IKKβ Couples Hepatocyte Death to Cytokine-Driven Compensatory Proliferation that Promotes Chemical Hepatocarcinogenesis
Copyright policy )IKKβ Couples Hepatocyte Death to Cytokine-Driven Compensatory Proliferation that Promotes Chemical Hepatocarcinogenesis
IkappaB kinase beta (IKKbeta), required for NF-kappaB activation, links chronic inflammation with carcinogenesis. We investigated whether IKKbeta is involved in chemically induced liver cancer, a model not involving overt inflammation. Surprisingly, mice lacking IKKbeta only in hepatocytes (Ikkbeta(Deltahep) 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 Ikkbeta(Deltahep) mice. Decreased hepatocarcinogenesis was also found in mice lacking IKKbeta in both hepatocytes and hematopoietic-derived Kupffer cells. These mice exhibited reduced hepatocyte regeneration and diminished induction of hepatomitogens, which were unaltered in Ikkbeta(Deltahep) mice. IKKbeta, therefore, orchestrates inflammatory crosstalk between hepatocytes and hematopoietic-derived cells that promotes chemical hepatocarcinogenesis.
- University of California, San Diego United States
- University of California, San Diego United States
Inflammation, Male, Mice, Knockout, Cell Death, Biochemistry, Genetics and Molecular Biology(all), Kupffer Cells, JNK Mitogen-Activated Protein Kinases, I-kappa B Kinase, Liver Regeneration, Mice, Inbred C57BL, Disease Models, Animal, Mice, Cell Transformation, Neoplastic, Liver Neoplasms, Experimental, Carcinogens, Hepatocytes, Animals, Cytokines, Diethylnitrosamine, Female, Cell Proliferation
Inflammation, Male, Mice, Knockout, Cell Death, Biochemistry, Genetics and Molecular Biology(all), Kupffer Cells, JNK Mitogen-Activated Protein Kinases, I-kappa B Kinase, Liver Regeneration, Mice, Inbred C57BL, Disease Models, Animal, Mice, Cell Transformation, Neoplastic, Liver Neoplasms, Experimental, Carcinogens, Hepatocytes, Animals, Cytokines, Diethylnitrosamine, Female, Cell Proliferation
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