The NF-κB subunit RelA/p65 is dispensable for successful liver regeneration after partial hepatectomy in mice.
BACKGROUND
The transcription factor NF-κB consisting of the subunits RelA/p65 and p50 is known to be quickly activated after partial hepatectomy (PH), the functional relevance of which is still a matter of debate. Current concepts suggest that activation of NF-κB is especially critical in non-parenchymal cells to produce cytokines (TNF, IL-6) to adequately prime hepatocytes to proliferate after PH, while NF-κB within hepatocytes mainly bears cytoprotective functions.


METHODS
To study the role of the NF-κB pathway in different liver cell compartments, we generated conditional knockout mice in which the transactivating NF-κB subunit RelA/p65 can be inactivated specifically in hepatocytes (Rela(F/F)AlbCre) or both in hepatocytes plus non-parenchymal cells including Kupffer cells (Rela(F/F)MxCre). 2/3 and 80% PH were performed in controls (Rela(F/F)) and conditional knockout mice (Rela(F/F)AlbCre and Rela(F/F)MxCre) and analyzed for regeneration.


RESULTS
Hepatocyte-specific deletion of RelA/p65 in Rela(F/F)AlbCre mice resulted in an accelerated cell cycle progression without altering liver mass regeneration after 2/3 PH. Surprisingly, hepatocyte apoptosis or liver damage were not enhanced in Rela(F/F)AlbCre mice, even when performing 80% PH. The additional inactivation of RelA/p65 in non-parenchymal cells in Rela(F/F)MxCre mice reversed the small proliferative advantage observed after hepatocyte-specific deletion of RelA/p65 so that Rela(F/F)MxCre mice displayed normal cell cycle progression, DNA-synthesis and liver mass regeneration.


CONCLUSIONS
The NF-κB subunit RelA/p65 fulfills opposite functions in different liver cell compartments in liver regeneration after PH. However, the effects observed after conditional deletion of RelA/p65 are small and do not alter liver mass regeneration after PH. We therefore do not consider RelA/p65-containing canonical NF-κB signalling to be essential for successful liver regeneration after PH.
2nd Medical Department, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Marc
M
Ringelhan
Roland M
RM
Schmid
Fabian
F
Geisler
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D006498:Hepatectomy; D022781:Hepatocytes / Q000378:metabolism* / Q000502:physiology; D015151:Immunoblotting; D007728:Kupffer Cells / Q000378:metabolism; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*
C498144:Rela protein, mouse; D051996:Transcription Factor RelA