A paradoxical reduction in susceptibility to colonic injury upon targeted transgenic ablation of goblet cells

Goblet cells are the major mucus-producing cells of the intestine and are p resumed to play an important role in mucosal protection. However, their fun ctional 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 cel l lineages were unaffected. We administered 2 exogenous agents, dextran sod ium 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 muc osal administration of acetic acid, compared with 3.2% of the transgenic mi ce. Despite the reduction in goblet-cell number, the total amount of ITF wa s increased in the mITF/DT-A transgenic mice, indicating inducible compensa tory mechanisms. These results suggest that goblet cells contribute to muco sal protection and repair predominantly through production of trefoil pepti des.