TY - JOUR
T1 - A paradoxical reduction in susceptibility to colonic injury upon targeted transgenic ablation of goblet cells
AU - Itoh, Hiroshi
AU - Beck, Paul L.
AU - Inoue, Nagamu
AU - Xavier, Ramnik
AU - Podolsky, Daniel K.
PY - 1999/12
Y1 - 1999/12
N2 - 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 goblet cells in the intestine, we generated transgenic mice in which ~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 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.
AB - 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 goblet cells in the intestine, we generated transgenic mice in which ~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 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.
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U2 - 10.1172/JCI6211
DO - 10.1172/JCI6211
M3 - Article
C2 - 10587517
AN - SCOPUS:0033454060
SN - 0021-9738
VL - 104
SP - 1539
EP - 1547
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
ER -