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IL-6 pathway in the liver: From physiopathology to therapy
Open accessAbstract
Interleukin 6 (IL-6) is a pleiotropic four-helix-bundle cytokine that exerts multiple functions in the body. In the liver, IL-6 is an important inducer of the acute phase response and infection defense. IL-6 is furthermore crucial for hepatocyte homeostasis and is a potent hepatocyte mitogen. It is not only implicated in liver regeneration, but also in metabolic function of the liver. However, persistent activation of the IL-6 signaling pathway is detrimental to the liver and might ultimately result in the development of liver tumors. On target cells IL-6 can bind to the signal transducing subunit gp130 either in complex with the membrane-bound or with the soluble IL-6 receptor to induce intracellular signaling. In this review we describe how these different pathways are involved in the physiology and pathophyiology of the liver. We furthermore discuss how IL-6 pathways can be selectively inhibited and therapeutically exploited for the treatment of liver pathologies.
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“Interleukin-6 (IL-6) plays an important role in both the acute-phase response against infections as well as liver regeneration (Figure 1).”
From The Role of Perioperative Interleukin-6 Serum Levels on Liver Dysfunction and Infectious Complications After Hepatectomy—A Systematic Review (2025) · cites this paper as [2]
In the citing paper
“As a pro-inflammatory cytokine IL-6 is produced at local tissue sites by various cells [1,2].”
From The Role of Perioperative Interleukin-6 Serum Levels on Liver Dysfunction and Infectious Complications After Hepatectomy—A Systematic Review (2025) · cites this paper as [2]
In the citing paper
“Moreover, IL-6 is a major factor in hepatic regeneration [2].”
From The Role of Perioperative Interleukin-6 Serum Levels on Liver Dysfunction and Infectious Complications After Hepatectomy—A Systematic Review (2025) · cites this paper as [2]
In the citing paper
“The acute phase response in the liver usually does not exceed 48 h, after which the organism returns to normal hepatic function, except in chronic states of inflammation [2].”
From The Role of Perioperative Interleukin-6 Serum Levels on Liver Dysfunction and Infectious Complications After Hepatectomy—A Systematic Review (2025) · cites this paper as [2]
In the citing paper
“However, the deletion of il6 gene also impairs the hepatocyte homeostasis and liver regeneration [3–5].”
From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [5]
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“Compared to OV-mOX40L or neutralizing antibody treatment alone, the combination therapy of OV-mOX40L with anti-IL6 or anti-PD-1 antibody significantly delayed tumor growth, and the most effective tumor inhibition was observed with the Theranostics 2023, Vol. 13, Issue 12 https://www.thno.org 4027 triple therapy (OV-mO…”
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Ghanemi, A., & St‐Amand, J. (2018) · Cytokine · doi:10.1016/j.cyto.2018.06.034 · Cited by 58
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InfluentialDifferent roles of interleukin 6 and interleukin 11 in the liver: implications for therapy
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“Profiling of primary human HSCs at the protein level shows high expression of IL11RA and gp130 but no (or very low) detectable IL6R.10 As with hepatocytes, HSCs are known to be IL6-responsive and are a source of IL6 themselves.33,34 However, based on the receptor expression data,10 HSCs do not appear to be a direct ta…”
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BackgroundImportance of Dietary Changes During the Coronavirus Pandemic: How to Upgrade Your Immune Response
Châari, A., Bendriss, G., Zakaria, D., & McVeigh, C. (2020) · Frontiers in Public Health · doi:10.3389/fpubh.2020.00476 · Cited by 62
“Inflammation could also be induced by a wide range of cytokines such as IL-6, which, in addition to its pro-inflammatory function, together with transforming growth factor (TGF)-β, stimulate the differentiation of “CD4+ Th cells or Th cells” into the proinflammatory Th17 subset (54, 55).”
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Novel goose-origin astrovirus infection in geese: the effect of age at infection
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“IL-6 was produced by a variety of lymphocytes and nonlymphocytes, in the liver; IL-6 is an important inducer of the acute phase response and infection defense (Schmidt-Arras and Rose-John, 2016).”
BackgroundThe peculiar aging of human liver: A geroscience perspective within transplant context
Morsiani, C., Bacalini, M. G., Santoro, A., Garagnani, P., Collura, S., D’Errico, A., de Eguileor, M., Grazi, G. L., Cescon, M., Franceschi, C., et al. (2019) · Ageing Research Reviews · doi:10.1016/j.arr.2019.02.002 · Cited by 54
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“This leads to the activation of a variety of intracellular signaling pathways, includingMAP kinase and PI3 kinase pathways, as well as STAT1 and the STAT3 pathways (Schmidt-Arras and Rose-John, 2016).”
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“In hepatic inflammation, IL-6 secreted macrophages facilitated transformation of hepatocytes at early stages of hepato-carcinogenesis [86].”
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“IL6 is produced inmonocytes, macrophages, T cells, fibroblasts, and endothelial cells; initiates the production of acute-phase proteins; and is an important inductor of infection defense.(15,16) The aim of our study was to compare the mortality prediction of IL6 with that of the MELD/MELD-Na score, CRP, and white bloo…”
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“In vitro, IL-6- as well as gp130-deficient mice show a lower HCC incidence and a prolonged survival in the Diethylnitrosamine (DEN) and high-fat diet (HFD) HCC mouse models, which was associated with a reduced expression of STAT3 [22,24].”
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CD1d protects against hepatocyte apoptosis in non-alcoholic steatohepatitis
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“Although IL-6 has been reported to play an important role in hepatic gluconeogenesis [37], we did not observe changes in the hepatic expression of this cytokine in Gdf15 (cid:0) / (cid:0) mice, which is consistent with a previous study reporting that stress-inducible IL-6 that increases…”
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“Thus, in HCC, IL6mediated hepcidin upregulation would be expected.”
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PRMT1-Dependent Macrophage IL-6 Production Is Required for Alcohol-Induced HCC Progression
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“However, persistent activation of the IL-6 pathway in the liver is associated with the development of liver tumors [131] through a mechanism of hypermethylation of tumor suppressor genes.”
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“TNFα and IL6 together increase the secretion of CRP from the liver.(159) An increase in cytokines additionally stimulate inflammatory pathways, JNK and NF-κB in the liver and skeletal muscle, increasing insulin resistance.”
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“27–29 In addition, it also has a crucial effect on LR. 30–32 IL-6 is mainly responsible for sending mitotic signals into hepatocytes via Jak/STAT3 pathway, besides, it exerts an essential effect on the initiation stage of LR and controls 40% of early gene expression in LR. 33–35 As discovered in…”
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“During liver regeneration after injury, cytokine IL-6 secreted upon inflammation activation binds to the IL-6 receptor complexed with the signal transducer glycoprotein 130 (gp130) on hepatocytes and triggers various downstream signaling pathways [376].”
BackgroundZhang, H., Shi, H., Li, X., Zhou, S., Song, X., Ma, N., Meng, M., Chang, G., & Shen, X. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103557 · Cited by 47
“As the primary ligand of gp130, IL-6 was reported to be a STAT3 activator [28].”
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“IL-6 binds with the IL-6 receptor which subsequently forms a complex with glycoprotein 130 (gp 130), driving signal transduction and liver regeneration [46].”
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Cholangiokines: undervalued modulators in the hepatic microenvironment
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Neurochemical effects of sepsis on the brain
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Metadata
- Authors
- Schmidt-Arras, D., & Rose-John, S.
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 64
- Issue
- 6
- Pages
- 1403-1415
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W2253819322
- Semantic Scholar
- 475d5a2af141aef15b1a1a8fb6b45473f2ce0e4b
- Cited by
- 881
- References
- 125
- Citations by year
- 2026: 59 · 2025: 106 · 2024: 97 · 2023: 106 · 2022: 121 · 2021: 114 · 2020: 98 · 2019: 72 · 2018: 54 · 2017: 37 · 2016: 17
- FWCI
- 27.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Hepatology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Hepatitis C virus research
- Keywords
- interleukin-6, IL-6 signaling, liver, acute phase response, liver regeneration, hepatic metabolism, gp130, soluble IL-6 receptor, IL-6 inhibition, liver disease treatment, liver tumors
- MeSH terms
- Interleukin-6 Inhibitors, Acute-Phase Reaction, Animals, Humans, Insulin Resistance, Liver, Liver Neoplasms, Liver Regeneration, Signal Transduction, Interleukin-6, Receptors, Interleukin-6, STAT3 Transcription Factor
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