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A novel technique for selective NF-κB inhibition in Kupffer cells - contrary effects in fulminant hepatitis and ischemia/reperfusion
  1. Florian Hoffmann
  1. Department of Pharmacy, Center of Drug Research, University of Munich, Germany
    1. Gabriele Sass
    1. Department of Pharmacology, University of Erlangen, Germany
      1. Jan Zillies
      1. Department of Pharmacy, Center of Drug Research, University of Munich, Germany
        1. Stefan Zahler
        1. Department of Pharmacy, Center of Drug Research, University of Munich, Germany
          1. Gisa Tiegs
          1. Department of Internal Medicine 1, University Medical Centre Hamburg, Germany
            1. Andreas Hartkorn
            1. Department of Pharmacy, Center of Drug Research, University of Munich, Germany
              1. Sebastian Fuchs
              1. Department of Pharmacy, Center of Drug Research, University of Munich, Germany
                1. Jenny Wagner
                1. Institute of Pathology, University of Munich, Germany
                  1. Gerhard Winter
                  1. Department of Pharmacy, Center of Drug Research, University of Munich, Germany
                    1. Conrad Coester
                    1. Department of Pharmacy, Center of Drug Research, University of Munich, Germany
                      1. Alexander L Gerbes
                      1. Klinikum Großhadern, University of Munich, Germany
                        1. Angelika M Vollmar (angelika.vollmar{at}cup.uni-muenchen.de)
                        1. Department of Pharmacy, Center of Drug Research, University of Munich, Germany

                          Abstract

                          Background and aims: The transcription factor 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. We here present a novel approach, which may be suitable for clinical application, to selectively target NF-κB in Kupffer cells and analyze the effects in experimental models of liver injury.

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

                          Results: D-NP 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 antiapoptotic protein expression in liver tissue was not reduced, pro-apoptotic players such as JNK were inhibited. In contrast, selective inhibition of NF-κB augmented reperfusion injury.

                          Conclusions: NF-κB inhibiting decoy oligodeoxynucleotide loaded gelatin nanoparticles are 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 ischemia/reperfusion.

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