Localization of transforming growth factor alpha and its receptor in gastric mucosal cells. Implications for a regulatory role in acid secretion and mucosal renewal.

Abstract

Transforming growth factor a (TGFa) shares with epidermal growth factor (EGF) structural homology (35%), a common cell-surface membrane receptor (TGFa/EGF receptor), and a nearly identical spectrum of biological activity, including inhibition of gastric acid secretion. Herein, we report expression of TGFa mRNA in normal gastric mucosa of the adult guinea pig, rat, and dog. TGFa mRNA was also detected in matched surgically resected gastric mucosa and adjacent gastric carcinoma from 10 patients, and in gastric mucosa adjacent to a benign ulcer from an additional patient. TGFa protein was quantitated by radioimmunoassay and was present in tumor and adjacent mucosa. TGFa/EGF receptor mRNA was also detected in gastric mucosa from all species studied. Localization of TGFa and TGFa/EGF receptor mRNA expression was examined in samples of unfractionated guinea pig gastric mucosa and from chief cell-enriched and parietal cell-enriched fractions. All samples exhibited TGFa and TGFa/EGF receptor expression. The TGFa signal was greatest in the parietal cell fraction (5.8-fold increase), but was also enhanced in the chief cell fraction (1.9-fold increase) relative to the unfractionated gastric mucosa. Like TGFa expression, TGFa/EGF receptor mRNA expression was most intense in the parietal cellenriched fraction (7.8-fold increase), but was also increased in the chief cell-enriched fraction (2.7-fold increase) relative to the unfractionated guinea pig gastric mucosa. We conclude that TGFa and TGFa/EGF receptor genes are expressed in normal adult mammalian gastric mucosa. These findings, when interpreted in light of described actions of TGFa and EGF, provide evidence that local production of TGFa could play an important role in the regulation of acid secretion and mucosal renewal in the stomach.

Transgenic overexpression of Reg protein caused gastric cell proliferation and differentiation along parietal cell and chief cell lineages

“…Reg may drive 'downward' differentiation, while TGFa may drive 'upward' differentiation. TGFa also has been shown to be upregulated following acute gastric injury (Beauchamp et al, 1989;Polk et al, 1992). During the healing stage of the gastric mucosal lesion, balanced production of the two growth factors might be maintained, in order to reconstruct the properly organized epithelial structure.…”

Transforming growth factor‐α stimulates prostaglandin generation through cytosolic phospholipase A2 under the control of p11 in rat gastric epithelial cells

“…Several growth factors including epidermal growth factor (EGF) (Nakano et al, 1995), transforming growth factor (TGF)-a (Sawaoka et al, 1999), basic ®broblast growth factor (Sasaki et al, 1998), and hepatocyte growth factor (Jones et al, 1999) have been shown to stimulate expression of an inducible COX isoform, termed COX-2, in guinea-pig gastric mucosal cells and rat gastric epithelial RGM1 cells, suggesting involvement of COX-2 in prostaglandin generation upon stimulation with these growth factors. Among these growth factors, TGF-a is produced by gastric epithelial cells (Beauchamp et al, 1989), and stimulates prostaglandin generation in the cells (Sawaoka et al, 1999). Furthermore, exogenous prostaglandin activates gastric ®broblasts to stimulate expression of hepatocyte growth factor (Takahashi et al, 1996), which induces proliferation of gastric epithelial cells (Takahashi et al, 1995).…”

Regulation and Function of the Sonic Hedgehog Signal Transduction Pathway in Isolated Gastric Parietal Cells

“…Immunohistochemical studies conducted in the gastric mucosa of both mice and humans have demonstrated that Shh is expressed in the parietal cells (21), highly specialized gastric epithelial cells, known to produce and secrete growth factors, and regulatory peptides in the gastric mucosa (21,31,32). Indeed, loss of mature parietal cells, achieved by genetic, pharmacological, and immunological methods, appears to be associated with profound abnormalities in the differentiation and development of multiple cell lineages in the stomach (33)(34)(35)(36)(37).…”