Molecular mechanisms of endotoxin tolerance
Molecular mechanisms of endotoxin tolerance
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DOI：
10.1179/096805104225003997
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发表时间：
2004-01-01
期刊：
影响因子：
--
通讯作者：
Cook, JA
中科院分区：
文献类型：
--
作者：
Fan, HK;Cook, JA
内毒素耐受现象已被广泛研究，但到目前为止，内毒素耐受的分子机制尚不清楚。Toll样受体(TLR)家族作为脂多糖(LPS)和其他细菌产物的主要受体的发现，重新引起了人们对内毒素耐受机制的兴趣。检测细胞表面分子、信号蛋白、促炎和抗炎细胞因子等介质的变化。内毒素结合蛋白(LBP)、CD14、髓系分化蛋白-2(MD-2)和TLR2在耐受期间表达不变或上调，而TLR4一过性抑制或不变。在耐受性中改变的近端受体后信号蛋白包括白细胞介素1受体相关激酶(IRAK)的增强降解，以及TLR4-髓系分化因子88(MyD88)和IRAK-MyD88关联的降低。耐受性还与G、蛋白质含量和活性降低，蛋白激酶C(PKC)活性降低，丝裂原活化蛋白激酶(MAP)活性降低，以及激活蛋白-1(AP-1)和核因子kappaB(NF-kappaB)诱导的基因反式激活减少有关。然而，并不是所有的信号蛋白和信号通路都在耐受中被抑制，诱导特定的抗炎蛋白和信号通路可能具有重要的抗炎功能。后者包括诱导IRAK-M和抑制细胞因子信号转导-1(SOCS-1)、磷脂酰肌醇-3-激酶(PI3K)信号转导，以及增加或维持抑制物-kappaB(IkappaB)亚型的表达。此外，在核水平，核因子-kappaB亚单位p50同源二聚体的表达增加和过氧化体增殖物激活受体-γ(PPARGamma)的激活增加与耐受表型有关。尽管在内毒素耐受表型的表现上存在物种和细胞的差异，但很明显，耐受现象已经演变为对炎症的复杂的协调的反调节反应。
The phenomenon of endotoxin tolerance has been widely investigated, but to date, the molecular mechanisms of endotoxin tolerance remain to be resolved clearly. The discovery of the Toll-like receptor (TLR) family as the major receptors for lipopolysaccharide (LPS) and other bacterial products has prompted a resurgence of interest in endotoxin tolerance mechanisms. Changes of cell surface molecules, signaling proteins, pro-inflammatory and anti-inflammatory cytokines and other mediators have been examined. During tolerance expression of LPS-binding protein (LBP), CD14, myeloid differentiation protein-2 (MD-2) and TLR2 are unchanged or up-regulated, whereas TLR4 is transiently suppressed or unchanged. Proximal post-receptor signaling proteins that are altered in tolerance include augmented degradation of interleukin-1 receptor-associated kinase (IRAK), and decreased TLR4-myeloid differentiation factor 88 (MyD88) and IRAK-MyD88 association. Tolerance has also been shown to be associated with decreased G, protein content and activity, decreased protein kinase C (PKC) activity, reduction in mitogen-activated protein kinase (MAP kinase) activity, and reduced activator protein-1 (AP-1) and nuclear factor kappa B (NF-kappaB) induced gene transactivation. However, not all signaling proteins and pathways are suppressed in tolerance and induction of specific anti-inflammatory proteins and signaling pathways may serve important counter inflammatory functions. The latter include induction of IRAK-M and suppressor of cytokine-signaling-1 (SOCS-1), phosphoinositide-3-kinase (PI3K) signaling, and increased or maintained expression of inhibitor-kappaB (IkappaB) isoforms. Also at the nuclear level, increase in the NF-kappaB subunit p50 homodimer expression and increased activation of peroxisome-proliferator-activated receptors-gamma (PPARgamma) have been linked to tolerance phenotype. Although there are species and cellular variations in manifestation of the LPS tolerant phenotype, it is clear that the tolerance phenomena have evolved as a complex orchestrated counter regulatory response to inflammation.