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B ACTIVATION IN PANCREATIC ACINAR CELLS THROUGH CALCIUM AND PROTEIN KINASE C PATHWAYS
1 USC-UCLA Research Center for Alcoholic Liver and Pancreatic Injury, VA Greater Los Angeles Healthcare System, and the University of California, Los Angeles, Los Angeles, CA, USA
* To whom correspondence should be addressed. E-mail: agukovsk{at}ucla.edu.
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 pro-inflammatory 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 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. Pharmacologic 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.
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