IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis

I kappa B kinase beta (IKK beta), required for NF-kappa B activation, links chronic inflammation with carcinogenesis. We investigated whether IKK beta is involved in chemically induced liver cancer, a model not involving overt inflammation. Surprisingly, mice lacking IKK beta only in hepatocytes (Ikk beta(Delta hep) mice) exhibited a marked increase in hepatocarcinogenesis caused by diethylnitrosamine (DEN). This correlated with enhanced reactive oxygen species (ROS) production, increased JNK activation, and hepatocyte death, giving rise to augmented compensatory proliferation of surviving hepatocytes. Brief oral administration of an antioxidant around the time of DEN exposure blocked prolonged JNK activation and compensatory proliferation and prevented excessive DEN-induced carcinogenesis in Ikk beta(Delta hep) mice. Decreased hepatocarcinogenesis was also found in mice lacking IKKP in both hepatocytes and hematopoietic-derived Kupffer cells. These mice exhibited reduced hepatocyte regeneration and diminished induction of hepatomitogens, which were unaltered in Ikk beta(Delta hep) mice. IKK beta, therefore, orchestrates inflammatory crosstalk between hepatocytes and hematopoietic-derived cells that promotes chemical hepatocarcinogenesis.