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

Gukovskaya, Anna S., Saeed Hosseini, Akihiko Satoh, Jason H. Cheng, Kyung J. Nam, Ilya Gukovsky, and Stephen J. Pandol. Ethanol differentially regulates NFB activation in pancreatic acinar cells through calcium and protein kinase C pathways. Am J Physiol Gastrointest Liver Physiol 286: G204–G213, 2004. First published September 4, 2003; 10.1152/ajpgi.00088.2003.—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 NFB. To elucidate the mechanism of sensitization, here we investigate the effect of ethanol on Ca and PKC-mediated pathways of CCK-induced NFB activation using an in vitro system of rat pancreatic acini incubated with ethanol. Ethanol augmented CCK-8-induced activation of NFB, similar to our in vivo findings with ethanol-fed rats. In contrast, ethanol prevented NFB activation caused by thapsigargin, an agent that mobilizes intracellular Ca bypassing the receptor. Pharmacological analysis showed that NFB 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 NFB activation could be through inhibiting this pathway. Ethanol augmented NFB activation induced by the phorbol ester PMA, a direct activator of PKC. Inhibitory analysis demonstrated that Ca -independent (novel and/or atypical) PKC isoforms are involved in NFB activation induced by both CCK-8 and PMA in cells treated and not treated with ethanol. The results indicate that ethanol differentially affects the Ca /calcineurinand PKC-mediated pathways of NFB 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.