Protein kinase C-zeta (PKC-ζ) regulates Kupffer cell apoptosis during experimental sepsis

Kupffer cells play an important role in sepsis-mediated liver injury. We tested the hypothesis that PKC-ζ plays a critical role in Kupffer cell apoptosis during sepsis. Sepsis was induced in rats by cecal ligation and puncture (CLP); 12 h later, livers were assayed for PKC-ζ, IKKα, IKKβ, IKKγ, NF-κB, Fas/FasL, Caspase-3, and DNA fragmentation. Kupffer cells from control rats were infected with AdPKC-ζ DN to inhibit PKC-ζ, or transfected with pCMVPKC-ζ to overexpress PKC-ζ, and then treated with lipopolysaccharide (LPS). Cellular extracts were assayed for PKC-ζ, IKKα, IKKβ, IKKγ, NF-κB, Fas/FasL, Caspase-3, and DNA fragmentation. During sepsis, PKC-ζ localized in cells positive for the macrophage marker (F4/80). CLP 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). AdPKC-ζ DN attenuated the LPS-induced upregulation of PKC-ζ activity, IKKβ, IKKγ, NF-κB, Fas/FasL, Caspase-3, and DNA fragmentation in Kupffer cells (all p∈<∈0.001), whereas overexpression of PKC-ζ augmented LPS-induced upregulation of IKKβ, IKKγ, NF-κB, Caspase-3, and DNA fragmentation (p∈<∈0.001). PKC-ζ plays an important role in sepsis-induced apoptosis of Kupffer cells via activation of NF-κB and Fas/FasL. Manipulating the response of Kupffer cells to cellular stress may have important therapeutic implications.