NDLI: Protein kinase D1 mediates NF-κB activation induced by cholecystokinin and cholinergic signaling in pancreatic acinar cells

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Protein kinase D1 mediates NF-κB activation induced by cholecystokinin and cholinergic signaling in pancreatic acinar cells

Content Provider	PubMed Central
Author	Yuan, Jingzhen Lugea, Aurelia Zheng, Ling Gukovsky, Ilya Edderkaoui, Mouad Enrique, Rozengurt Pandol, Stephen J.
Abstract	The transcription factor NF-κB plays a critical role in inflammatory and cell death responses during acute pancreatitis. Previous studies in our laboratory demonstrated that protein kinase C (PKC) isoforms PKCδ and ɛ are key regulators of NF-κB activation induced by cholecystokinin-8 (CCK-8), tumor necrosis factor-α, and ethanol. However, the downstream participants in regulating NF-κB activation in exocrine pancreas remain poorly understood. Here, we demonstrate that protein kinase D1 (PKD1) is a key downstream target of PKCδ and PKCɛ in pancreatic acinar cells stimulated by two major secretagogues, CCK-8 and the cholinergic agonist carbachol (CCh), and that PKD1 is necessary for NF-κB activation induced by CCK-8 and CCh. Both CCK-8 and CCh dose dependently induced a rapid and striking activation of PKD1 in rat pancreatic acinar cells, as measured by in vitro kinase assay and by phosphorylation at PKD1 activation loop (Ser744/748) or autophosphorylation site (Ser916). The phosphorylation and activation of PKD1 correlated with NF-κB activity stimulated by CCK-8 or CCh, as measured by NF-κB DNA binding. Either inhibition of PKCδ or ɛ by isoform-specific inhibitory peptides, genetic deletion of PKCδ and ɛ in pancreatic acinar cells, or knockdown of PKD1 by using small interfering RNAs in AR42J cells resulted in a marked decrease in PKD1 and NF-κB activation stimulated by CCK-8 or CCh. Conversely, overexpression of PKD1 resulted in augmentation of CCK-8- and CCh-stimulated NF-κB activation. Finally, the kinetics of PKD1 and NF-κB activation during cerulein-induced rat pancreatitis showed that both PKD1 and NF-κB activation were early events during acute pancreatitis and that their time courses of response were similar. Our results identify PKD1 as a novel early convergent point for PKCδ and ɛ in the signaling pathways mediating NF-κB activation in pancreatitis.
Related Links	http://dx.doi.org/10.1152/ajpgi.90452.2008
Starting Page	1190
File Format	PDF
ISSN	01931857
e-ISSN	15221547
Journal	American Journal of Physiology - Gastrointestinal and Liver Physiology
Issue Number	6
Volume Number	295
Language	English
Publisher	American Physiological Society
Publisher Date	2008-10-01
Access Restriction	Open
Rights Holder	American Physiological Society
Subject Keyword	Hepatology Gastroenterology Physiology (medical) Physiology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Hepatology Physiology Physiology (medical) Gastroenterology

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