title: Cholecystokinin induces caspase activation and mitochondrial dysfunction in pancreatic acinar cells. Roles in cell injury processes of pancreatitis.
abstract: Apoptosis and necrosis are critical parameters of pancreatitis, the mechanisms of which remain unknown. Many characteristics of pancreatitis can be studied in vitro in pancreatic acini treated with high doses of cholecystokinin (CCK). We show here that CCK stimulates apoptosis and death signaling pathways in rat pancreatic acinar cells, including caspase activation, cytochrome c release, and mitochondrial depolarization. The mitochondrial dysfunction is mediated by upstream caspases (possibly caspase-8) and, in turn, leads to activation of caspase-3. CCK causes mitochondrial alterations through both permeability transition pore-dependent (cytochrome c release) and permeability transition pore-independent (mitochondrial depolarization) mechanisms. Caspase activation and mitochondrial alterations also occur in untreated pancreatic acinar cells; however, the underlying mechanisms are different. In particular, caspases protect untreated acinar cells from mitochondrial damage. We found that caspases not only mediate apoptosis but also regulate other parameters of CCK-induced acinar cell injury that are characteristic of pancreatitis; in particular, caspases negatively regulate necrosis and trypsin activation in acinar cells. The results suggest that the observed signaling pathways regulate parenchymal cell injury and death in CCK-induced pancreatitis. Protection against necrosis and trypsin activation by caspases can explain why the severity of pancreatitis in experimental models correlates inversely with the extent of apoptosis.
authors.affiliation: Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System and the UCLA, Los Angeles, California 90073, USA. agukovsk@ucla.edu
authors.forename: Anna S
authors.initials: AS
authors.lastname: Gukovskaya
authors.forename: Ilya
authors.initials: I
authors.lastname: Gukovsky
authors.forename: Yoon
authors.initials: Y
authors.lastname: Jung
authors.forename: Michelle
authors.initials: M
authors.lastname: Mouria
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pandol
mesh_terms: D000681:Amylases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D002766:Cholecystokinin / Q000378:metabolism*; D003574:Cytochrome c Group / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D009336:Necrosis; D010179:Pancreas / Q000166:cytology*; D010195:Pancreatitis / Q000378:metabolism; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D051745:Protein Kinase C-delta; D051381:Rats; D015398:Signal Transduction; D014357:Trypsin / Q000378:metabolism
chemical_list: D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D004247:DNA; D002766:Cholecystokinin; D007770:L-Lactate Dehydrogenase; C497260:Prkcd protein, rat; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D000681:Amylases; D014357:Trypsin; C505410:Casp3 protein, rat; C505528:Casp8 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D002118:Calcium