Van de Casteele Mark, Kefas Benjamin Ate, Ling Zhidong, Heimberg Harry, Pipeleers Daniel G
Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium.
Endocrinology. 2002 Jan;143(1):320-6. doi: 10.1210/endo.143.1.8574.
Cytokines have been implicated in the process of pancreatic beta-cell destruction that leads to type 1 diabetes. This study investigates the beta-cell expression of pro- and antiapoptotic proteins from the Bcl-2 family and their variation during cytokine-mediated apoptosis. Exposure of rat beta-cells to the combination of IL-1beta plus interferon-gamma causes a time-dependent increase in apoptotic cells starting after 3 d (<10% on d 3 and 28 +/- 2% on d 7). This effect was preceded by a marked down-regulation of two antiapoptotic proteins, Bcl-2 and Bax-omega (respectively reduced by 60% and 80% after 3 d), whereas no changes occurred in the expression of Bcl-x(L) and the proapoptotic protein Bax-alpha. No apoptosis or down-regulation of Bcl-2 and Bax-omega proteins was observed with individual cytokines or in the presence of N-methyl-L-arginine, an inhibitor of nitric oxide synthase. The lowered Bcl-2 protein content was associated with a decrease in Bcl-2 mRNA, which was initiated after 24 h of exposure. In MIN6 cells, the cytokine-induced suppression of Bcl-2- and Bax-omega, and apoptosis, occurred within 24 h. Primary rat beta-cells exhibited a higher expression of Bax-omega than MIN6 cells or than other rat cell types. These data suggest that suppression of the antiapoptotic proteins Bcl-2 and Bax-omega mediates cytokine-induced apoptosis of beta-cells. The beta-cell-specific expression of Bax-omega makes this protein a possible effector in the protection of this cell type against apoptosis.
细胞因子与导致1型糖尿病的胰腺β细胞破坏过程有关。本研究调查了Bcl-2家族促凋亡和抗凋亡蛋白在β细胞中的表达及其在细胞因子介导的凋亡过程中的变化。将大鼠β细胞暴露于白细胞介素-1β加干扰素-γ的组合中，会导致凋亡细胞数量随时间增加，从第3天开始（第3天<10%，第7天为28±2%）。在这种效应之前，两种抗凋亡蛋白Bcl-2和Bax-ω明显下调（3天后分别降低60%和80%），而Bcl-x(L)和促凋亡蛋白Bax-α的表达没有变化。单独使用细胞因子或在一氧化氮合酶抑制剂N-甲基-L-精氨酸存在的情况下，未观察到凋亡或Bcl-2和Bax-ω蛋白的下调。Bcl-2蛋白含量降低与Bcl-2 mRNA减少有关，这种减少在暴露24小时后开始。在MIN6细胞中，细胞因子诱导的Bcl-2和Bax-ω抑制以及凋亡在24小时内发生。原代大鼠β细胞中Bax-ω的表达高于MIN6细胞或其他大鼠细胞类型。这些数据表明，抗凋亡蛋白Bcl-2和Bax-ω的抑制介导了细胞因子诱导的β细胞凋亡。Bax-ω在β细胞中的特异性表达使其成为保护这种细胞类型免于凋亡的可能效应分子。
