Dalpke Alexander H, Lehner Martin D, Hartung Thomas, Heeg Klaus
Institute of Medical Microbiology and Hygiene, Philipps-University Marburg, Marburg, Germany.
Immunology. 2005 Oct;116(2):203-12. doi: 10.1111/j.1365-2567.2005.02211.x.
Lipopolysaccharide (LPS) tolerance is a state of refractoriness towards a second stimulation by LPS after a preceding stimulation. LPS is recognized by Toll-like receptor-4 (TLR-4), which belongs to a group of pattern recognition receptors mediating activation of innate immunity by microbial components. To date, it is not known in detail to what extent other TLR-dependent stimuli also induce tolerance and whether preceding and challenging stimuli are interchangeable. We have examined tolerance induction in detail for lipoteichoic acid (LTA), LPS and CpG-DNA, which are recognized by TLR-2, -4 and -9, respectively. In RAW264.7 macrophages, all three stimuli induced tolerance towards a subsequent challenge with the same stimulus used for priming, as well as cross-tolerance towards subsequent challenge with other stimuli signalling via different TLRs. However, whereas LPS/LTA cross-tolerance was also functional in an in vivo model of galactosamine (GalN)-primed liver damage, pretreatment with CpG only protected against GalN/CpG challenge and failed to induce cross-tolerance for LPS and LTA. CpG-DNA pretreatment even enhanced tumour necrosis factor (TNF)-alpha production and liver damage upon subsequent challenge with LPS or LTA. Stimulation with CpG-DNA resulted in a peculiar sensitization for interferon (IFN)-gamma secretion. The data indicate that, in contrast to in vitro macrophage desensitization, the in vivo consequences of repeated TLR stimulation greatly differ amongst different TLR ligands.
脂多糖（LPS）耐受是指在先前受到刺激后，对LPS的再次刺激产生不应答的状态。LPS由Toll样受体4（TLR-4）识别，TLR-4属于一组模式识别受体，可介导微生物成分激活固有免疫。迄今为止，尚不清楚其他依赖TLR的刺激在多大程度上也会诱导耐受，以及先前刺激和激发刺激是否可以互换。我们已经详细研究了脂磷壁酸（LTA）、LPS和CpG-DNA的耐受诱导情况，它们分别由TLR-2、-4和-9识别。在RAW264.7巨噬细胞中，所有这三种刺激均诱导对随后用用于致敏的相同刺激进行激发的耐受，以及对随后用通过不同TLR发出信号的其他刺激进行激发的交叉耐受。然而，虽然LPS/LTA交叉耐受在半乳糖胺（GalN）致敏的肝损伤体内模型中也起作用，但用CpG预处理仅能保护免受GalN/CpG激发，并且未能诱导对LPS和LTA的交叉耐受。CpG-DNA预处理甚至在随后用LPS或LTA激发时增强了肿瘤坏死因子（TNF）-α的产生和肝损伤。用CpG-DNA刺激导致对干扰素（IFN）-γ分泌的特殊致敏。数据表明，与体外巨噬细胞脱敏不同，重复TLR刺激的体内后果在不同的TLR配体之间有很大差异。
