Department of Endocrinology and Metabolism, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, Japan.
Apoptosis. 2011 Apr;16(4):438-48. doi: 10.1007/s10495-011-0576-2.
C/EBP homologous protein (CHOP) has been proposed as a key transcription factor for endoplasmic reticulum (ER) stress-mediated β-cell death induced by inflammatory cytokines in vitro. However, the contribution of CHOP induction to the pathogenesis of type 1 diabetes is not yet clear. To evaluate the relevance of CHOP in the pathogenesis of type 1 diabetes in vivo, we generated CHOP-deficient non-obese diabetic (NOD.Chop (-/-)) mice. CHOP deficiency did not affect the development of insulitis and diabetes and apoptosis in β-cells. Interestingly, NOD.Chop (-/-) mice exhibited a delayed appearance of insulin autoantibodies compared to wild-type (wt) mice. Adoptive transfer with the diabetogenic, whole or CD8(+)-depleted splenocytes induced β-cell apoptosis and the rapid onset of diabetes in the irradiated NOD.Chop (-/-) recipients with similar kinetics as in wt mice. Expression of ER stress-associated genes was not significantly up-regulated in the islets from NOD.Chop (-/-) compared to those from wt mice or NOD-scid mice. These findings suggest that CHOP expression is independent of the development of insulitis and diabetes but might affect the early production of insulin autoantibodies in the NOD mouse.
C/EBP 同源蛋白（CHOP）已被提议为体外炎症细胞因子诱导的内质网（ER）应激介导的β细胞死亡的关键转录因子。然而，CHOP 诱导在 1 型糖尿病发病机制中的作用尚不清楚。为了评估 CHOP 在体内 1 型糖尿病发病机制中的相关性，我们生成了 CHOP 缺陷型非肥胖型糖尿病（NOD.Chop（-/-））小鼠。CHOP 缺陷不影响胰岛炎和糖尿病的发展以及β细胞的凋亡。有趣的是，与野生型（wt）小鼠相比，NOD.Chop（-/-）小鼠的胰岛素自身抗体出现时间延迟。用致糖尿病的、完整的或 CD8（+）耗尽的脾细胞进行过继转移，可在照射的 NOD.Chop（-/-）受体中诱导β细胞凋亡，并以类似于 wt 小鼠的动力学迅速引发糖尿病。与 wt 小鼠或 NOD-scid 小鼠相比，NOD.Chop（-/-）小鼠胰岛中 ER 应激相关基因的表达没有明显上调。这些发现表明，CHOP 表达独立于胰岛炎和糖尿病的发展，但可能影响 NOD 小鼠中胰岛素自身抗体的早期产生。
