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 CRF(1) and CRF(2), in the human stomach. We examined CRF(1) and CRF(2) expression in the same tissue. Using RT-PCR, CRF(2) but not CRF(1) 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 CRF(2) in these cells, an in vitro model was established, using the gastric cancer cell line AGS transiently transfected to express functional CRF(2). The effect of the CRF(2) endogenous ligands CRF, Ucns I and II on the growth parameters of the AGS/CRF(2) 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 CRF(2) receptors. Administration of CRF, Ucns I and II had no effect on the proliferation rate of AGS/CRF(2) cells or on the release of PGE(2) by them. Our results demonstrate CRF(2) 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. J. Cell. Physiol. 209: 905-911, 2006. (c) 2006 Wiley-Liss, Inc.