CHOP deletion does not impact the development of diabetes but suppresses the early production of insulin autoantibody in the NOD mouse
CHOP deletion does not impact the development of diabetes but suppresses the early production of insulin autoantibody in the NOD mouse
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DOI：
10.1007/s10495-011-0576-2
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发表时间：
2011-01
期刊：
影响因子：
7.2
通讯作者：
T. Satoh;N. Abiru;Masakazu Kobayashi;Hongbo Zhou;Kan Nakamura;G. Kuriya;Hideki Nakamura;Y. Nagayama;E. Kawasaki;H. Yamasaki;Liping Yu;G. Eisenbarth;E. Araki;Masataka Mori;S. Oyadomari;K. Eguchi
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文献类型：
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作者：
T. Satoh;N. Abiru;Masakazu Kobayashi;Hongbo Zhou;Kan Nakamura;G. Kuriya;Hideki Nakamura;Y. Nagayama;E. Kawasaki;H. Yamasaki;Liping Yu;G. Eisenbarth;E. Araki;Masataka Mori;S. Oyadomari;K. Eguchi
C/EBP同源蛋白（CHOP）被认为是炎症细胞因子诱导的内质网应激介导的β细胞死亡的关键转录因子，但CHOP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，我们产生了CHOP缺陷型非肥胖糖尿病（NOD.Chop−/−）小鼠。CHOP缺乏不影响胰岛炎、糖尿病的发生和胰岛β细胞凋亡。有趣的是，与野生型（wt）小鼠相比，NOD.Chop−/−小鼠表现出胰岛素自身抗体的延迟出现。连续转移致糖尿病的完整或CD 8+耗尽的脾细胞诱导β细胞凋亡，并在辐照NOD.Chop−/−受体中快速发生糖尿病，其动力学与野生型小鼠相似。与野生型小鼠或NOD-scid小鼠相比，来自NOD.Chop−/−的胰岛中ER应激相关基因的表达没有显著上调。这些发现表明，CHOP的表达是独立的胰岛炎和糖尿病的发展，但可能会影响早期生产的胰岛素自身抗体在NOD小鼠。
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 irradiatedNOD.Chop−/−recipients with similar kinetics as in wt mice. Expression of ER stress-associated genes was not significantly up-regulated in the islets fromNOD.Chop−/−compared to those from wt mice or NOD-scidmice. 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.