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Ethanol differentially regulates NF-B activation in pancreatic acinar cells through calcium and protein kinase C pathways

Research Center for Alcoholic Liver and Pancreatic Injury, Veterans Affairs Greater Los Angeles Healthcare System, and the University of California, Los Angeles, California 90073

Submitted 20 February 2003 ; accepted in final form 28 August 2003

Mechanisms of alcoholic pancreatitis remain unknown. Previously, we showed that ethanol feeding sensitizes rats to pancreatitis caused by CCK-8, at least in part, by augmenting activation of the proinflammatory transcription factor NF-B. To elucidate the mechanism of sensitization, here we investigate the effect of ethanol on Ca²⁺- and PKC-mediated pathways of CCK-induced NF-B activation using an in vitro system of rat pancreatic acini incubated with ethanol. Ethanol augmented CCK-8-induced activation of NF-B, similar to our in vivo findings with ethanol-fed rats. In contrast, ethanol prevented NF-B activation caused by thapsigargin, an agent that mobilizes intracellular Ca²⁺ bypassing the receptor. Pharmacological analysis showed that NF-B activation by thapsigargin but not by CCK-8 is mediated through the calcineurin pathway and that the inhibitory effect of ethanol on the thapsigargin-induced NF-B activation could be through inhibiting this pathway. Ethanol augmented NF-B activation induced by the phorbol ester PMA, a direct activator of PKC. Inhibitory analysis demonstrated that Ca²⁺-independent (novel and/or atypical) PKC isoforms are involved in NF-B activation induced by both CCK-8 and PMA in cells treated and not treated with ethanol. The results indicate that ethanol differentially affects the Ca²⁺/calcineurin- and PKC-mediated pathways of NF-B activation in pancreatic acinar cells. These effects may play a role in the ability of ethanol to sensitize pancreas to the inflammatory response and pancreatitis.

alcoholic pancreatitis; inflammatory response; cholecystokinin; calcineurin

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