TNFalpha and IFNgamma potentiate IL-1beta induced mitogen activated protein kinase activity in rat pancreatic islets of Langerhans.
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.[1]References
- TNFalpha and IFNgamma potentiate IL-1beta induced mitogen activated protein kinase activity in rat pancreatic islets of Langerhans. Andersen, N.A., Larsen, C.M., Mandrup-Poulsen, T. Diabetologia (2000) [Pubmed]
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