNF-alpha, IL-8, G-CSF, and M-CSF the cytokine response was reduced to baseline levels. In contrast, significant increases in serum IL-6 were detected up to day 5 of repeated LPS injections. Hematological changes included transient decreases in WBCs affecting granulocytes, monocytes, and lymphocytes, followed by a marked granulocytosis. The drop in WBCs remained unaltered throughout the 5 day course of repeated LPS injections whereas the granulocyte overshoot recovery diminished gradually. When PBMCs of the cancer patients were restimulated ex vivo a marked enhancement of the capacity to produce TNF-alpha, IL-113, and IL-6 occurred, which is in contrast to the decreasing TNF-alpha serum levels obtained in vivo. In parallel, a shift in monocyte subpopulations from CD14+/CD16- to CD14+/CD16+ cells was observed. The data provide evidence that different mechanisms are implicated in the cytokine downregulation following repeated LPS injections to cancer patients. Furthermore, PBMCs from LPS tolerant patients do not demonstrate a reduction in their capacity to produce cytokines.
内毒素（脂多糖，LPS）具有诱导自身生物学效应耐受性的特性。这种现象在动物模型中已得到广泛研究，但关于人类中的调节机制仅有少数研究。在此，我们描述了旨在确定重复注射LPS诱导人类LPS耐受性过程中的细胞因子调节和细胞变化的实验。向癌症患者静脉注射纯化的马流产沙门氏菌LPS可诱导大量循环肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、白细胞介素-8（IL-8）、粒细胞集落刺激因子（G-CSF）和巨噬细胞集落刺激因子（M-CSF）。每天间隔重复注射LPS导致细胞因子反应显著下调，就TNF-α、IL-8、G-CSF和M-CSF而言，细胞因子反应降至基线水平。相比之下，在重复注射LPS的第5天之前，血清IL-6显著增加。血液学变化包括影响粒细胞、单核细胞和淋巴细胞的白细胞短暂减少，随后是明显的粒细胞增多。在重复注射LPS的5天过程中，白细胞的下降保持不变，而粒细胞过度恢复逐渐减少。当对癌症患者的外周血单核细胞（PBMC）进行体外再刺激时，产生TNF-α、IL-1β和IL-6的能力显著增强，这与体内获得的TNF-α血清水平下降形成对比。同时，观察到单核细胞亚群从CD14+/CD16-细胞向CD14+/CD16+细胞的转变。数据表明，重复向癌症患者注射LPS后细胞因子下调涉及不同机制。此外，来自LPS耐受患者的PBMC产生细胞因子的能力并未降低。
