Hoffmann, F.; Sass, G.; Zillies, Jan; Zahler, Stefan; Fuchs, S.; Wagner, J.; Winter, Gerhard; Coester, C.; Gerbes, Alexander L.; Vollmar, Angelika M.
A novel technique for selective NF-kappa B inhibition in Kupffer cells: contrary effects in fulminant hepatitis and ischaemia-reperfusion.
In: Gut, Vol. 58:
Background and aims: The transcription factor nuclear
factor kappa B (NF-kB) has risen as a promising target for
anti-inflammatory therapeutics. In the liver, however, NFkB
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-kB in hepatocytes, whereas the
role of NF-kB 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-kB in Kupffer cells and analyse the
effects in experimental models of liver injury.
Methods: NF-kB inhibiting decoy oligodeoxynucleotides
were loaded upon gelatin nanoparticles (D-NPs) and their
in vivo distribution was determined by confocal microscopy.
Liver damage, NF-kB 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-kB activation. Inhibition of NF-kB 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-kB augmented reperfusion injury.
Conclusions: NF-kB inhibiting decoy oligodeoxynucleotide-
loaded gelatin nanoparticles is a novel tool to
selectively inhibit NF-kB activation in Kupffer cells in vivo.
Thus, liver injury can be reduced in experimental fulminant
hepatitis, but increased at ischaemia–reperfusion.