Growth Factor Effects on Apoptosis of Rat Gastric Enterochromaffin-Like Cells

Abstract

Enterochromaffin-like (ECL) cells are histamine-containing endocrine cells in the gastric epithelium that show increased density during chronic atrophic gastritis. The current study determined cell number and apoptosis of isolated rat ECL cells in response to several growth factors. Isolated ECL cells from fundic mucosa (enrichment >90%) were grown in serum-free medium over 2-5 days. Cell number was determined by mitochondrial formazan production; apoptosis was measured by Tdt-mediated dUTP nick end labeling reaction and DNA fragmentation-based enzyme-linked immunosorbent assay. Immunocytochemistry and RT-PCR demonstrated the presence of epidermal growth factor receptor, neuronal growth factor receptor (type 1), and fibroblast growth factor (FGF) receptor (type 1). Gastrin (EC50, approximately 2 pM), transforming growth factor-alpha (TGF alpha; 10-30 ng/ml), and basic FGF (bFGF; 1-10 ng/ml) increased the total number of cultured ECL cells. bFGF augmented the gastrin (1 pM)-induced response. Beta-neuronal growth factor (10 ng/ml) and bFGF (2 ng/ml) decreased the programed death of ECL cells. Interleukin-1beta (100 pg/ml, 24 h) stimulated apoptosis 2- to 3-fold in ECL cells, and simultaneous incubation with TGF alpha (20 ng/ml) or bFGF (2 ng/ml) significantly inhibited this effect. ECL cells express specific receptors for gastrin, epidermal growth factor, neuronal growth factor, and FGF. bFGF prolonged ECL cell survival by inhibiting spontaneous apoptosis. Our data further indicate that TGF alpha and bFGF increase ECL cell number by inhibiting cytokine-induced programed cell death.

Gastrin upregulates the prosurvival factor secretory clusterin in adenocarcinoma cells and in oxyntic mucosa of hypergastrinemic rats

“…Gastrin has been shown to increase the expression of antiapoptotic genes also in rat ECL cells (18). In agreement of the latter, the results of Mahr et al (39) indicate that gastrin may have a direct antiapoptotic effect on ECL cells, although their results were not statistically significant. On the basis of our observation on the central role of clusterin as a mediator of gastrin's antiapoptotic effect in AR42J adenocarcinoma cells in culture, we suggest that clusterin may play a role in mediating an antiapoptotic effect also in the gastric mucosa.…”

Gastrin: old hormone, new functions

“…There is evidence that these cells have the capacity for proliferation so that ECL cell hyperplasia may reflect a direct mitogenic action of gastrin [76]. Present interest in the trophic effects of gastrin on ECL cells stems from two facts: patients treated with proton pump inhibitors (PPIs) have elevated plasma gastrin, and in both patients and animals ECL cell hyperplasia can lead to dysplasia and ECL cell carcinoid tumours.…”

Insights into the Mechanisms of Gastric Adaptation to Aspirin-Induced Injury: A Role for Regenerating Protein but Not Trefoil Peptides

“…Studies on cultured rat gastric ECL cells have shown that the growth factor TGF-␣ increases ECL cell number by inhibiting cytokine-induced apoptosis (Mahr et al, 1998). Considering this, together with our finding that apoptosis is reduced (Alderman et al, 2000) and TGF-␣ is increased in adapted stomach (Doljanin et al, 1996;Romano et al, 1996), it is plausible that increased expression of TGF-␣ during adaptation might be an upstream signal that contributes to increased numbers of gastric mucosal ECL cells, in turn enhancing mucosal levels of RegI.…”