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

Abstract

Nuclear factor kappaB (NF-κB) plays an important role in the regulation of innate immune responses, apoptosis, inflammation, and oncogenesis. NF-κB 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 (IKKβ), which is the critical kinase of the IKK complex, and NF-κB activation in metastasis, we injected LLC cells into hepatocyte-specific IKKβ knockout mice (IkkβΔhep), whole-liver knockout (Ikkβ ΔL+H) mice, and control (IkkβF/F) mice. IkkβΔL+H mice developed liver metastasis with significantly lower liver weights and fewer metastatic foci compared to IkkβΔhep and IkkβF/F mice. Furthermore, intrasplenic LLC injection induced the messenger RNA (mRNA) expression of interleukin (IL)-6 and IL-1β in IkkβF/F mice, whereas these genes were less expressed in IkkβΔL+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 IKKβ/NF-κB activation controls the development of liver metastasis by way of IL-6 expression and is a potential target for the development of antimetastatic drugs. Copyright © 2009 by the American Association for the Study of Liver Diseases.