Caerulein and gastrin(2–17 ds) regulate differently synthesis of secretory enzymes, mRNA levels and cell proliferation in pancreatic acinar cells (AR4-2J)

Abstract

In order to characterize the biological functions coupled to cholecystokinin (CCK) A and B receptors, the effects of gastrin(2-17 ds) and caerulein were compared. An isolated cell model, the pancreatic acinar cell line AR4-2J, was used and the experiments were carried out in serum-free media. Caerulein was found to evoke no mitogenic effects either alone or in the presence of the CCK antagonists L364,718 and CR1409. Gastrin(2-17 ds) increased cell proliferation by 2-fold with an IC50 of 150 pM, corresponding to the occupancy of the CCK B receptors. CR1409, at concentrations that fully occupied CCK B receptors, inhibited the gastrin(2-17 ds) effects. Caerulein enhanced chymotrypsinogen biosynthesis by 100% and the corresponding mRNA level by 75%; amylase biosynthesis and mRNA level were enhanced by 40% only. Half-maximal increases in chymotrypsin activity and mRNA level were recorded in response to caerulein at concentrations of 100 pM and 50 pM respectively. Gastrin(2-17 ds) at 100 nM enhanced chymotrypsinogen biosynthesis by 26% and its mRNA level by 35%; these responses were lower than those evoked by 0.1 nM caerulein. Furthermore, CR1409 completely inhibited caerulein- and gastrin(2-17 ds)-stimulated chymotrypsinogen synthesis, with similar IC50 (4 microM). These results suggest that both peptides induced the synthesis of the secretory enzyme after occupancy of CCK A receptors.

Selective exocytosis of zymogen granules induces non-parallel secretion in short-term cholecystokinin-stimulated rats

“…This is associated with a modulatory effect of CCK on biosynthesis, acting preferentially on serine proteases (Renaud et al 1986, Pradel et al 1993, Lloste et al 1994, de Dios et al 1997b. In agreement with previous reports (Dagorn 1978, Grendell et al 1984, our results also show a non-parallel secretion of enzymes in response to short-term CCK stimulation.…”

Gastrin Stimulates β-Cell Neogenesis and Increases Islet Mass From Transdifferentiated but Not From Normal Exocrine Pancreas Tissue

“…Not only during pancreatic regeneration (as in the case of duct ligation [25]) but also during cancer development, gastrin and its receptors become expressed and gastrin exerts its mitogenic effect on the pancreas (32)(33)(34). This may represent a recapitulation of embryonic development, because it is known that gastrin and its receptor are expressed in the fetal pancreas (8 -11), and a role of gastrin in pancreatic development has been postulated (10,35).…”

Differential Regulation of Fibroblast Growth Factor (FGF) Receptor-1 mRNA and Protein by Two Molecular Forms of Basic FGF

“…In these transfected cells, the FGFR down-regulation induced by secreted FGF-2 might mask the increased receptor biosynthesis by the FGF-2 forms localized in the intracellular compartments. Therefore, we used a retroviral infection system to obtain the production of lower levels of FGF-2 (about 0.5-2 ng/million cells) (13,34) and we chose a pancreatic acinar cell line (AR4-2J) in which cell differentiation can be easily determined by morphological analysis and by measuring the biosynthesis rate of the secretory enzymes (24). Inasmuch as AR4-2J cells do not produce FGF-2 (21), the biological effects resulting from the induction of low level expression of each isoform can be more easily analyzed.…”

“…Quantification of RNA was made spectrophotometrically at 260 nm. Northern blot analysis was performed as described previously (24). The FGFR-1 probe pCD115 (25) was a human cDNA encoding the extracellular domain (gift from Dr. M. Jaye, Rorer Central Research, Inc., King of Prussia, PA).…”