The anti-inflammatory effects of heat shock protein 72 involve inhibition of high-mobility-group box 1 release and proinflammatory function in macrophages
The anti-inflammatory effects of heat shock protein 72 involve inhibition of high-mobility-group box 1 release and proinflammatory function in macrophages
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DOI：
10.4049/jimmunol.179.2.1236
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发表时间：
2007-07-15
影响因子：
4.4
通讯作者：
Xiao, Xianzhong
中科院分区：
文献类型：
--
作者：
Tang, Daolin;Kang, Rui;Xiao, Xianzhong
高迁移率族蛋白1（HMGB 1）是一种核蛋白，当其释放到细胞外环境中时，最近已被确定为局部和全身炎症性疾病的重要介质。当宿主遇到有害刺激时，应激反应的抗炎调节是一种有效的自我保护机制，但其作用机制仍不完全阐明。在这项研究中，我们证明了一个主要的应激诱导蛋白，热休克蛋白72（Hsp 72）的基因转染衰减LPS或TNF-α诱导的HMGB 1细胞质易位和释放的水平增加。其机制涉及抑制染色体区域维持1（CRM 1）依赖的核输出途径.过表达Hsp 72抑制LPS和TNF-α处理后巨噬细胞中CRM 1的移位以及HMGB 1和CRM 1之间的相互作用。此外，Hsp 72的过表达强烈抑制HMGB 1诱导的细胞因子（TNF-α、IL-1 β）的表达和释放，这与：1）MAP激酶（p38、JNK和ERK）的抑制;和2）NF-κ B途径的抑制密切相关。综上所述，这些实验表明Hsp 72的抗炎活性是通过干扰HMGB 1的释放和促炎功能来实现的。我们的实验数据为热休克蛋白保护的抗炎机制提供了重要的见解。
High-mobility-group box 1 (HMGB1), a nuclear protein, has recently been identified as an important mediator of local and systemic inflammatory diseases when released into the extracellular milieu. Anti-inflammatory regulation by the stress response is an effective autoprotective mechanism when the host encounters harmful stimuli, but the mechanism of action remains incompletely delineated. In this study, we demonstrate that increases in levels of a major stress-inducible protein, heat shock protein 72 (Hsp72) by gene transfection attenuated LPS- or TNF-alpha-induced HMGB1 cytoplasmic translocation and release. The mechanisms involved inhibition of the chromosome region maintenance 1 (CRM 1) -dependent nuclear export pathway. Overexpression of Hsp72 inhibited CRM1 translocation and interaction between HMGB1 and CRM1 in macrophages post-LPS and TNF-alpha treatment. In addition, overexpression of Hsp72 strongly inhibited HMGB1-induced cytokine (TNF-alpha, IL-1 beta) expression and release, which correlated closely with: 1) inhibition of the MAP kinases (p38, JNK, and ERK); and 2) inhibition of the NF-kappa B pathway. Taken together, these experiments suggest that the anti -inflammatory activity of Hsp72 is achieved by interfering with both the release and proinflammatory function of HMGB1. Our experimental data provide important insights into the anti-inflammatory mechanisms of heat shock protein protection.