Ikappa B Kinaseβ/Nuclear Factor-κB Activation Controls the Development of Liver Metastasis by Way of Interleukin-6 Expression

Nuclear factor kappaB (NF-kappa B) plays an important role in the regulation of innate immune responses, apoptosis, inflammation, and oncogenesis. NF-kappa B 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 (IKK beta), which is the critical kinase of the IKK complex, and NF-kappa B activation in metastasis, we injected LLC cells into hepatocyte-specific IKK beta knockout mice (Ikk beta(Delta hep)), whole-liver knockout (Ikk beta(Delta L+H)) mice, and control (Ikk beta(F/F)) mice. Ikk beta(Delta L+H) mice developed liver metastasis with significantly lower liver weights and fewer metastatic foci compared to Ikk beta(Delta hep) and Ikk beta(F/F) mice. Furthermore, intrasplenic LLC injection induced the messenger RNA (mRNA) expression of interleukin (IL)-6 and IL-1 beta in Ikk beta(F/F) mice, whereas these genes were less expressed in Ikk beta(Delta L+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 IKK beta/NF-kappa B activation controls the development of liver metastasis byway of IL-6 expression and is a potential target for the development of antimetastatic drugs. (HEPATOLOGY 2009;50:1851-1860.)