Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein
Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein
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DOI：
10.1074/jbc.m306793200
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发表时间：
2004-02-27
影响因子：
4.8
通讯作者：
Abraham, E
中科院分区：
文献类型：
--
作者：
Park, JS;Svetkauskaite, D;Abraham, E
高迁移率族蛋白1(HMGB1)最初被描述为一种稳定核小体和促进转录的DNA结合蛋白，在急性炎症反应中也可以被释放到细胞外。中性粒细胞、单核细胞或巨噬细胞暴露于HMGB1可增加核因子-kappaB的核转位，并增强促炎细胞因子的表达。虽然晚期糖基化终末产物受体(RAGE)已被证明与HMGB1相互作用，但其他假定的HMGB1受体也是已知的，但尚未被鉴定。在目前的实验中，我们探索了RAGE、Toll样受体(TLR)2和TLR4及其相关的激酶在HMGB1诱导的细胞激活中的作用。中性粒细胞或巨噬细胞与HMGB1共同培养后，可通过TLR4非依赖机制激活核因子-kappaB。与主要增加IKKβ活性的脂多糖(LPS)不同，HMGB1暴露导致IKKalpha和IKKβ的激活。TLR2和TLR4下游的激酶和支架蛋白参与了HMGB1对NF-kappaB依赖转录的增强，而TLR/白细胞介素1受体(IL-1R)非依赖性的激酶如肿瘤坏死因子受体相关因子2则不参与。结果表明，TLR2和TLR4均参与HMGB1诱导的核因子-kappaB的激活。相反，RAGE在HMGB1激活巨噬细胞过程中只起到很小的作用。HMGB1与TLR2和TLR4的相互作用可能为HMGB1产生与内毒素类似的炎症反应的能力提供了解释。
High mobility group box 1 (HMGB1) protein, originally described as a DNA-binding protein that stabilizes nucleosomes and facilitates transcription, can also be released extracellularly during acute inflammatory responses. Exposure of neutrophils, monocytes, or macrophages to HMGB1 results in increased nuclear translocation of NF-kappaB and enhanced expression of proinflammatory cytokines. Although the receptor for advanced glycation end products (RAGE) has been shown to interact with HMGB1, other putative HMGB1 receptors are known to exist but have not been characterized. In the present experiments, we explored the role of RAGE, Toll-like receptor (TLR) 2, and TLR 4, as well as associated kinases, in HMGB1-induced cellular activation. Culture of neutrophils or macrophages with HMGB1 produced activation of NF-kappaB through TLR 4-independent mechanisms. Unlike lipopolysaccharide (LPS), which primarily increased the activity of IKKbeta, HMGB1 exposure resulted in activation of both IKKalpha and IKKbeta. Kinases and scaffolding proteins downstream of TLR 2 and TLR 4, but not TLR/interleukin- 1 receptor (IL-1R)-independent kinases such as tumor necrosis factor receptor-associated factor 2, were involved in the enhancement of NF-kappaB-dependent transcription by HMGB1. Transfections with dominant negative constructs demonstrated that TLR 2 and TLR 4 were both involved in HMGB1-induced activation of NF-kappaB. In contrast, RAGE played only a minor role in macrophage activation by HMGB1. Interactions of HMGB1 with TLR 2 and TLR 4 may provide an explanation for the ability of HMGB1 to generate inflammatory responses that are similar to those initiated by LPS.