The NF-κB subunit RelA/p65 is dispensable for successful liver regeneration after partial hepatectomy in mice

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.

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.

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.

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.