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 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 approximately 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.
Itoh
H
H
Gastrointestinal Unit, Center for the Study of Inflammatory Bowel Disease, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Beck
P L
PL
Inoue
N
N
Xavier
R
R
Podolsky
D K
DK
D019342:Acetic Acid; D000818:Animals; D001835:Body Weight; D003106:Colon / Q000187:drug effects*; D016264:Dextran Sulfate; D004167:Diphtheria Toxin / Q000235:genetics; D017930:Genes, Reporter; D020397:Goblet Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006133:Growth Substances / Q000235:genetics* / Q000378:metabolism; D006651:Histocytochemistry; D051379:Mice; D008822:Mice, Transgenic; D055262:Mucin-2; D055263:Mucin-3; D009077:Mucins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins; D009479:Neuropeptides; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D001616:beta-Galactosidase / Q000378:metabolism
D004167:Diphtheria Toxin; D006133:Growth Substances; C524626:Muc2 protein, mouse; C524628:Muc2 protein, rat; C524641:Muc3 protein, mouse; C524651:Muc3 protein, rat; D055262:Mucin-2; D055263:Mucin-3; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D010455:Peptides; D012333:RNA, Messenger; C099037:TFF3 protein, rat; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D016264:Dextran Sulfate; D001616:beta-Galactosidase; D019342:Acetic Acid