Distinction between interleukin-1-induced necrosis and apoptosis of islet cells

Interleukin (IL)-1 beta is known to cause beta -cell death in isolated rat islets. This effect has been attributed to induction of nitric oxide (NO) s ynthase in beta -cells and subsequent generation of toxic NO levels; it was not observed, however, in dispersed rat beta -cells. The present study dem onstrates that IL-1 beta induces NO-dependent necrosis in rat beta -cells c ultured for 3 days at high cell density or in cell aggregates but not as si ngle cells. Its cytotoxic condition is not explained by higher NO productio n rates but might result from higher intercellular NO concentrations in sta tically cultured cell preparations with cell-to-cell contacts; nitrite leve ls in collected culture medium are not a reliable index for these intercell ular concentrations. Absence of IL-1-induced necrosis in rat alpha -cells o r in human beta -cells is attributed to the cytokine's failure to generate NO in these preparations, not to their reduced sensitivity to NO: the NO do nor GEA 3162 (15 min, 50-100 mu mol/l) exerts a comparable necrotic effect in rat and human alpha- or beta -cells. In preparations in which IL-1 beta does mot cause beta -cell necrosis, its combination with gamma -interferon (IFN-gamma) results in NO-independent apoptosis, starting after 3 days and increasing with the duration of exposure. Because IFN-gamma alone was apopt otic far rat alpha -cells, it is proposed that IL-1 beta can make beta -cel ls susceptible to this effect, conceivably through altering their phenotype . It is concluded that IL-1 beta can cause NO-dependent necrosis or NO-inde pendent apoptosis of islet cells, depending on the species and on the envir onmental conditions. The experiments in isolated human beta -cell preparati ons suggest that these cells may preferentially undergo apoptosis when expo sed to IL-1 beta plus IFN-gamma unless neighboring non-beta -cells produce toxic NO levels.