Interferon-gamma induces interleukin-1 converting enzyme expression in pancreatic islets by an interferon regulatory factor-1-dependent mechanism

Whereas nitric oxide (NO) production is associated with the toxic effect of cytokines on rodent pancreatic beta-cells, cytokine-induced apoptosis in h uman islets may occur independently of NO. The cysteine protease interleuki n (IL)-1 converting enzyme (ICE) is a key proapoptotic caspase. Our aim was therefore to analyze the effect of cytokines on ICE expression in human, r at, and mouse islets and rat insulinoma cells. ICE messenger RNA (mRNA) expression was highly up-regulated after 6-, 24-, and 72-h exposure of human islets to interferon (IFN)gamma, tumor necrosis factor (TNF)alpha + IFN gamma or IL-1 beta + TNF alpha + IFN gamma, paralle led by increased iNOS (the inducible form of NO synthase) expression and NO production after exposure to the combined cytokines but not to IFN gamma o r TNF alpha + IFN gamma. Cytokine-induced NO-independent ICE transcription was confirmed using iNOS inhibitors. Exposure of rat and mouse islets, or rat insulinoma cells, for 24 h to IFN gamma alone or in combination with the two other cytokines also resulted in a highly significant ICE mRNA expression. ICE transcription was not induci ble in islets from IFN regulatory factor-1 knock-out mice, suggesting a key -role of this transcription-factor in cytokine-mediated TCE expression in p ancreatic islets. In conclusion, cytokines and IFN gamma in particular increase ICE mRNA expr ession in pancreatic islet cells and beta-cell lines, independently of NO s ynthesis, suggesting that ICE up-regulation may be involved in cytokine-ind uced NO-independent; apoptosis of human islets.