Role and regulation of p65/β-catenin association during liver injury and regeneration: a 'complex' relationship.

Abstract An important role for β-catenin in regulating p65 (a subunit of NF-κB) during acute liver injury has recently been elucidated through use of conditional β-catenin knockout mice, which show protection from apoptosis through increased activation of p65. Thus, we hypothesized that the p65/β-catenin complex may play a role in regulating processes such as cell proliferation during liver regeneration. We show through in vitro and in vivo studies that the p65/β-catenin complex is regulated through the TNF- pathway, and not through Wnt signaling. However, this complex is unchanged after partial hepatectomy (PH), despite increased p65 and -catenin nuclear translocation as well as cyclin D1 activation. We demonstrate through both in vitro silencing experiments and chromatin immunoprecipitation after PH that β-catenin, and not p65, regulates cyclin D1 expression. Conversely, using reporter mice we show p65 is activated exclusively in the non-parenchymal (NPC) compartment during liver regeneration. Furthermore, stimulation of macrophages by TNF- induces activation of NF-κB and subsequent secretion of Wnts essential for β-catenin activation in hepatocytes. Thus, we show that -catenin and p65 are activated in separate cellular compartments during liver regeneration, with p65 activity in NPCs contributing to the activation of hepatocyte -catenin, cyclin D1 expression, and subsequent proliferation.