PKC-δ and -ε regulate NF-κB activation induced by cholecystokinin and TNF-α in pancreatic acinar cells

Akihiko Satoh, Anna S. Gukovskaya, Jose M. Nieto, Jason H. Cheng, Ilya Gukovsky, Joseph R. Reeve, Tooru Shimosegawa, Stephen J. Pandol

Research output: Contribution to journalArticlepeer-review

130 Citations (Scopus)

Abstract

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

Original languageEnglish
Pages (from-to)G582-G591
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume287
Issue number3 50-3
DOIs
Publication statusPublished - 2004 Sep

Keywords

  • Phosphatidylcholine-specific phospholipase C
  • Phosphatidylinositol-specific phospholipase C
  • Src kinases
  • Translocation
  • Tyrosine phosphorylation

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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