title: IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice.
abstract: 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).
authors: Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.|Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
authors: Juri
authors: J
authors: Bergmann
authors: Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.
authors: Miryam
authors: M
authors: Müller
authors: Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.
authors: Niklas
authors: N
authors: Baumann
authors: Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.|Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
authors: Manuel
authors: M
authors: Reichert
authors: Department of Radiology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors: Carola
authors: C
authors: Heneweer
authors: Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.
authors: Julia
authors: J
authors: Bolik
authors: Institute of Immunology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors: Karsten
authors: K
authors: Lücke
authors: Max-Planck-Institute for Metabolism Research, CECAD and Institute for Genetics, Cologne, Germany.
authors: Sabine
authors: S
authors: Gruber
authors: Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors: Antonella
authors: A
authors: Carambia
authors: Department of Radiology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors: Susanne
authors: S
authors: Boretius
authors: Institute of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors: Ivo
authors: I
authors: Leuschner
authors: Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
authors: Thomas
authors: T
authors: Becker
authors: Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.
authors: Björn
authors: B
authors: Rabe
authors: Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors: Johannes
authors: J
authors: Herkel
authors: Max-Planck-Institute for Metabolism Research, CECAD and Institute for Genetics, Cologne, Germany.
authors: F Thomas
authors: FT
authors: Wunderlich
authors: Institute of Immunology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors: Hans-Willi
authors: HW
authors: Mittrücker
authors: Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.
authors: Stefan
authors: S
authors: Rose-John
authors: Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.
authors: Dirk
authors: D
authors: Schmidt-Arras
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology*; D015850:Interleukin-6 / Q000502:physiology*; D008113:Liver Neoplasms / Q000209:etiology*; D008297:Male; D051379:Mice; D015398:Signal Transduction
chemical_list: D015850:Interleukin-6