Effects of TGF-alpha gene knockout on epithelial cell kinetics and repair of methotrexate-induced damage in mouse small intestine.
While previous studies have indicated that exogenous TGF-alpha stimulates epithelial growth, maintenance, and repair of the gut, roles of endogenous TGF-alpha are less well-defined particularly in the small bowel. The current study examined effects of TGF-alpha knockout on adult small intestinal epithelial cell proliferation, migration, apoptosis, and damage/repair response after methotrexate treatment. Compared to normal mice, TGF-alpha gene knockout did not affect crypt cell production, mitosis position, migration, and apoptosis in non-injured intestine. RT-PCR gene expression analysis revealed presence of four out of six TGF-alpha related EGF family ligands in the normal intestine, suggesting a possible functional redundancy of the EGF family in maintenance of the intestine. Although TGF-alpha gene knockout did not significantly impair the overall mucosal repair in methotrexate-induced acute damage in the small intestine, it resulted in a higher apoptotic response in the early hours following methotrexate challenge, and a delayed and reduced crypt cell proliferation during repair. Consistently, after methotrexate challenge, intestinal TGF-alpha mRNA was found to be markedly upregulated in the early hours and during repair in the wild type, and there were similar profiles in the increased expression of all other ligands (except EGF) between the wild type and knockout intestines. Therefore, despite a possible functional redundancy among the EGF family ligands in the normal small intestine, TGF-alpha may play a role in modulating the early apoptotic events and in enhancing the subsequent reparative proliferative response in the methotrexate-damaged intestine.
Xian
Cory J
CJ
Child Health Research Institute and Cooperative Research Centre for Tissue Growth and Repair, North Adelaide, South Australia, Australia. cory.xian@adelaide.edu.au
Cool
Jo C
JC
Howarth
Gordon S
GS
Read
Leanna C
LC
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002453:Cell Cycle; D066246:ErbB Receptors / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000473:pathology / Q000503:physiopathology*; D007421:Intestine, Small / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D008024:Ligands; D008727:Methotrexate / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D012016:Reference Values; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology*
D000964:Antimetabolites, Antineoplastic; D008024:Ligands; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors; D008727:Methotrexate