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

Cardiovasc Res. 2009 Mar 1;81(4):733-41. doi: 10.1093/cvr/cvn336. Epub 2008 Nov 29.


Aims: 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.

Methods and results: 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.

Conclusion: JNK1/c-fos inhibits ERK1/2 and p38 MAPK signalling, leading to decreased cardiomyocyte TNF-alpha expression and improvements in cardiac function during endotoxaemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • Disease Models, Animal
  • Endotoxemia / chemically induced
  • Endotoxemia / metabolism*
  • Endotoxemia / physiopathology
  • Hemodynamics
  • Janus Kinase 1 / deficiency
  • Janus Kinase 1 / genetics
  • Janus Kinase 1 / metabolism*
  • Lipopolysaccharides
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Mutation
  • Myocytes, Cardiac / enzymology*
  • Phosphorylation
  • Proto-Oncogene Proteins c-fos / deficiency
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction*
  • Transduction, Genetic
  • Tumor Necrosis Factor-alpha / metabolism*
  • Ventricular Function, Left
  • Ventricular Pressure
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Lipopolysaccharides
  • Proto-Oncogene Proteins c-fos
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • Jak1 protein, mouse
  • Janus Kinase 1
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases