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

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Abstract
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-κB. To elucidate the mechanism of sensitization, here we investigate the effect of ethanol on Ca2+- and PKC-mediated pathways of CCK-induced NF-κB activation using an in vitro system of rat pancreatic acini incubated with ethanol. Ethanol augmented CCK-8-induced activation of NF-κB, similar to our in vivo findings with ethanol-fed rats. In contrast, ethanol prevented NF-κB activation caused by thapsigargin, an agent that mobilizes intracellular Ca2+bypassing the receptor. Pharmacological analysis showed that NF-κB 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-κB activation could be through inhibiting this pathway. Ethanol augmented NF-κB 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-κB 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-κB 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.