Corticotropin-releasing factor (CRF) receptor type 2 in the human stomach:: Protective biological role by inhibition of apoptosis

Corticotropin-releasing factor agonists exert inhibitory effects in stomach functions possibly through peripheral routes. We have previously reported the expression of Urocortin (Ucn) I, an endogenous ligand of both CRF receptor types CRF1 and CRF2, in the human stomach. We examined CRF, and CRF2 expression in the same tissue. Using RT-PCR, CRF2 but not CRF, transcripts were detected in RNA extracts from normal human stomach. In addition, immunohistochemical analysis revealed receptor protein in epithelial gastric cells. In order to investigate the biological role of CRF2 in these cells, an in vitro model was established, using the gastric cancer cell line AGS transiently transfected to express functional CRF2. The effect of the CRF2 endogenous ligands CRF, Ucns I and II on the growth parameters of the AGS/CRF2 was examined. After 1 day of exposure, all three ligands reduced the degree of apoptosis (16%-19%, n = 9, P < 0.05) compared to non-treated controls and this effect was observed for 3 days of treatment. No such effect was detected in non-transfected cells, suggesting mediation through CRF2 receptors. Administration of CRF, Ucns I and II had no effect on the proliferation rate of AGS/CRF2 cells or on the release of PGE(2) by them. Our results demonstrate CRF2 expression in the human gastric mucosa and indicate a physiological role of this receptor type in regulating apoptosis, an important parameter of gastric cell regeneration. Paracrine effects exerted by locally expressed endogenous ligands, such as Ucn I, support a significant role of the peripheral CRF system in gastric physiology.