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

Academic Article
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Overview

authors

  • Maeda, S.
  • Kamata, H.
  • Luo, Junli
  • Leffert, H.
  • Karin, M.

publication date

  • July 2005

journal

  • Cell  Journal

abstract

  • 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.

subject areas

  • Animals
  • Carcinogens
  • Cell Death
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Cytokines
  • Diethylnitrosamine
  • Disease Models, Animal
  • Female
  • Hepatocytes
  • I-kappa B Kinase
  • Inflammation
  • JNK Mitogen-Activated Protein Kinases
  • Kupffer Cells
  • Liver Neoplasms, Experimental
  • Liver Regeneration
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Oxidative Stress
  • Protein Serine-Threonine Kinases
  • Reactive Oxygen Species
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Identity

International Standard Serial Number (ISSN)

  • 0092-8674

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2005.04.014

PubMed ID

  • 15989949
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Additional Document Info

start page

  • 977

end page

  • 990

volume

  • 121

issue

  • 7

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