Hoorens A, Stangé G, Pavlovic D, Pipeleers D
Diabetes Research Center, Vrije Universiteit Brussel, Belgium.
Diabetes. 2001 Mar;50(3):551-7. doi: 10.2337/diabetes.50.3.551.
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.
白细胞介素（IL）-1β已知可导致分离的大鼠胰岛中的β细胞死亡。这种作用归因于β细胞中一氧化氮（NO）合酶的诱导以及随后产生的毒性NO水平；然而，在分散的大鼠β细胞中未观察到这种现象。本研究表明，IL-1β在高细胞密度培养3天的大鼠β细胞或细胞聚集体中诱导NO依赖性坏死，但在单细胞中不诱导。其细胞毒性情况不能用更高的NO产生率来解释，而可能是由于在具有细胞间接触的静态培养细胞制剂中细胞间NO浓度更高；收集的培养基中的亚硝酸盐水平不是这些细胞间浓度的可靠指标。大鼠α细胞或人β细胞中不存在IL-1诱导的坏死归因于细胞因子在这些制剂中未能产生NO，而不是它们对NO的敏感性降低：NO供体GEA 3162（15分钟，50 - 100微摩尔/升）在大鼠和人α或β细胞中产生类似的坏死作用。在IL-1β不引起β细胞坏死的制剂中，其与γ干扰素（IFN-γ）联合可导致NO非依赖性凋亡，从3天后开始并随着暴露时间延长而增加。由于单独的IFN-γ对大鼠α细胞具有凋亡作用，因此提出IL-1β可能通过改变其表型使β细胞易受这种作用影响。结论是，IL-1β可导致胰岛细胞的NO依赖性坏死或NO非依赖性凋亡，这取决于物种和环境条件。在分离的人β细胞制剂中的实验表明，这些细胞在暴露于IL-1β加IFN-γ时可能优先发生凋亡，除非相邻的非β细胞产生毒性NO水平。
