Hepatocyte-Specific Inhibitor-Of-Kappab-Kinase Deletion Triggers The Innate Immune Response And Promotes Earlier Cell Proliferation During Liver Regeneration

Nuclear factor kappa B (NF-kappa B) is one of the main transcription factors involved in liver regeneration after partial hepatectomy (PH). It is activated upon I kappa B phosphorylation by the I kappa B kinase (IKK) complex comprising inhibitor of kappaB kinase 1 (IKK1), inhibitor of kappaB kinase 2 (IKK2), and nuclear factor-B essential modifier (NEMO). We studied the impact of hepatocyte-specific IKK2 deletion during liver regeneration. A 70% PH was performed on IKK2(f/f) (wildtype) and IKK2 Delta LPCmice (hepatocyte-specific IKK2 knockout mice). PH in IKK2 Delta LPC compared with IKK2(f/f) mice resulted in weaker and delayed NF-kappa B activation in hepatocytes, while nonparenchymal liver cells showed earlier NF-kappa B activation and higher tumor necrosis factor expression. Additionally, these animals showed increased and earlier serum amyloid A and chemotactic cytokine L-1 levels followed by enhanced polymorphonuclear cell recruitment to the liver. These results correlated with earlier Jun kinase activity, c-myc expression, and matrix metalloproteinase-9 activity, suggesting earlier priming in IKK2 Delta LPC mice after PH. These data preceded a more rapid cell cycle progression and earlier hepatocyte proliferation as evidenced through cyclin and 5-bromo-2-deoxyuridine analysis. Interestingly, despite faster G(1)/S progression, IKK2 Delta LPC mice exhibited an enduring mitosis phase, because mitotic bodies were still observed at later stages after PH. Conclusion: We demonstrate that PH in IKK2 Delta LPC mice triggers a more rapid and pronounced inflammatory response in nonparenchymal liver cells, which triggers earlier hepatocyte proliferation.