Dunger A, Schröder D, Augstein P, Witstruck T, Wachlin G, Vogt L, Ziegler B, Schmidt S
Institute of Diabetes Gerhardt Katsch, University of Greifswald, Karlsburg, Germany.
Acta Diabetol. 1995 Dec;32(4):217-24. doi: 10.1007/BF00576253.
The influence of beta cell activity on cytokine-induced functional and structural impairments as well as the ability of those damaged cells to recover were investigated. Rat islets cultured for 4 days in the presence of 5, 10, and 30 mmol/l glucose were exposed to interferon-gamma (IFN, 500 U/ml) and tumor necrosis factor-alpha (TNF, 250 U/ml) for the last 24 h. After cytokine removal islets were allowed to recover spontaneously in culture medium containing 10 mmol/l glucose for a further 7 days. Cytokines significantly inhibited insulin release into culture medium, insulin storage, glucose-stimulated insulin secretion, protein, and DNA synthesis. In the presence of cytokines there was a six- to eightfold increase in nitrite production by the islets. The functional impairments were more pronounced in metabolically stimulated beta cells. In addition, cytokines caused membrane alterations as indicated by increased spontaneous chromium-51 release. The cytokines specifically induced the synthesis of two proteins (72 and 88 kDa, respectively). By immunoblotting, the 72-kDa protein was identified as heat shock protein. After a 1-week recovery period, insulin storage and stimulated insulin secretion of cytokine-treated islets were still significantly diminished. However, protein and DNA synthesis of cytokine-exposed islets returned to pre-exposure levels. In conclusion, high beta cell activity increases islet susceptibility to TNF+IFN. Cytokine-induced, long-lasting, inhibitory effects are primarily directed to beta-cell-specific functions, while general vital cell functions clearly recover after cytokine removal. The induction of certain proteins and the increased protein synthesis and replication rate after cytokine removal might reflect activated repair processes.
研究了β细胞活性对细胞因子诱导的功能和结构损伤的影响，以及这些受损细胞的恢复能力。将在5、10和30 mmol/l葡萄糖存在下培养4天的大鼠胰岛在最后24小时暴露于γ干扰素（IFN，500 U/ml）和肿瘤坏死因子-α（TNF，250 U/ml）。去除细胞因子后，胰岛在含有10 mmol/l葡萄糖的培养基中再自发恢复7天。细胞因子显著抑制胰岛素释放到培养基中、胰岛素储存、葡萄糖刺激的胰岛素分泌、蛋白质和DNA合成。在细胞因子存在的情况下，胰岛亚硝酸盐生成增加了6至8倍。代谢刺激的β细胞功能损伤更明显。此外，细胞因子导致膜改变，表现为自发的51铬释放增加。细胞因子特异性诱导两种蛋白质（分别为72 kDa和88 kDa）的合成。通过免疫印迹法，72 kDa的蛋白质被鉴定为热休克蛋白。经过1周的恢复期后，细胞因子处理的胰岛的胰岛素储存和刺激的胰岛素分泌仍然显著减少。然而，暴露于细胞因子的胰岛的蛋白质和DNA合成恢复到暴露前水平。总之，高β细胞活性增加了胰岛对TNF + IFN的敏感性。细胞因子诱导的长期抑制作用主要针对β细胞特异性功能，而在去除细胞因子后，一般的重要细胞功能明显恢复。细胞因子去除后某些蛋白质的诱导以及蛋白质合成和复制率的增加可能反映了激活的修复过程。
