Cytokines are thought to contribute to the induction of pancreatic beta-cell destruction in insulin-dependent diabetes mellitus. The molecular mechanisms that underlie beta-cell death were investigated by studying cytokine-induced cell death in beta-cell lines. A combination of three cytokines (interleukin-1, tumour necrosis factor-, and interferon-) induced apoptotic cell death in the mouse pancreatic beta-cell line TC1, as judged from the appearance of cells with hypodiploid nuclei and oligonucleosomal DNA fragmentation. The same treatment also induced apoptosis in the mouse pancreatic alpha-cell line TC1 and the NOD/Lt mouse beta-cell line NIT-1, although to a lesser extent than in TC1 cells. The abundance of endogenous Bcl-2 in TC1 cells was lower than that in the other two cell lines. Overexpression of human Bcl-2 in TC1 cells partially protected them from cytokine-induced cell death. These results suggest that apoptosis may be responsible, at least in part, for cytokine-induced beta-cell destruction and that Bcl-2 prevents apoptosis in pancreatic islet cells.