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Hepatology. 2017 Jan;65(1):89-103. doi: 10.1002/hep.28874. Epub 2016 Nov 22.

IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice.

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Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.
Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
Department of Radiology, University Hospital Schleswig-Holstein, Kiel, Germany.
Institute of Immunology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Max-Planck-Institute for Metabolism Research, CECAD and Institute for Genetics, Cologne, Germany.
Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Institute of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany.


Hepatocellular carcinoma (HCC) is one of the most frequent tumors worldwide with rising incidence. The inflammatory cytokine, interleukin-6 (IL-6), is a critical mediator of HCC development. It can signal through two distinct pathways: the IL-6 classic and the IL-6 trans-signaling pathway. Whereas IL-6 classic signaling is important for innate and acquired immunity, IL-6 trans-signaling has been linked to accelerated liver regeneration and several chronic inflammatory pathologies. However, its implication in liver tumorigenesis has not been addressed yet. Here, we show that IL-6 trans-signaling, but not IL-6 classic signaling, is essential to promote hepatocellular carcinogenesis by two mechanisms: First, it prevents DNA-damage-induced hepatocyte apoptosis through suppression of p53 and enhances β-catenin activation and tumor proliferation. Second, IL-6 trans-signaling directly induces endothelial cell proliferation to promote tumor angiogenesis. Consequently, soluble gp130 fused to Fc transgenic mice lacking IL-6 trans-signaling are largely protected from tumor formation in a diethylnitrosamine/3,3',5,5'-tetrachloro-1,4-bis(pyridyloxy)benzene model of HCC.


IL-6 trans-signaling, and not IL-6 classic signaling, is mandatory for development of hepatocellular carcinogenesis. Therefore, specific inhibition of IL-6 trans-signaling, rather than total inhibition of IL-6 signaling, is sufficient to blunt tumor initiation and impair tumor progression without compromising IL-6 classic signaling-driven protective immune responses. (Hepatology 2017;65:89-103).

[Indexed for MEDLINE]

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