LPS-Induced TNF-α release from and apoptosis in rat cardiomyocytes:: Obligatory role for CD14 in mediating the LPS response
LPS-Induced TNF-α release from and apoptosis in rat cardiomyocytes:: Obligatory role for CD14 in mediating the LPS response
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DOI：
10.1006/jmcc.1998.0851
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发表时间：
1998-12-01
影响因子：
5
通讯作者：
Sabbadini, RA
中科院分区：
文献类型：
--
作者：
Comstock, KL;Krown, KA;Sabbadini, RA
细菌内毒素脂多糖（LPS）有助于心血管衰竭和死亡观察败血症患者。由于LPS对心脏功能有如此深远的影响，我们推测LPS的直接作用可以在培养的心肌细胞上证明，并且这些直接作用是由LPS受体CD 14介导的。因此，在这项研究中，我们提供的证据CD 14依赖性的LPS的心脏毒性作用，包括LPS刺激的分泌肿瘤坏死因子α（TNF-α）从心肌细胞。TNF-α是一种炎症细胞因子，因其对心脏功能的负性肌力作用而闻名，但直到最近才显示出由心脏细胞产生。在这项研究中，发现LPS以剂量依赖性方式强烈刺激培养的成年大鼠心肌细胞分泌TNF-α。此外，LPS诱导的TNF-α分泌被TNF-α加工金属基质蛋白酶抑制剂（TAPI）的抑制剂阻断。分子和免疫学证据表明心肌细胞上存在LPS受体（CD 14）。PI-PLC治疗后TNF-α分泌减弱证实了CD 14对LPS介导的心肌效应的功能重要性。重要的是，LPS还引发了培养的心肌细胞中的细胞凋亡，如通过细胞核的单细胞凝胶电泳所定量的，细胞核表现出细胞凋亡特征性的DNA片段化模式（即心脏彗星）。通过与可溶性TNF-α受体片段（TNFRII：Fc）预孵育阻断凋亡细胞死亡，表明LPS诱导的凋亡是TNF-α依赖性的，并且可能涉及TNF-α的自分泌功能，其分泌受LPS控制。本研究的结果表明，LPS的心肌保护作用依赖于CD 14信号传导，可能不仅是由于TNE-α的急性负性肌力作用，而且可能与TNF-α诱导的细胞凋亡有关，后者有效地减少了工作心肌细胞的数量。(C)北京：科学出版社.
The bacterial endotoxin lipopolysaccharide (LPS) contributes to the cardiovascular collapse and death observed in patients with sepsis. Because LPS has such profound effects on cardiac performance, we speculate that direct effects of LPS could be demonstrated on cardiomyocytes in culture, and that these direct effects are mediated by the LPS receptor, CD14. Accordingly, in this study, we provide evidence for CD14-dependent cardiotoxic effects of LPS including the LPS-stimulated secretion of tumor necrosis factor alpha (TNF-alpha) from cardiomyocytes. TNF-alpha is an inflammatory cytokine which is renown for its negative inotropic effects on cardiac performance, but has not until recently been shown to be produced by cardiac cells. In this study, LPS was found to stimulate strongly in a dose-dependent manner the secretion of TNF-alpha from cultured adult rat cardiomyocytes. Further, LPS-induced TNF-alpha secretion was blocked by an inhibitor of TNF-alpha processing metallomatrix protease inhibitor (TAPI). Molecular and immulogical evidence demonstrated the presence of LPS receptors (CD14) on cardiomyocytes. Attenuated TNF-alpha secretion following PI-PLC treatment confirmed the functional importance of CD14 for LPS-mediated myocardial effects. Importantly, LPS also triggered apoptosis in cultured cardiomyocytes as quantified by single-cell gel electrophoresis of nuclei exhibiting DNA fragmentation patterns characteristic of apoptosis (i.e. cardiac comets). Apoptotic cell death was blocked by pre-incubation with the soluble TNF-alpha receptor fragment (TNFRII:Fc), suggesting that LPS-induced apoptosis was TNF-alpha-dependent and probably involved an autocrine function for the TNF-alpha whose secretion was under LPS control. The results of this study suggest that the cardiodepressant effects of LPS are dependent on CD14 signaling and may not only be due to acute negative inotropic effects of TNE-alpha but also may be complicated by TNF-alpha-induced apoptotic cell death which effectively reduces the number of working myocardial cells. (C) 1998 Academic Press.