JNK1/c-fos inhibits cardiomyocyte TNF- expression via a negative crosstalk with ERK and p38 MAPK in endotoxaemia

Abstract

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.