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Distinction Between Interleukin-1–Induced Necrosis and Apoptosis of Islet Cells

Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium

Interleukin (IL)-1ß is known to cause ß-cell death in isolated rat islets. This effect has been attributed to induction of nitric oxide (NO) synthase in ß-cells and subsequent generation of toxic NO levels; it was not observed, however, in dispersed rat ß-cells. The present study demonstrates that IL-1ß induces NO-dependent necrosis in rat ß-cells cultured for 3 days at high cell density or in cell aggregates but not as single cells. Its cytotoxic condition is not explained by higher NO production rates but might result from higher intercellular NO concentrations in statically cultured cell preparations with cell-to-cell contacts; nitrite levels in collected culture medium are not a reliable index for these intercellular concentrations. Absence of IL-1–induced necrosis in rat -cells or in human ß-cells is attributed to the cytokine’s failure to generate NO in these preparations, not to their reduced sensitivity to NO: the NO donor GEA 3162 (15 min, 50–100 µmol/l) exerts a comparable necrotic effect in rat and human - or ß-cells. In preparations in which IL-1ß does not cause ß-cell necrosis, its combination with -interferon (IFN-) results in NO-independent apoptosis, starting after 3 days and increasing with the duration of exposure. Because IFN- alone was apoptotic for rat -cells, it is proposed that IL-1ß can make ß-cells susceptible to this effect, conceivably through altering their phenotype. It is concluded that IL-1ß can cause NO-dependent necrosis or NO-independent apoptosis of islet cells, depending on the species and on the environmental conditions. The experiments in isolated human ß-cell preparations suggest that these cells may preferentially undergo apoptosis when exposed to IL-1ß plus IFN- unless neighboring non–ß-cells produce toxic NO levels.

Abbreviations: HO 342, Hoechst 33342; IFN-, -interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; NO, nitric oxide; PI, propidium iodide; TNF, tumor necrosis factor

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