Extracellular heat shock cognate protein 70 induces cardiac functional tolerance to endotoxin: differential effect on TNF-alpha and ICAM-1 levels in heart tissue.
Extracellular heat shock cognate protein 70 induces cardiac functional tolerance to endotoxin: differential effect on TNF-alpha and ICAM-1 levels in heart tissue.
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DOI：
10.1016/j.cyto.2010.04.014
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发表时间：
2010-07
期刊：
影响因子：
3.8
通讯作者：
Meng, Xianzhong
中科院分区：
文献类型：
--
作者：
Su, Xin;Sykes, Joshua B.;Ao, Lihua;Raeburn, Christopher D.;Fullerton, David A.;Meng, Xianzhong
内毒素可引起心功能障碍，诱导对内毒素的耐受具有治疗潜力。热休克蛋白70(HSP70)可诱导巨噬细胞产生内毒素耐受。我们最近发现，热休克相关蛋白70(HSC70)通过激活巨噬细胞和心肌中的TLR4来诱导促炎细胞因子。我们推测HSC70预适应可诱导心脏对内毒素的耐受。热休克蛋白70预处理24 h可降低内毒素刺激后巨噬细胞肿瘤坏死因子-α水平。内毒素前24小时用HSC70对小鼠进行预适应可减轻内毒素血症心功能障碍。HSC70预适应使血浆和心脏组织中肿瘤坏死因子-α水平分别降低33.3%和35.4%，心肌组织中ICAM-1水平降低63.5%。热休克蛋白70对肿瘤坏死因子-α的影响不如内毒素预适应强(血浆和心脏组织中肿瘤坏死因子-α水平分别下降79.7%和75.0%)，而热休克蛋白70和内毒素预适应对心肌组织中细胞间黏附分子-1水平的影响相似。HSC70预适应对心肌TLR4蛋白水平无影响，但可抑制内毒素诱导的NF-κB活化。我们的结论是，HSC70预适应1)减轻巨噬细胞对内毒素的肿瘤坏死因子-α反应，2)诱导心功能对内毒素的耐受，3)降低核因子-κB活性，降低心肌组织中肿瘤坏死因子-α和细胞间黏附分子-1的水平。因此，HSC70诱导的心脏对内毒素耐受的机制似乎涉及下调心肌TLR4信号和炎症反应。
Endotoxin provokes cardiac dysfunction, and induction of tolerance to endotoxin has therapeutic potential. Heat shock protein 70 (HSP70) can induce endotoxin tolerance in macrophages. We recently found that heat shock cognate protein 70 (HSC70) induces pro-inflammatory cytokines via activation of TLR4 in macrophages and the myocardium. We hypothesize that HSC70 preconditioning induces cardiac tolerance to endotoxin. Pretreatment of peritoneal macrophages with HSC70 for 24 h reduced TNF-α levels following endotoxin stimulation. Preconditioning of mice with HSC70 24 h prior to endotoxin attenuated endotoxemic cardiac dysfunction. HSC70 preconditioning reduced TNF-α levels in plasma and heart tissue by 33.3% and 35.4%, respectively, and decreased ICAM-1 levels in heart tissue by 63.5% following endotoxin challenge. The effect of HSC70 on TNF-α was less robust than endotoxin preconditioning (79.7% and 75.0% reduction in TNF-α levels in plasma and heart tissue, respectively); however, HSC70 and endotoxin preconditioning had comparable effects on ICAM-1 levels in heart tissue. While HSC70 preconditioning had no effect on myocardial TLR4 protein levels, it suppressed NF-κB activation induced by endotoxin. We conclude that HSC70 preconditioning 1) attenuates the TNF-α response to endotoxin in macrophages in vitro, 2) induces cardiac functional tolerance to endotoxin and 3) reduces NF-κB activity, and TNF-α and ICAM-1 levels in heart tissue. Thus, the mechanism of HSC70-induced cardiac tolerance to endotoxin appears to involve down-regulation of myocardial TLR4 signaling and inflammatory responses.
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