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PKC- and - regulate NF-B activation induced by cholecystokinin and TNF- in pancreatic acinar cells

¹Research Center for Alcoholic Liver and Pancreatic Diseases, Veterans Affairs Greater Los Angeles Health Care System and University of California, Los Angeles, California 90073; and ²Division of Gastroenterology, Tohoku University Graduate School of Medicine, Miyagi 980-8574, Japan

Submitted 24 February 2004 ; accepted in final form 24 April 2004

Although NF-B plays an important role in pancreatitis, mechanisms underlying its activation remain unclear. We investigated the signaling pathways mediating NF-B activation in pancreatic acinar cells induced by high-dose cholecystokinin-8 (CCK-8), which causes pancreatitis in rodent models, and TNF-, 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-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-B activation. Both CCK-8 and TNF- activated the novel isoforms PKC- and - and the atypical isoform PKC- but not the conventional isoform PKC-. Inhibition of the novel PKC isoforms but not the conventional or the atypical isoform resulted in the prevention of NF-B activation induced by CCK-8 and TNF-. NF-B activation by CCK-8 and TNF- required translocation but not tyrosine phosphorylation of PKC-. Activation of PKC-, PKC-, and NF-B with CCK-8 involved both phosphatidylinositol-specific PLC and phosphatidylcholine (PC)-specific PLC, whereas with TNF- they only required PC-specific PLC for activation. Results indicate that CCK-8 and TNF- initiate NF-B activation by different PLC pathways that converge at the novel PKCs ( and ) to mediate NF-B activation in pancreatic acinar cells. These findings suggest a key role for the novel PKCs in pancreatitis.

phosphatidylcholine-specific phospholipase C; phosphatidylinositol-specific phospholipase C; Src kinases; translocation; tyrosine phosphorylation

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