Transforming growth factor-alpha and epidermal growth factor receptor in colonic mucosa in active and inactive inflammatory bowel disease.

Transforming growth factor-alpha (TGF-alpha) is overexpressed in colonic carcinomas and promotes mucosal wound healing. It may be implicated in chronic inflammatory bowel disease (IBD). We analyzed the expression of TGF-alpha and its receptor, epidermal growth factor receptor (EGF-r), in the colonic mucosa of patients with Crohn's disease (CD) or ulcerative colitis (UC), in active or inactive stages, as compared with controls. Proteins and mRNA were detected in biopsies from the right and left colon and in surgical colonic specimens. Immunoblot analysis revealed TGF-alpha protein as a 29 kDa band. This band was normally expressed in uninvolved colonic mucosa of patients with CD or UC whether in active or inactive stages, but decreased or absent in involved mucosa of active IBD, even when TGF-alpha mRNA and EGF-r protein were detected. In the unaffected mucosa of CD, the intensity of TGF-alpha immunoreactivity was similar to that of controls in the right colon but stronger (P = 0.05) in the left colon. There was no TGF-alpha overexpression in dysplastic regions. In conclusion, in active IBD disease, the decreased TGF-alpha protein amount seems not only related to epithelial cell loss but reflects a down-regulation at least at the protein level. We speculate that TGF-alpha does not play a role within the active stage but may be implicated later in the repair process.

Developmental expression and functionality of hepatocyte growth factor and c-Met in human fetal digestive tissues.

BACKGROUND & AIMS: Hepatocyte growth factor (HGF) and its receptor c-Met are presumed to play a morphogenic role during embryogenesis. The possible implication of HGF and c-Met during the digestive system development was approached by investigating their ontogeny, distribution, and functionality in human fetal tissues. METHODS: Thirty fetuses, 7-24 weeks old, were obtained. HGF and c-Met messenger RNAs and proteins were detected in liver, pancreas, esophagus, stomach, and small and large intestine. Tyrosine phosphorylation assays were realized on homogenates and membrane preparations from fetal tissues. RESULTS: The temporal appearance of HGF and c-Met was established between 7 and 8 weeks of gestation in digestive tissues. Immunoblot analysis showed the presence of the c-Met beta-subunit 145-kilodalton band and of the HGF alpha-subunit 70-kilodalton band. c-Met was localized in epithelia, especially in fundic parietal cells, pancreatic and gut endocrine cells, and in muscular layers. HGF immunoreactivity was first detected in epithelia and then in mesenchyme and muscular layers. In young fetal stages, the c-Met immunoprecipitated 145-kilodalton band showed tyrosine phosphorylation after HGF stimulation. CONCLUSIONS: This study provides evidence for HGF and c-Met expression early in all human fetal digestive tissues and implicates HGF-c-Met in the digestive system morphogenesis.

Transforming growth factor-alpha in vivo stimulates epithelial cell proliferation in digestive tissues of suckling rats.

BACKGROUND: The role that exogenous transforming growth factor-alpha (TGF-alpha) may exert on cell proliferation in vivo is poorly understood. AIM: To investigate the effect of rat TGF-alpha on epithelial cell proliferation in all suckling rat digestive tissues and to compare it with that of rat epidermal growth factor (EGF). ANIMAL AND METHODS: TGF-alpha and EGF were given three times daily either subcutaneously (10 or 20 micrograms/kg) or intraperitoneally (100 micrograms/kg) to rats from the ninth postnatal day. Cell proliferation was assessed through 5-bromo- 2-deoxyuridine incorporation and estimation of labelling indices. RESULTS: For both growth factors, the highest dose given for only two days significantly increased stomach and intestinal weights compared with controls (p < 0.05 to p < 0.001). The proliferative responded depended on the dose given, colonic mucosa being the most sensitive whereas oxyntic mucosa remained unresponsive. TGF-alpha was as potent as EGF in stimulating epithelial cell proliferation in antral, duodenal, and colonic mucosae. However, EGF was more active on oesophageal and jejunal cell proliferation whereas TGF-alpha was more active on pancreatic exocrine cell proliferation and the differences between the two growth factor treated groups were significant. CONCLUSIONS: These results prove for the first time the stimulating effect in vivo of exogenous rat TGF-alpha on epithelial cell proliferation in rat digestive tissues during the developmental period and support a functional role for TGF-alpha at that time.

Developmental expression of transforming growth factor-alpha in the upper digestive tract and pancreas of the rat.

This study was designed to examine the developmental expression and the localization of the transforming growth factor alpha (TGF-alpha) in the upper gastrointestinal tract and pancreas of the rat. Immunohistochemical techniques using an antibody against rat TGF-alpha were performed on the stomach, duodenum and pancreas of fetuses (19 to 21 days of gestation), of pups during the suckling period (days 0 to 13 postpartum) and after weaning (day 25 postpartum) and of adults. The temporal appearance of TGF alpha varied depending on the tissues. In the antral mucosa it likely appeared before 19 days of gestation. In this tissue, the immunostaining was intense from 20 days of gestation and did not decline after birth. In the duodenum, the TGF alpha immunoreactivity was definitely present with a high intensity at 20 days of gestation in villi, crypts and Brünner's glands and there after became irregular. In the fundic mucosa, TGF alpha expression was weak but clearly-established at 21 days of gestation, at least in parietal cells, and regularly increased after birth. In the pancreas, it appeared only after birth and solely in the exocrine gland. The TGF alpha immunoreactivity displayed as age progressed, first a granular pattern apparently confined in the supranuclear, i.e., Golgi area, then a diffuse cytoplasmic pattern. These findings suggest that TGF alpha may have a functional role during the developmental process of the digestive system.

Developmental expression of transforming growth factor-alpha and epidermal growth factor receptor proteins in the human pancreas and digestive tract.

This study was designed to localize transforming growth factor alpha (TGF-alpha) and epidermal growth factor receptor (EGFR) expression in the developing human gastrointestinal tract and pancreas. Immunohistochemical techniques using specific antibodies against human TGF-alpha and EGFR were performed on digestive tissues of fetuses from 9 to 10 to 24 weeks of gestation, children and adults. In fetuses, TGF-alpha and EGFR proteins were expressed in all epithelial tissues studied with a good correlation and from an age as early as 9 to 10 weeks of gestation, except for TGF-alpha in the esophagus. The strongest TGF-alpha immunostaining was noted in the stomach and the proximal colon. Unexpectedly, immunoreactive gut endocrine cells were observed with the two antibodies used. Relatively numerous in fetuses, they decreased in number with age and were rare in adults particularly along the colon. Enteroglucagonsecreting cells were shown to express TGF-alpha, while some gastrin, somatostatin and pancreatic glucagon cells were immunostained with EGFR antibodies. The presence of TGF-alpha and its receptor in digestive tract epithelium and pancreatic tissues early in fetal life suggests a functional role for TGF-alpha during the developmental process of the digestive system. We demonstrate that TGF-alpha is also produced by endocrine cells and might have an additional mode of action other than paracrine, at least during fetal life.