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

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Journal of Gastrointestinal Surgery Aims and scope

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Abstract

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.

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Abbreviations

ABTS:

2, 2′azino-di [3-ethylbenzthiazoline sulfonate (6)] and H2O2 in glycine/citric acid buffer

AdLacZ:

adenovirus which expresses LacZ gene

AdPKCζ-DN:

adenovirus which expresses domain negative protein kinase C zeta

DMEM:

Dulbecco Modified Eagle’s Medium

ELISA:

enzyme-linked immunosorbent assay

FBS:

fetal bovine serum

IKKα:

IκB kinase α

IKKβ:

IκB kinase β

IKKγ:

IκB kinase γ

LPS:

lipopolysaccharide

MOI:

muliplicity of infection

NF-κB:

nuclear factor kappa-B

NP-40:

non-ionic surfactant

PCMVcDNA3.1:

empty expression vector driven by cytomegalovirus (CMV) promoter

PCMVPKC-ζ:

expression plasmid of protein kinase C zeta driven by CMV promoter

PKC-ζ:

protein kinase C zeta

PMSF:

phenylmethylsulfonyl fluoride

PRKC:

primary rat Kupffer cells

RIPA buffer:

PIPA buffer (50 mM Tris–HCl (pH 7.5), containing 1% Nonidet P-40, 0.05% SDS, 0.5% sodium deoxycholate, 1 mM EDTA, 150 mM NaCl, and protease inhibitors)

SDS:

sodium dodecyl sulfate

TNF-α:

tumor necrosis factor-α

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Acknowledgment

M.M. was supported by the Dr. Bob Haines Pancreatitis Research Fund and received a VA Merit Award.

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Authors and Affiliations

  1. Department of Surgery, James A. Haley Veterans Affairs Medical Center, University of South Florida Health Sciences Center, Tampa, FL, USA

    Yanhua Peng, Celia A. Sigua, Scott F. Gallagher & Michel M. Murr

  2. Tampa General Hospital, PO Box 1289, Tampa, FL, 33601, USA

    Michel M. Murr

Authors
  1. Yanhua Peng
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  2. Celia A. Sigua
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  3. Scott F. Gallagher
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  4. Michel M. Murr
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Correspondence to Michel M. Murr.

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Peng, Y., Sigua, C.A., Gallagher, S.F. et al. Protein Kinase C-ζ is Critical in Pancreatitis-Induced Apoptosis of Kupffer Cells. J Gastrointest Surg 11, 1253–1261 (2007). https://doi.org/10.1007/s11605-007-0193-0

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  • DOI: https://doi.org/10.1007/s11605-007-0193-0

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