Mehta V, Hao W, Brooks-Worrell B M, Palmer J P
Veterans Affairs Medical Center, Seattle, WA.
Lymphokine Cytokine Res. 1993 Aug;12(4):255-9.
Insulin-dependent diabetes is an autoimmune disease specifically targeting the pancreatic beta cells and several observations, both experimental and clinical, suggest that the interaction of the immune system with the beta cells is in part determined by the functional state of the target cells, increased beta cell activity resulting in augmented immunologic mechanisms and vice versa for suppressed beta cell activity and decreased immune attack. In this study we investigated whether cytokine induced islet cell cytotoxicity in vitro was in part dependent on the functional state of the beta cells. Cytotoxicity of cultured rat islets was induced by IL-1 (100 pg/ml) and TNF (62.5 ng/ml) individually and in combination and beta cell activity was modulated by culturing the islets in media containing 3.3, 5.5, 11, and 20 mmol/liter glucose. Both IL-1 and TNF were cytotoxic when administered individually and the combination of IL-1 and TNF was more cytotoxic than either cytokine alone. Maximum cytotoxicity was observed at 11 mmol/liter glucose with cytotoxicity being reduced at 5.5 mmol/liter glucose and further reduced at 3.3 mmol/liter glucose. Interestingly, the degree of cytotoxicity was lower in 20 mmol/liter glucose compared to 11 mmol/liter. These results firmly establish that islet cytotoxicity of IL-1 and TNF is highly dependent on the functional state of the beta cells. This suggests that during the IDDM disease process as some beta cells are destroyed, the compensatory increased activity of the remaining beta cells may increase their susceptibility to cytokine attack. Furthermore, our observations provide rational support for the use of beta cell rest as intervention therapy for IDDM.
胰岛素依赖型糖尿病是一种特异性靶向胰腺β细胞的自身免疫性疾病，一些实验和临床观察表明，免疫系统与β细胞的相互作用部分取决于靶细胞的功能状态，β细胞活性增加会导致免疫机制增强，反之，β细胞活性受抑制则免疫攻击减少。在本研究中，我们调查了细胞因子在体外诱导的胰岛细胞毒性是否部分取决于β细胞的功能状态。分别单独及联合使用白细胞介素-1（100 pg/ml）和肿瘤坏死因子（62.5 ng/ml）诱导培养的大鼠胰岛的细胞毒性，并通过在含有3.3、5.5、11和20 mmol/L葡萄糖的培养基中培养胰岛来调节β细胞活性。单独给予白细胞介素-1和肿瘤坏死因子时均具有细胞毒性，且白细胞介素-1和肿瘤坏死因子联合使用时的细胞毒性比单独使用任一细胞因子时更强。在11 mmol/L葡萄糖浓度下观察到最大细胞毒性，在5.5 mmol/L葡萄糖浓度下细胞毒性降低，在3.3 mmol/L葡萄糖浓度下进一步降低。有趣的是，与11 mmol/L相比，20 mmol/L葡萄糖浓度下的细胞毒性程度更低。这些结果有力地证实，白细胞介素-1和肿瘤坏死因子的胰岛细胞毒性高度依赖于β细胞的功能状态。这表明在胰岛素依赖型糖尿病的疾病过程中，随着一些β细胞被破坏，剩余β细胞的代偿性活性增加可能会增加它们对细胞因子攻击的易感性。此外，我们的观察结果为将β细胞休息作为胰岛素依赖型糖尿病的干预治疗方法提供了合理依据。
