title: Protein kinase C-zeta (PKC-zeta) regulates Kupffer cell apoptosis during experimental sepsis.
abstract: BACKGROUND
  Kupffer cells play an important role in sepsis-mediated liver injury. We tested the hypothesis that PKC-zeta plays a critical role in Kupffer cell apoptosis during sepsis.
  
  
  METHODS
  Sepsis was induced in rats by cecal ligation and puncture (CLP); 12 h later, livers were assayed for PKC-zeta, IKKalpha, IKKbeta, IKKgamma, NF-kappaB, Fas/FasL, Caspase-3, and DNA fragmentation. Kupffer cells from control rats were infected with AdPKC-zeta DN to inhibit PKC-zeta, or transfected with pCMVPKC-zeta to overexpress PKC-zeta, and then treated with lipopolysaccharide (LPS). Cellular extracts were assayed for PKC-zeta, IKKalpha, IKKbeta, IKKgamma, NF-kappaB, Fas/FasL, Caspase-3, and DNA fragmentation.
  
  
  RESULTS
  During sepsis, PKC-zeta localized in cells positive for the macrophage marker (F4/80). CLP upregulated PKC-zeta protein and activity, IKKbeta, IKKgamma, NF-kappaB, Fas/FasL, Caspase-3, and increased DNA fragmentation in rat livers (all p<0.001). AdPKC-zeta DN attenuated the LPS-induced upregulation of PKC-zeta activity, IKKbeta, IKKgamma, NF-kappaB, Fas/FasL, Caspase-3, and DNA fragmentation in Kupffer cells (all p<0.001), whereas overexpression of PKC-zeta augmented LPS-induced upregulation of IKKbeta, IKKgamma, NF-kappaB, Caspase-3, and DNA fragmentation (p<0.001).
  
  
  CONCLUSIONS
  PKC-zeta plays an important role in sepsis-induced apoptosis of Kupffer cells via activation of NF-kappaB and Fas/FasL. Manipulating the response of Kupffer cells to cellular stress may have important therapeutic implications.
authors: Department of Surgery, James A. Haley Veterans Affairs Medical Center, University of South Florida Health Sciences Center, C/O Tampa General Hospital, Tampa, FL 33601, USA.
authors: Yanhua
authors: Y
authors: Peng
authors: Celia A
authors: CA
authors: Sigua
authors: Cynthia
authors: C
authors: Karsonovich
authors: Michel M
authors: MM
authors: Murr
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053938:DNA Fragmentation; D051550:I-kappa B Kinase / Q000502:physiology; D007728:Kupffer Cells / Q000502:physiology*; D008297:Male; D018832:Molecular Chaperones / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000503:physiopathology*; D014178:Translocation, Genetic; D015854:Up-Regulation / Q000502:physiology; D000099221:Protein Kinase C zeta
chemical_list: D051550:I-kappa B Kinase; D018832:Molecular Chaperones; C490392:Prkcz protein, rat; D000099221:Protein Kinase C zeta