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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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.