Leiter E H, Fewell J W, Kuff E L
J Exp Med. 1986 Jan 1;163(1):87-100. doi: 10.1084/jem.163.1.87.
C57BL/KsJ (BKs) and CBA/J, but not C57BL/6J (B6) mice are susceptible to the diabetogenic action of the obesity gene, "diabetes" (db). BKs and CBA/J, but not B6 mice, constitutively express intracisternal type A particles (IAP), an endogenous class of retrovirus, in beta cells and in cortical thymocytes. IAP genetic expression in these cell types included production of the group-specific antigen, p73, as well as higher-molecular mass p73-related antigens (p114-120). We used islet culture techniques to show that both transcription and translation of IAP genomes in beta cells in enhanced by glucose. Maintenance of CBA/J islets for 48 h in 16.5 mM glucose-containing medium effected a fivefold induction of IAP protein synthesis in comparison to islets cultured in low- (5.5 mM) glucose medium. Analysis of RNA from 16.5 mM glucose-cultured islets revealed induction of 7.2 and 5.4 kbp transcripts known to code for p73 and the p114-120 polypeptides, respectively. This induction in CBA/J islets was 10-15-fold on a tissue basis, and 5-7-fold on an RNA basis. Glucose induction of preproinsulin mRNA levels was also analyzed in the same samples. Islets cultured in 16.5 mM glucose showed an eightfold higher level on a tissue basis, and a fourfold increase in terms of total recovered RNA. Comparison of these glucose-inducible parameters in islets isolated from the diabetes-susceptible BKs strain vs. the resistant B6 strain revealed that expression of the group-specific retroviral p73 antigen was limited to BKs beta cells. This inbred strain control of p73 expression was also found in cortical thymocytes, with B6 thymocytes producing a 117 kD component to the exclusion of p73, while both components were expressed in thymocytes from normal BKs mice. In comparison to normal BKs males, thymocytes from four week-old genetically diabetic (db/db) BKs males showed no change in labeling of p117, but showed a sharply diminished incorporation into p73. This suggested that accelerated thymic involution characteristic of db/db mice may entail selective elimination of p73-producing cells. The possibility that glucose-stressed BKs pancreatic beta cells are marked for autoimmune elimination by the elaboration of p73 or other IAP-related proteins is discussed.
C57BL/KsJ（BKs）和CBA/J小鼠对肥胖基因“糖尿病”（db）的致糖尿病作用敏感，而C57BL/6J（B6）小鼠则不敏感。BKs和CBA/J小鼠，但不是B6小鼠，在β细胞和皮质胸腺细胞中组成性表达A型颗粒内包涵体（IAP），这是一种内源性逆转录病毒。这些细胞类型中的IAP基因表达包括群特异性抗原p73以及高分子量p73相关抗原（p114 - 120）的产生。我们使用胰岛培养技术表明，葡萄糖可增强β细胞中IAP基因组的转录和翻译。与在低（5.5 mM）葡萄糖培养基中培养的胰岛相比，将CBA/J胰岛在含16.5 mM葡萄糖的培养基中培养48小时，IAP蛋白合成诱导了五倍。对来自16.5 mM葡萄糖培养的胰岛的RNA分析显示，分别诱导了已知编码p73和p114 - 120多肽的7.2和5.4 kbp转录本。CBA/J胰岛中的这种诱导在组织基础上为10 - 15倍，在RNA基础上为5 - 7倍。在相同样本中还分析了葡萄糖对胰岛素原前体mRNA水平的诱导。在16.5 mM葡萄糖中培养的胰岛在组织基础上显示出高八倍的水平，在总回收RNA方面增加了四倍。比较从糖尿病易感的BKs品系与抗性B6品系分离的胰岛中这些葡萄糖诱导参数发现，群特异性逆转录病毒p73抗原的表达仅限于BKsβ细胞。在皮质胸腺细胞中也发现了这种p73表达的近交系控制，B6胸腺细胞产生一种117 kD成分而不产生p73，而正常BKs小鼠的胸腺细胞中两种成分都有表达。与正常BKs雄性小鼠相比，四周龄遗传性糖尿病（db/db）BKs雄性小鼠的胸腺细胞中p117的标记没有变化，但掺入p73的量急剧减少。这表明db/db小鼠特征性的加速胸腺退化可能需要选择性消除产生p73的细胞。讨论了葡萄糖应激的BKs胰腺β细胞通过产生p73或其他IAP相关蛋白而被标记用于自身免疫消除的可能性。
