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

Yanhua Peng, Celia A. Sigua, Cynthia Karsonovich, Michel M. Murr

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1712-1721
Number of pages10
JournalJournal of Gastrointestinal Surgery
Volume11
Issue number12
DOIs
StatePublished - Dec 1 2007

Keywords

  • Apoptosis
  • Kupffer cells
  • Liver injury
  • PKC-ζ
  • Sepsis

ASJC Scopus subject areas

  • Surgery
  • Gastroenterology

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