A paradoxical reduction in susceptibility to colonic injury upon targeted transgenic ablation of goblet cells
A paradoxical reduction in susceptibility to colonic injury upon targeted transgenic ablation of goblet cells
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DOI：
10.1172/jci6211
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发表时间：
1999-12-01
影响因子：
15.9
通讯作者：
Podolsky, DK
中科院分区：
文献类型：
--
作者：
Itoh, H;Beck, PL;Podolsky, DK
杯状细胞是肠道的主要粘液产生细胞，被认为在粘膜保护中起重要作用。然而，它们的功能作用尚未在体内直接评估。在最初的研究中，发现鼠肠三叶因子（ITF）基因的5'侧翼序列赋予转基因的杯状细胞特异性表达。为了评估球细胞在肠道中的作用，我们产生了转基因小鼠，其中近似60%的杯状细胞被ITF启动子驱动的减毒白喉毒素（DT）基因的表达所消融;其他细胞谱系不受影响。我们给药2种外源性药物，葡聚糖硫酸钠（DSS）和乙酸，以评估mITF/DT-A转基因小鼠对结肠损伤的易感性。口服DSS后，55%的对照小鼠死亡，而DT转基因小鼠保持其体重，死亡率不到5%。同样，30%的野生型小鼠在粘膜给予乙酸后死亡，而转基因小鼠的死亡率为3.2%。尽管杯状细胞数量减少，但mITF/DT-A转基因小鼠中ITF的总量增加，表明诱导型代偿机制。这些结果表明，杯状细胞主要通过产生三叶肽来促进粘膜保护和修复。
Goblet cells are the major mucus-producing cells of the intestine and are presumed to play an important role in mucosal protection. However, their functional role has not been directly assessed in vivo. In initial studies, a 5' flanking sequence of the murine intestinal trefoil factor (ITF) gene was found to confer goblet cell-specific expression of a transgene. To assess the role of globlet cells in the intestine, we generated transgenic mice in which similar to 60% of goblet cells were ablated by the expression of an attenuated diphtheria toxin (DT) gene driven by the ITF promoter; other cell lineages were unaffected. We administered 2 exogenous agents, dextran sodium sulfate (DSS) and acetic acid, to assess the susceptibility of mITF/DT-A transgenic mice to colonic injury. After oral administration of DSS, 55% of control mice died, whereas DT transgenic mice retained their body weight and less than 5% died. Similarly, 30% of the wild-type mice died after mucosal administration of acetic acid, compared with 3.2% of the transgenic mice. Despite the reduction in goblet-cell number, the total amount of ITF was increased in the mITF/DT-A transgenic mice, indicating inducible compensatory mechanisms. These results suggest that goblet cells contribute to mucosal protection and repair predominantly through production of trefoil peptides.