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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >NF-κB prevents β cell death and autoimmune diabetes in NOD mice
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NF-κB prevents β cell death and autoimmune diabetes in NOD mice

机译：NF-κB可预防NOD小鼠的β细胞死亡和自身免疫性糖尿病

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摘要

Whereas NF-κB has potent antiapoptotic function in most cell types, it was reported that in pancreatic β cells it serves a proapo-ptotic function and may contribute to the pathogenesis of autoimmune type 1 diabetes. To investigate the role of β cell NF-κB in autoimmune diabetes, we produced transgenic mice expressing a nondegradable form of IκBα in pancreatic β cells (RIP-mIκBα mice). β cells of these mice were more susceptible to killing by TNF-α plus IFN-γ but more resistant to IL-1β plus IFN-γ than normal β cells. Similar results were obtained with β cells lacking IκB kinase β, a protein kinase required for NF-κB activation. Inhibition of β cell NF-κB accelerated the development of autoimmune diabetes in nonobese diabetic mice but had no effect on glucose tolerance or serum insulin in C57BL/6 mice, precluding a nonphysiological effect of transgene expression. Development of diabetes after transfer of diabetogenic CD4~+ T cells was accelerated in RIP-mIκBαonobese diabetic mice and was abrogated by anti-TNF therapy. These results suggest that under conditions that resemble autoimmune type 1 diabetes, the dominant effect of NF-κB is prevention of TNF-induced apoptosis. This differs from the proapoptotic function of NF-κB in IL-1β-stimulated β cells.
机译：尽管NF-κB在大多数细胞类型中均具有有效的抗凋亡功能，但据报道，在胰腺β细胞中，NF-κB具有促凋亡功能，并可能有助于自身免疫性1型糖尿病的发病。为了研究β细胞NF-κB在自身免疫性糖尿病中的作用，我们制备了在胰腺β细胞中表达不可降解形式的IκBα的转基因小鼠（RIP-mIκBα小鼠）。与正常的β细胞相比，这些小鼠的β细胞更易被TNF-α加IFN-γ杀死，但对IL-1β加IFN-γ的耐药性更高。对于缺少IκB激酶β（NF-κB激活所需的蛋白激酶）的β细胞，也获得了类似的结果。抑制β细胞NF-κB可以加速非肥胖糖尿病小鼠自身免疫性糖尿病的发展，但对C57BL / 6小鼠的糖耐量或血清胰岛素没有影响，从而排除了转基因表达的非生理作用。在RIP-mIκBα/非肥胖糖尿病小鼠中，促糖尿病的CD4〜+ T细胞转移后，糖尿病的发展得以加速，并通过抗TNF治疗被废止。这些结果表明，在类似于自身免疫性1型糖尿病的情况下，NF-κB的主要作用是预防TNF诱导的细胞凋亡。这与IL-1β刺激的β细胞中NF-κB的促凋亡功能不同。

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