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首页> 外文期刊>American Journal of Physiology >Endotoxin stress-response in cardiomyocytes: NF-kappaB activation and tumor necrosis factor-alpha expression.
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Endotoxin stress-response in cardiomyocytes: NF-kappaB activation and tumor necrosis factor-alpha expression.

机译：心肌细胞内毒素应激反应：NF-κB激活和肿瘤坏死因子-α表达。

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摘要

Although tumor necrosis factor (TNF)-alpha is implicated in numerous cardiac pathologies, the intracellular events leading to its production by heart cells are largely unknown. The goal of the present study was to identify the role of the transcription factor nuclear factor (NF)-kappaB in this process. Among the many inducers of TNF-alpha expression in myeloid cells, only lipopolysaccharide (LPS) led to its induction in cultured neonatal myocytes. LPS also activated the NF-kappaB pathway, as evidenced by the degradation of the inhibitory protein IkappaB and the appearance of NF-kappaB-binding complexes in nuclear extracts. Furthermore, inhibitors of NF-kappaB activation, such as lactacystin, MG132, and pyrrolidine dithiocarbamate, were found to completely block the production of TNF-alpha in response to LPS stimulation, indicating a requirement of NF-kappaB for TNF-alpha expression. However, interleukin-1beta and phorbol 12-myristate 13-acetate also activated NF-kappaB but did not evoke TNF-alpha expression, revealing that this factor is not sufficient for cytokine production. Detailed examination of the NF-kappaB cascade revealed that cardiac cells displayed a unique pattern of IkappaB degradation in response to LPS, with IkappaBbeta but not IkappaBalpha being degraded upon stimulation. Additionally, two specific p65-containing DNA-binding complexes were observed in the nuclear extracts of neonatal cardiomyocytes: an inducible complex that is necessary for TNF-alpha expression and a constitutive species. Taken together, these results reveal that NF-kappaB is not only involved in cytokine production but also may be linked to other pathways that subserve a constitutive, protective mechanism for the heart cell.
机译：尽管肿瘤坏死因子（TNF）-α涉及许多心脏疾病，但导致心脏细胞产生其的细胞内事件在很大程度上尚不清楚。本研究的目的是确定转录因子核因子（NF）-κB在此过程中的作用。在髓样细胞中多种TNF-α表达诱导剂中，只有脂多糖（LPS）导致其在培养的新生儿肌细胞中诱导。 LPS还激活了NF-kappaB途径，如抑制蛋白IkappaB的降解和核提取物中NF-kappaB结合复合物的出现所证明。此外，发现NF-κB活化的抑制剂，例如乳胞素，MG132和吡咯烷二硫代氨基甲酸酯，可以完全阻断LPS刺激而产生TNF-α，这表明需要NF-κB来表达TNF-α。但是，白介素-1β和佛波醇12-肉豆蔻酸酯13-乙酸酯也激活NF-κB，但没有引起TNF-α表达，表明该因子不足以产生细胞因子。 NF-kappaB级联的详细检查显示，心肌细胞在响应LPS时显示出独特的IkappaB降解模式，刺激后IkappaBbeta降解，但IkappaBalpha降解。此外，在新生儿心肌细胞的核提取物中观察到两种含p65的特定DNA结合复合物：TNF-α表达所必需的可诱导复合物和组成型物质。综上所述，这些结果表明，NF-κB不仅参与细胞因子的产生，而且可能与其他为心脏细胞提供组成型保护机制的途径相关。

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