IL‐6 trans‐signaling is essential for the development of hepatocellular carcinoma in mice
Open accessAbstract
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. CONCLUSION: 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).
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Specific inhibition of IL-6 trans-signaling, rather than total inhibition of IL-6 signaling, is sufficient to suppress tumor progression.
“Only the specific inhibition of IL-6 trans-signaling, rather than total inhibition of IL-6 signaling, is sufficient to suppress tumor progression [71, 72].”
From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [71]
IL-6 trans-signaling, but not IL-6 classic signaling, is essential to promote HCC carcinogenesis and progression; activation of membrane-bound IL-6R and gp130 in hepatocytes alone seems not sufficient for tumor formation.
“In addition, evidences suggest that IL-6 trans-signaling, but not IL-6 classic signaling, is essential to promote HCC carcinogenesis and progression, and only the activation of membrane-bound IL-6R and gp130 in hepatocytes seems not sufficient for tumor formation [71, 72].”
From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [71]
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“Only the specific inhibition of IL-6 trans -signaling, rather than total inhibition of IL-6 signaling, is sufficient to suppress tumor progression [71, 72].”
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Self-citation
- Authors
- Bergmann, J., Müller, M., Baumann, N., Reichert, M., Heneweer, C., Bolik, J., Lücke, K., Gruber, S., Carambia, A., Boretius, S., Leuschner, I., Becker, T., Rabe, B., Herkel, J., Wunderlich, F. T., Mittrücker, H., Rose‐John, S., & Schmidt‐Arras, D.
- Affiliations
- German Academic Exchange Service (DE)
- University Hospital Schleswig-Holstein (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Max Planck Institute for Metabolism Research (DE)
- Corresponding author
- Schmidt‐Arras, Dirk
- ORCID
- Venue
- Hepatology
- Published
- 2017-01
- Volume
- 65
- Issue
- 1
- Pages
- 89-103
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2532470837
- Cited by
- 152
- References
- 5
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 13 · 2023: 20 · 2022: 16 · 2021: 25 · 2020: 22 · 2019: 18 · 2018: 18 · 2017: 8
- FWCI
- 7.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Max Planck Digital Library (submittedVersion)
- GRO (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Bonn (SFB841, SFB877)
- Australian Technology Network/Deutscher Akademischer Austauschdienst
- Medical Faculty of the Christian-Albrechts-University Kiel
- Cluster of Excellence ‘Inflammation at Interfaces’
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- interleukin-6, IL-6 trans-signaling, hepatocellular carcinoma, hepatocarcinogenesis, soluble gp130, p53, β-catenin, hepatocyte apoptosis, DNA damage, tumor angiogenesis, endothelial cell proliferation, diethylnitrosamine
- MeSH terms
- Animals, Carcinoma, Hepatocellular, Liver Neoplasms, Male, Signal Transduction, Interleukin-6, Mice
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