Ikappa B kinasebeta/nuclear factor-kappaB activation controls the development of liver metastasis by way of interleukin-6 expression

Hepatology. 2009 Dec;50(6):1851-60. doi: 10.1002/hep.23199.


Nuclear factor kappaB (NF-kappaB) plays an important role in the regulation of innate immune responses, apoptosis, inflammation, and oncogenesis. NF-kappaB activation in the liver was observed after intrasplenic administration of a lung carcinoma cell line, LLC, which induces liver metastasis. To explore the role of Ikappa B kinase beta (IKKbeta), which is the critical kinase of the IKK complex, and NF-kappaB activation in metastasis, we injected LLC cells into hepatocyte-specific IKKbeta knockout mice (Ikkbeta(Deltahep)), whole-liver knockout (Ikkbeta(DeltaL+H)) mice, and control (Ikkbeta(F/F)) mice. Ikkbeta(DeltaL+H) mice developed liver metastasis with significantly lower liver weights and fewer metastatic foci compared to Ikkbeta(Deltahep) and Ikkbeta(F/F) mice. Furthermore, intrasplenic LLC injection induced the messenger RNA (mRNA) expression of interleukin (IL)-6 and IL-1beta in Ikkbeta(F/F) mice, whereas these genes were less expressed in Ikkbeta(DeltaL+H) mice. IL-6(-/-) mice and treatment with anti-IL-6 receptor antibody showed a lesser degree of metastatic tumor, indicating that IL-6 is associated with liver metastasis.

Conclusion: Collectively, these observations suggest that IKKbeta/NF-kappaB activation controls the development of liver metastasis by way of IL-6 expression and is a potential target for the development of antimetastatic drugs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • I-kappa B Kinase / physiology*
  • Interleukin-6 / physiology*
  • Liver Neoplasms / pathology
  • Liver Neoplasms / secondary*
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / physiology*
  • Neovascularization, Pathologic / etiology
  • Peptides / pharmacology
  • Tumor Necrosis Factor-alpha / physiology
  • Vascular Endothelial Growth Factor A / biosynthesis


  • Interleukin-6
  • NBD peptide, mouse
  • NF-kappa B
  • Peptides
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • I-kappa B Kinase