Synergistic activation of JNK/SAPK induced by TNF-alpha and IFN-gamma: apoptosis of pancreatic beta-cells via the p53 and ROS pathway

Cell Signal. 2005 Dec;17(12):1516-32. doi: 10.1016/j.cellsig.2005.03.020.


IFN-gamma and TNF-alpha are major proinflammatory cytokines implicated in islet beta-cell destruction, which results in type-1 diabetes; however, the underlying mechanism is not clear. Using pancreatic beta-cell line MIN6N8 cells, co-treatment with TNF-alpha and IFN-gamma, but neither cytokine alone, synergistically induced apoptosis, correlated with the activation of the JNK/SAPK, which resulted in the production of reactive oxidative species (ROS) and loss of mitochondrial transmembrane potential (delta psi m). Additionally, cells transfected with wild-type JNK1 became more susceptible to apoptosis induced by TNF-alpha/IFN-gamma through ROS production and loss of delta psi m, while cascading apoptotic events were prevented in dominant-negative JNK1-transfected or JNK inhibitor SP600125-treated cells. As the antioxidant, N-acetyl-cysteine, failed to completely suppress apoptosis induced by TNF-alpha/IFN-gamma, an additional pathway was considered to be involved. The level of p53 was significantly increased through synergistic activation of JNK by TNF-alpha/IFN-gamma. Furthermore, the synergistic effect of TNF-alpha/IFN-gamma on apoptosis and ROS production was further potentiated by the overexpression of wild-type p53, but not with mutant p53. This synergistic activation of JNK/SAPK by TNF-alpha/IFN-gamma was also induced in insulin-expressing pancreatic islet cells, and increased ROS production and p53 level, which was significantly inhibited by SP600125. Collectively, these data demonstrate that TNF-alpha/IFN-gamma synergistically activates JNK/SAPK, playing an important role in promoting apoptosis of pancreatic beta-cell via activation of p53 pathway together with ROS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anthracenes / pharmacology
  • Apoptosis
  • Caspase 3
  • Caspases / metabolism
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Insulin-Secreting Cells / metabolism*
  • Interferon-gamma / physiology*
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • MAP Kinase Signaling System*
  • Membrane Potentials
  • Mice
  • Mice, Inbred ICR
  • Mice, Inbred NOD
  • Mitochondria / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species / metabolism*
  • Transfection
  • Tumor Necrosis Factor-alpha / physiology*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • bcl-X Protein / metabolism


  • Anthracenes
  • Bcl2l1 protein, mouse
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Protein p53
  • bcl-X Protein
  • Bcl2 protein, mouse
  • pyrazolanthrone
  • Interferon-gamma
  • JNK Mitogen-Activated Protein Kinases
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases