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Am J Physiol Gastrointest Liver Physiol (April 29, 2004). doi:10.1152/ajpgi.00087.2004
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Submitted on February 24, 2004
Accepted on April 24, 2004

PKC delta and epsilon regulate NF-{kappa}B activation induced by cholecystokinin and TNF-{alpha} in pancreatic acinar cells

Akihiko Satoh1, Anna S. Gukovskaya2*, Jose M. Nieto2, Jason H. Cheng2, Ilya Gukovsky2, Joseph R. Reeve, Jr2, Tooru Shimosegawa3, and Stephen J. Pandol2

1 Research Center for Alcoholic Liver and Pancreatic Diseases, Veterans Affairs Greater Los Angeles Health Care System and University of California, Los Angeles, CA, USA; Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
2 Research Center for Alcoholic Liver and Pancreatic Diseases, Veterans Affairs Greater Los Angeles Health Care System and University of California, Los Angeles, CA, USA
3 Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan

* To whom correspondence should be addressed. E-mail: agukovsk{at}ucla.edu.

Although NF-{kappa}B plays an important role in pancreatitis, the mechanisms underlying its activation remain unclear. We investigated the signaling pathways mediating NF-{kappa}B activation in pancreatic acinar cells induced by high-dose of CCK-8 (which causes pancreatitis in rodent models) and TNF-{alpha} (which contributes to inflammatory responses of pancreatitis), especially, the role of PKC isoforms. We determined subcellular distribution and kinase activities of PKC isoforms, and NF-{kappa}B activation in dispersed rat pancreatic acini. We applied isoform-specific, cell-permeable peptide inhibitors to assess the role of individual PKC isoforms in NF-{kappa}B activation. Both CCK-8 and TNF-{alpha} activated the novel isoforms, PKC {delta} and {epsilon}, and the atypical isoform, PKC {zeta}, but not the conventional isoform, PKC {alpha}. Inhibition of the novel PKC isoforms but not the conventional or the atypical isoform resulted in the prevention of NF-{kappa}B activation induced by CCK-8 and TNF-{alpha}. NF-{kappa}B activation by CCK-8 and TNF-{alpha} required translocation but not tyrosine phosphorylation of PKC {delta}. The activation of PKC {delta}, PKC {epsilon}, and NF-{kappa}B with CCK-8 involved both phosphatidylinositol- specific PLC and phosphatidylcholine (PC)- specific PLC, whereas with TNF-{alpha} they only required PC- specific PLC for activation. The results indicate that CCK-8 and TNF-{alpha} initiate NF-{kappa}B activation by different PLC pathways, which converge at the novel PKCs, {delta} and {epsilon}, to mediate NF-{kappa}B activation in pancreatic acinar cells. These findings suggest a key role for the novel PKCs in pancreatitis.




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