TY - JOUR
T1 - Protein kinase C-zeta (PKC-ζ) regulates Kupffer cell apoptosis during experimental sepsis
AU - Peng, Yanhua
AU - Sigua, Celia A.
AU - Karsonovich, Cynthia
AU - Murr, Michel M.
N1 - Funding Information:
Acknowledgment This study was supported by the VA Merit Award (MM) and Dr. Bob Haines Pancreatitis Research Fund (MM).
PY - 2007/12
Y1 - 2007/12
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Kupffer cells
KW - Liver injury
KW - PKC-ζ
KW - Sepsis
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U2 - 10.1007/s11605-007-0314-9
DO - 10.1007/s11605-007-0314-9
M3 - Article
C2 - 17899301
AN - SCOPUS:36148993630
SN - 1091-255X
VL - 11
SP - 1712
EP - 1721
JO - Journal of Gastrointestinal Surgery
JF - Journal of Gastrointestinal Surgery
IS - 12
ER -