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.