Distinction between interleukin-1-induced necrosis and apoptosis of islet cells.
Interleukin (IL)-1beta is known to cause beta-cell death in isolated rat islets. This effect has been attributed to induction of nitric oxide (NO) synthase in beta-cells and subsequent generation of toxic NO levels; it was not observed, however, in dispersed rat beta-cells. The present study demonstrates that IL-1beta induces NO-dependent necrosis in rat beta-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 alpha-cells or 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 donor GEA 3162 (15 min, 50-100 micromol/l) exerts a comparable necrotic effect in rat and human alpha- or beta-cells. In preparations in which IL-1beta does not 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 apoptotic for rat alpha-cells, it is proposed that IL-1beta can make beta-cells susceptible to this effect, conceivably through altering their phenotype. It is concluded that IL-1beta 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 beta-cell preparations suggest that these cells may preferentially undergo apoptosis when exposed to IL-1beta plus IFN-gamma unless neighboring non-beta-cells produce toxic NO levels.
Diabetes Research Center, Vrije Universiteit Brussel, Belgium.
A
A
Hoorens
G
G
Stangé
D
D
Pavlovic
D
D
Pipeleers
D000818:Animals; D017209:Apoptosis; D002449:Cell Aggregation; D002452:Cell Count; D002478:Cells, Cultured; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D008297:Male; D009336:Necrosis; D009569:Nitric Oxide / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D007375:Interleukin-1; D009569:Nitric Oxide