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B Activation in Pancreatic Acinar Cells through effects on Protein Kinase C Epsilon
1 West Los Angeles Veterans Affairs Great Los Angeles Healthcare System, University of California, 11301 Wilshire Boulevard, Building 258 Room 340, Los Angeles, 90073, United States
2 Research Center for Alcoholic Liver and Pancreatic Diseases, Veterans Affairs Greater Los Angeles Healthcare System & University of California, Los Angeles, Los Angeles, California, United States
3 Division of Gastroenterology, Tokyo University Graduate School of Medicine, Japan
* To whom correspondence should be addressed. E-mail: stephen.pandol{at}med.va.gov.
Although ethanol abuse is the most common cause of pancreatitis, the mechanism of alcohol's effect on the pancreas is not well understood. Previously we demonstrated that in vitro ethanol treatment of pancreatic acinar cells augmented the cholecystokinin-8 (CCK-8)- induced activation of nuclear factor 
B (NF-B), a key signaling system involved in the inflammatory response of pancreatitis. In the present study, we determine the role for individual protein kinase C (PKC) isoforms in the sensitizing effect of ethanol on NF-B activation. Dispersed rat pancreatic acini were treated with/without ethanol, and then stimulated with CCK-8. 100nM CCK-8 caused both NF-B and PKC-
, -
, and -
activation whereas 0.1 nM CCK-8 did not increase PKC-, - or NF-B activity. 0.1nM CCK-8 did activate PKC-. PKC- activator alone did not cause NF-B activation, however, together with 0.1 nM CCK-8, it caused NF-B activation. Ethanol activated PKC- without affecting other PKC isoforms or NF-B activity. Of note, stimulation of acini with ethanol and 0.1 nM CCK-8 resulted in the activation of PKC-, PKC-, and NF-B. The NF-B activation to 0.1 nM CCK-8 in ethanol- pretreated acini was inhibited by both PKC- inhibitor and PKC- inhibitor. These results demonstrate the different modes of activation of PKC isoforms and NF-B in acini stimulated with ethanol, high dose- and low dose of CCK-8, and further suggests that activation of both PKC- and - is required for NF-B activation. These results suggest that ethanol enhances the CCK-8- induced NF-B activation at least in part through its effects on PKC-.
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