Cytotoxic effect of IFN-γ plus TNF-α on human islet cells

Abstract We have previously reported that the combination of IFN-γ plus TNF-α is able to induce the de novo expression of HLA class II on human β cells. In the present study, we have investigated the effect of these cytokines, alone or in combination, on the function and viability of human islet cells in vitro . Three hour insulin release was markedly reduced in human islet monolayer cultures after 4 days' exposure to 1000 U/ml of the combination TNF-α plus IFN-γ (36.7 ± 7.7, % of the control ± SEM) or to TNF-α alone (49.5 ± 7% of the control) while IFN-γ had little effect. On direct inspection cell damage was clearly detected only in the cultures treated with TNF-α plus IFN-γ in which staining by indirect immunofluorescence (IFL) for insulin revealed that the number of β cells was also significantly reduced, thus suggesting a real cytotoxic effect of this cytokine combination. This effect was not β cell specific since glucagon release and the number of α cells were also reduced in the cultures exposed to IFN-γ plus TNF-α. 51 Cr release experiments supported the cytoxicity of these cytokines to normal islet cells. There was a time course relationship between class II induction (2 days) and the cytotoxic effect of IFN-γ plus TNF-α (4 days) on the same islet cells. In conclusion, these results indicate that the combination of IFN-γ and TNF-α exerts a cytotoxic effect on human islet cells in vitro .