Rieser C, Papesh C, Herold M, Böck G, Ramoner R, Klocker H, Bartsch G, Thurnher M
Departments of Urology and Internal Medicine, University of Innsbruck, A-6020 Innsbruck, Austria.
Blood. 1998 May 1;91(9):3112-7.
The endotoxin (lipopolysaccharide)-induced cytokine response is followed by a state of unresponsiveness to lipopolysaccharide (LPS) referred to as LPS tolerance or endotoxin desensitization. LPS tolerance, which can be experimentally induced in vitro and in vivo, is also known to occur in septic disease. Here, we evaluated whether dendritic cells (DC), the most potent antigen-presenting cells, are also subject to this phenomenon. Single doses of LPS added at the initiation of DC culture inhibited in a dose-dependent fashion the production of tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), and IL-12, but not the production of IL-8, in response to a second LPS challenge in day-5 DC. In addition, the LPS-induced expression of the CD83 maturation antigen was inhibited in these cells. Moreover, the endocytic activity of DC generated in the presence of LPS was dramatically reduced. DC desensitized with LPS were potent stimulators of T-cell proliferation but poor inducers of interferon-gamma (IFN-gamma) production in the allogeneic mixed leukocyte reaction. TNF-alpha and prostaglandin E2, two major products of LPS stimulation, could replace LPS for the induction of tolerance to LPS. Moreover, treatment of desensitized DC with TNF-alpha plus prostaglandin E2 fully restored CD83 expression and partially restored IL-12 production as well as the IFN-gamma-inducing activity of DC in the mixed leukocyte reaction. Our data show that human DC are highly susceptible to the induction of LPS tolerance, which seems to be a state of differential deactivation in which some functions are impaired whereas others are retained. Tolerization at the level of the professional antigen-presenting cell by inflammatory mediators may play an important role in septic disease and in the origin of cancers associated with chronic inflammation.
内毒素（脂多糖）诱导的细胞因子反应之后会出现对脂多糖（LPS）无反应的状态，即LPS耐受或内毒素脱敏。LPS耐受可在体外和体内通过实验诱导产生，在脓毒症疾病中也会发生。在此，我们评估了最有效的抗原呈递细胞——树突状细胞（DC）是否也会出现这种现象。在DC培养开始时添加单剂量的LPS，以剂量依赖的方式抑制了第5天DC对第二次LPS刺激产生肿瘤坏死因子-α（TNF-α）、白细胞介素-10（IL-10）和IL-12，但不抑制IL-8的产生。此外，这些细胞中LPS诱导的CD83成熟抗原的表达受到抑制。而且，在LPS存在下产生的DC的内吞活性显著降低。用LPS脱敏的DC是T细胞增殖的有效刺激剂，但在同种异体混合淋巴细胞反应中诱导干扰素-γ（IFN-γ）产生的能力较差。TNF-α和前列腺素E2是LPS刺激的两种主要产物，它们可以替代LPS诱导对LPS的耐受。此外，用TNF-α加前列腺素E2处理脱敏的DC可完全恢复CD83表达，并部分恢复IL-12的产生以及DC在混合淋巴细胞反应中的IFN-γ诱导活性。我们的数据表明，人DC极易被诱导产生LPS耐受，这似乎是一种差异失活状态，其中一些功能受损而另一些功能得以保留。炎症介质在专业抗原呈递细胞水平上诱导的耐受可能在脓毒症疾病以及与慢性炎症相关的癌症起源中起重要作用。
