Ziegler-Heitbrock H W
Institute for Immunology, University of Munich, Germany.
J Inflamm. 1995;45(1):13-26.
Stimulation with lipopolysaccharide (LPS) will lead to the expression of a variety of genes in CD14+ monocytes/macrophages, but also in CD14- fibroblasts and endothelial cells. Upon secondary LPS stimulation, the expression of many of these genes is only minimal. This applies to several cytokines, most prominent among them tumor necrosis factor (TNF). Induction of tolerance appears to require some degree of activation in the primary exposure, as partial structures of LPS induce tolerance, as long as they are able to activate cells. Studies on the mechanism of unresponsiveness in tolerant cells show that the CD14 LPS receptor is not downregulated but may even increase in number at the cell surface. Furthermore, this receptor appears to be functional in that mobilization of the transcription factor NF-kappa B does still occur. This NF-kappa B complex is composed primarily of p50p50 homodimers, that bind to the respective DNA motif in the promoter region of many proinflammatory genes, thereby blocking transactivation. However, LPS tolerance does not lead to downregulation of all kinds of response, as some genes are even increased in expression upon secondary stimulation; these include p50 of NF-kappa B, TNF receptor type II and interleukin-10 (IL-10). These gene products are involved in the downregulation of proinflammatory cytokines and may thereby be instrumental in the unresponsiveness observed. Hence, tolerance to LPS is not a passive process that occurs in an exhausted cell; rather, it is a well-controlled active response that is orchestrated in order to prevent excessive inflammation. Important modulators of tolerance are glucocorticoids, which result in a general decrease of gene expression, and interferon-gamma (IFN-gamma), which enhances expression of proinflammatory genes. LPS tolerance does occur in some clinical settings, as in hemodialysis, in sepsis and in patients treated repeatedly with LPS or other monocyte activators. In fact, LPS tolerance may be exploited for prophylaxis of severe sepsis in patients at risk.
用脂多糖（LPS）刺激会导致CD14 +单核细胞/巨噬细胞中多种基因的表达，在CD14 -成纤维细胞和内皮细胞中也会如此。二次LPS刺激后，这些基因中的许多基因表达仅为微量。这适用于几种细胞因子，其中最突出的是肿瘤坏死因子（TNF）。耐受性的诱导似乎在初次接触时需要一定程度的激活，因为LPS的部分结构只要能够激活细胞就能诱导耐受性。对耐受细胞中无反应机制的研究表明，CD14 LPS受体并未下调，甚至在细胞表面数量可能增加。此外，该受体似乎具有功能，因为转录因子NF-κB的激活仍会发生。这种NF-κB复合物主要由p50p50同二聚体组成，它们与许多促炎基因启动子区域中的相应DNA基序结合，从而阻断反式激活。然而，LPS耐受性不会导致所有类型反应的下调，因为一些基因在二次刺激后表达甚至增加；这些基因包括NF-κB的p50、II型TNF受体和白细胞介素-10（IL-10）。这些基因产物参与促炎细胞因子的下调，因此可能有助于观察到的无反应状态。因此，对LPS的耐受性不是在耗尽的细胞中发生的被动过程；相反，它是一种精心控制的主动反应，其目的是防止过度炎症。耐受性的重要调节因子是糖皮质激素，它会导致基因表达普遍下降，以及干扰素-γ（IFN-γ），它会增强促炎基因的表达。LPS耐受性确实会在一些临床环境中出现，如血液透析、败血症以及用LPS或其他单核细胞激活剂反复治疗的患者中。事实上，LPS耐受性可用于对有风险患者的严重败血症进行预防。
