Ethanol differentially regulates NF-kappaB activation in pancreatic acinar cells through calcium and protein kinase C pathways.
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-kappaB. To elucidate the mechanism of sensitization, here we investigate the effect of ethanol on Ca(2+)- and PKC-mediated pathways of CCK-induced NF-kappaB activation using an in vitro system of rat pancreatic acini incubated with ethanol. Ethanol augmented CCK-8-induced activation of NF-kappaB, similar to our in vivo findings with ethanol-fed rats. In contrast, ethanol prevented NF-kappaB activation caused by thapsigargin, an agent that mobilizes intracellular Ca(2+) bypassing the receptor. Pharmacological analysis showed that NF-kappaB 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-kappaB activation could be through inhibiting this pathway. Ethanol augmented NF-kappaB activation induced by the phorbol ester PMA, a direct activator of PKC. Inhibitory analysis demonstrated that Ca(2+)-independent (novel and/or atypical) PKC isoforms are involved in NF-kappaB 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(2+)/calcineurin- and PKC-mediated pathways of NF-kappaB 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.
Gukovskaya
Anna S
AS
UCLA/VA Greater Los Angeles Healthcare System, West Los Angeles Center, Los Angeles, CA 90073, USA. agukovsk@ucla.edu
Hosseini
Saeed
S
Satoh
Akihiko
A
Cheng
Jason H
JH
Nam
Kyung J
KJ
Gukovsky
Ilya
I
Pandol
Stephen J
SJ
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D066298:In Vitro Techniques; D016328:NF-kappa B / Q000502:physiology*; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016328:NF-kappa B; D000431:Ethanol; D011493:Protein Kinase C; D002118:Calcium