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Originally published In Press as doi:10.1074/jbc.M202929200 on April 18, 2002

J. Biol. Chem., Vol. 277, Issue 25, 22595-22604, June 21, 2002
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Cholecystokinin Induces Caspase Activation and Mitochondrial Dysfunction in Pancreatic Acinar Cells
ROLES IN CELL INJURY PROCESSES OF PANCREATITIS*

Anna S. GukovskayaDagger , Ilya Gukovsky, Yoon Jung, Michelle Mouria, and Stephen J. Pandol

From the Departments of Medicine, Veterans Affairs Greater Los Angeles Healthcare System and the UCLA, Los Angeles, California 90073

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.

* This work was supported by Department of Veterans Affairs Merit Review grants (to A. S. G. and S. J. P.) and in part by Research Center for Alcoholic Liver and Pancreatic Diseases Grant P50-A11999 from NIAAA.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: VA Greater Los Angeles Healthcare System, West Los Angeles Healthcare Center, Bldg. 258, Rm. 340, 11301 Wilshire Blvd., Los Angeles, CA 90073. E-mail: agukovsk@ucla.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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