JNK1/c-fos inhibits cardiomyocyte TNF-α expression via a negative crosstalk with ERK and p38 MAPK in endotoxaemia
JNK1/c-fos inhibits cardiomyocyte TNF-α expression via a negative crosstalk with ERK and p38 MAPK in endotoxaemia
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DOI：
10.1093/cvr/cvn336
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发表时间：
2009-03-01
影响因子：
10.8
通讯作者：
Feng, Qingping
中科院分区：
文献类型：
--
作者：
Peng, Tianqing;Zhang, Ting;Feng, Qingping
心肌肿瘤坏死因子-α(TNF-α)的产生在脓毒症时心功能不全中起重要作用。本研究旨在探讨c-Jun NH2末端激酶(JNK)信号转导通路在脂多糖(LPS)刺激下心肌细胞TNF-α表达和内毒素血症心肌功能中的作用。在培养的新生小鼠心肌细胞中，JNK1的缺失或JNK1信号转导通路的选择性抑制增强了内毒素诱导的细胞外信号调节激酶(ERK)1/2和p38丝裂原活化蛋白激酶(MAPK)的磷酸化水平。在器官水平上，与野生型相比，内毒素诱导的肿瘤坏死因子-α在JNK1(-/-)中的表达显著增加。脂多糖激活JNK1也可诱导心肌细胞c-fos的表达，该作用可被抑制JNK1信号通路所阻断。在培养的c-fos(-/-)心肌细胞和分离的c-fos(-/-)心肌细胞上，研究c-fos表达在脂多糖诱导的肿瘤坏死因子-α表达中的作用。C-fos基因缺失可显著增加内毒素诱导的心肌细胞和心脏组织中肿瘤坏死因子-α的表达。C-fos的过度表达降低了脂多糖刺激的心肌细胞中肿瘤坏死因子-α的表达，这与ERK1/2和p38的磷酸化减少有关。在内毒素血症小鼠中，与相应的野生型对照相比，JNK1或c-fos的缺失进一步降低了心功能。JNK1/c-fos抑制ERK1/2和p38MAPK信号转导，导致内毒素血症时心肌细胞TNF-α表达减少，心功能改善。
Myocardial tumour necrosis factor-alpha (TNF-alpha) production plays an important role in cardiac dysfunction during sepsis. The aim of this study was to investigate the role of c-Jun NH2-terminal kinases (JNK) signalling in cardiomyocyte TNF-alpha expression during lipopolysaccharide (LPS) stimulation and myocardial function in endotoxaemic mice.In cultured neonatal mouse cardiomyocytes, deficiency of JNK1 or selective inhibition of JNK1 signalling by over-expression of a dominant negative mutant of JNK1 enhanced LPS-induced TNF-alpha expression, which was associated with elevations in phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK). At the organ level, LPS-induced TNF-alpha expression was significantly increased in JNK1(-/-) compared with wild-type hearts. JNK1 activation by LPS also induced immediate c-fos expression in cardiomyocytes, which was blocked by inhibition of JNK1 signalling. The role of c-fos expression in LPS-induced TNF-alpha expression was investigated in both cultured c-fos(-/-) cardiomyocytes and isolated c-fos(-/-) hearts. Deficiency of c-fos significantly enhanced LPS-induced TNF-alpha expression in cardiomyocytes and isolated hearts. Over-expression of c-fos decreased TNF-alpha expression in LPS-stimulated cardiomyocytes, which was associated with a decrease in phosphorylation of ERK1/2 and p38. In mice with endotoxaemia, deficiency of either JNK1 or c-fos further decreased cardiac function compared with corresponding wild-type controls.JNK1/c-fos inhibits ERK1/2 and p38 MAPK signalling, leading to decreased cardiomyocyte TNF-alpha expression and improvements in cardiac function during endotoxaemia.