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A novel technique for selective NF-κB inhibition in Kupffer cells: contrary effects in fulminant hepatitis and ischaemia–reperfusion
  1. F Hoffmann1,2,
  2. G Sass3,
  3. J Zillies1,
  4. S Zahler1,
  5. G Tiegs3,
  6. A Hartkorn1,
  7. S Fuchs1,
  8. J Wagner4,
  9. G Winter1,
  10. C Coester1,
  11. A L Gerbes2,
  12. A M Vollmar1
  1. 1
    Department of Pharmacy, Center of Drug Research, University of Munich, Germany
  2. 2
    Klinikum Großhadern, University of Munich, Germany
  3. 3
    Division of Experimental Immunology and Hepatology, University Medical Centre Hamburg Eppendorf, Hamburg, Germany
  4. 4
    Institute of Pathology, University of Munich, Germany
  1. Correspondence to Professor A M Vollmar, Department of Pharmacy, Center of Drug Research, Butenandtstrasse 5-13, D-81377 Munich, Germany; Angelika.Vollmar{at}cup.uni-muenchen.de

Abstract

Background and aims: The transcription factor nuclear factor kappa B (NF-κB) has risen as a promising target for anti-inflammatory therapeutics. In the liver, however, NF-κB inhibition mediates both damaging and protective effects. The outcome is deemed to depend on the liver cell type addressed. Recent gene knock-out studies focused on the role of NF-κB in hepatocytes, whereas the role of NF-κB in Kupffer cells has not yet been investigated in vivo. Here we present a novel approach, which may be suitable for clinical application, to selectively target NF-κB in Kupffer cells and analyse the effects in experimental models of liver injury.

Methods: NF-κB inhibiting decoy oligodeoxynucleotides were loaded upon gelatin nanoparticles (D-NPs) and their in vivo distribution was determined by confocal microscopy. Liver damage, NF-κB activity, cytokine levels and apoptotic protein expression were evaluated after lipopolysaccharide (LPS), d-galactosamine (GalN)/LPS, or concanavalin A (ConA) challenge and partial warm ischaemia and subsequent reperfusion, respectively.

Results: D-NPs were selectively taken up by Kupffer cells and inhibited NF-κB activation. Inhibition of NF-κB in Kupffer cells improved survival and reduced liver injury after GalN/LPS as well as after ConA challenge. While anti-apoptotic protein expression in liver tissue was not reduced, pro-apoptotic players such as cJun N-terminal kinase (JNK) were inhibited. In contrast, selective inhibition of NF-κB augmented reperfusion injury.

Conclusions: NF-κB inhibiting decoy oligodeoxynucleotide-loaded gelatin nanoparticles is a novel tool to selectively inhibit NF-κB activation in Kupffer cells in vivo. Thus, liver injury can be reduced in experimental fulminant hepatitis, but increased at ischaemia–reperfusion.

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Footnotes

  • Funding This work was supported by grants of the Deutsche Forschungsgemeinschaft (DFG, FOR 440).

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • See Commentary, p 1580

  • Ethics approval All animals used in this study received human care in compliance with the “Principles of Laboratory Animal Care”. The study was registered with the local animal welfare committee.

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