Protein Kinase C-ζ is Critical in Pancreatitis-Induced Apoptosis of Kupffer Cells

Protein kinase C-zeta (PKC-ζ) regulates cell death via NF-κB; therefore, we tested the hypothesis that PKC-ζ plays a critical role in pancreatitis-induced Kupffer cell apoptosis. Acute pancreatitis was induced in rats by cerulein injection 24 h later, livers were assayed for PKC-ζ, IKKα, IKKβ, IKKγ, NF-κB, Fas/FasL, and apoptosis was assessed with Caspase-3 and DNA fragmentation. Kupffer cells from unoperated rats were infected with a PKC-ζ domain-negative adenovirus (AdPKCζ-DN) to inhibit PKC-ζ, or transfected with pCMVPKC-ζ to overexpress PKC-ζ, and then stimulated with pancreatic elastase; cellular extracts were assayed for PKC-ζ, IKKα, IKKβ, IKKγ, NF-κB, Fas/FasL, Caspase-3, and DNA fragmentation. Cerulein-induced pancreatitis upregulated PKC-ζ protein and activity, IKKβ, IKKγ, NF-κB, Fas/FasL, Caspase-3 and increased DNA fragmentation in rat livers (all p < 0.001 vs control). AdPKCζ-DN abolished elastase-induced upregulation of PKC-ζ activity, IKKβ, IKKγ, NF-κB, Fas/FasL, Caspase-3 and DNA fragmentation (all p < 0.001 vs infection control), whereas overexpression of PKC-ζ augmented elastase-induced upregulation of IKKβ, IKKγ, Fas/FasL, Caspase-3 and DNA fragmentation (p < 0.001 vs control). PKC-ζ plays a critical role in pancreatitis-induced Kupffer cell apoptosis via NF-κB and Fas/FasL. The ability of Kupffer cells to autoregulate their stress response by upregulating their death receptor/ligand and key proapoptotic cell signaling systems warrants further investigation.