TNFalpha and IFNgamma potentiate IL-1beta induced mitogen activated protein kinase activity in rat pancreatic islets of Langerhans

Diabetologia. 2000 Nov;43(11):1389-96. doi: 10.1007/s001250051544.


Aims/hypothesis: Interleukin-1 beta (IL-1beta) in synergy with tumour necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma) is cytotoxic to pancreatic beta cells. Mitogen-activated protein kinase (MAPK) activity that is induced by interleukin-1 beta has been suggested to signal nitric oxide-dependent as well as nitric oxide-independent beta-cell destructive pathways. The aim of this study was to investigate if TNFalpha and IFNgamma signal through mitogen-activated protein kinases in isolated rat islets of Langerhans and if they potentiate mitogen-activated protein kinase activity induced by IL-1beta.

Methods: Islets of Langerhans were isolated from 5- to 7-day-old Wistar rats and precultured for 7 days before stimulation with IL-1beta, TNFalpha and/or IFNgamma for 20 min followed by lysis. Kinase activity was measured with a whole cell lysate kinase assay and after immunoprecipitation of the kinase using immunocomplex kinase assay.

Results: Exposure to IL-1beta or TNFalpha significantly increased mitogen-activated protein kinase activity, whereas IFNgamma tended to decrease extracellular-signal-regulated kinase activity. Further, TNFalpha and IFNgamma were found to synergistically increase mitogen-activated protein kinase activity induced by IL-1beta.

Conclusion/interpretation: We hypothesise that the synergistic effect of IL-1beta, TNFalpha and IFNgamma in the functional inhibition and induction of cell death in pancreatic beta cells is signalled through a synergistic activation of mitogen-activated protein kinase activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 2
  • Animals
  • Cell Death
  • Culture Techniques
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • DNA-Binding Proteins*
  • Drug Synergism
  • Enzyme Induction
  • HSP27 Heat-Shock Proteins
  • Heat-Shock Proteins*
  • Humans
  • Immunosorbent Techniques
  • Interferon-gamma / pharmacology*
  • Interleukin-1 / pharmacology*
  • Islets of Langerhans / enzymology*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neoplasm Proteins / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins / metabolism
  • Rats
  • Rats, Inbred WF
  • Signal Transduction
  • Transcription Factors / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology*
  • ets-Domain Protein Elk-1


  • Activating Transcription Factor 2
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Elk1 protein, rat
  • HSP27 Heat-Shock Proteins
  • HSPB1 protein, human
  • Heat-Shock Proteins
  • Hspb1 protein, rat
  • Interleukin-1
  • Neoplasm Proteins
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • ets-Domain Protein Elk-1
  • Interferon-gamma
  • Mitogen-Activated Protein Kinases