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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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“IL-6 interacts with its coreceptors IL-6R and glycoprotein 130 (gp130) to regulate multiple signaling pathways, including JAK/STAT3, SRC family kinase/Yes-associated protein (SFK/YAP), Src homology phosphotyrosyl phosphatase 2/RAS/ERK, and PI3K/AKT/mTOR (42, 43).”
Modeling alcohol-associated liver disease in a human Liver-Chip
Nawroth, J. C., Petropolis, D. B., Manatakis, D. V., Maulana, T. I., Burchett, G., Schlünder, K., Witt, A., Shukla, A., Kodella, K., Ronxhi, J., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109393 · Cited by 88
“The cytokine rise is most likely linked to oxidative stress (Figure 4B) and the associated cell injury or other mechanisms as previously described (Schmidt-Arras and Rose-John, 2016).”
Systemic inflammation as fuel for acute liver injury in COVID-19
Effenberger, M., Grander, C., Grabherr, F., Griesmacher, A., Ploner, T., Hartig, F., Bellmann‐Weiler, R., Joannidis, M., Zoller, H., Weiß, G., et al. (2020) · Digestive and Liver Disease · doi:10.1016/j.dld.2020.08.004 · Cited by 88
The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases
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“Indeed, hepatocytes express far more amounts of gp130 on the surface than IL-6R, and hyper-IL-6 thus can lead to a profound down-stream effector signaling [5, 27, 29].”
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“IL-6 induced compensatory proliferation of hepatocytes in a diethylnitrosamine (DEN)-induced hepatocarcinogenesis model, and either deletion of IL-6 or gp130, a second receptor protein associated with the IL-6 receptor, suppressed liver tumor development in a DEN model in mice [15].”
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“3) [43], cytotoxic T lymphocyte (CTL) activating [44], inducing hepatocytes-mediated acute phase reactive proteins secretion [45], and hematopoietic stem cells differentiation [46].”
The Role of Autophagy for the Regeneration of the Aging Liver
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“It is considered as being an effective hepatocyte mitogen [42].”
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Sick fat: the good and the bad of old and new circulating markers of adipose tissue inflammation
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“(48) The IL-6Rα is expressed on multiple cell types in the liver including hepatocytes, stellate cells, Kupffer cells, leukocytes, and endothelial cells.(48) Our studies using hepatocyte-specific IL-6Rα knockout mice show that AILI is more severe in IL-6Rαhep/− than WT mice.”
BackgroundInfluentialAletaha, D., Kerschbaumer, A., Kastrati, K., Dejaco, C., Dougados, M., McInnes, I. B., Sattar, N. A., Stamm, T., Takeuchi, T., Trauner, M., et al. (2022) · Annals of the Rheumatic Diseases · doi:10.1136/ard-2022-222784 · Cited by 85
“26 IL-6 is the most abundant cytokine in the circulation and uses a variety of means to bind to and activate target cells either directly or indirectly.”
Kidney–liver pathophysiological crosstalk: its characteristics and importance
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“It is known that these interleukins have an essential role in liver regeneration, but they have also been related with hepatocellular carcinoma development, and they have also been found elevated in cirrhotic patients [6].”
BackgroundInfluentialAnger, F., Camara, M., Ellinger, E., Germer, C., Schlegel, N., Otto, C., & Klein, I. (2019) · Stem Cells and Development · doi:10.1089/scd.2019.0085 · Cited by 77
Laval, K., Vernejoul, J. B., Cleemput, J. V., Koyuncu, O. Ö., & Enquist, L. W. (2018) · Journal of Virology · doi:10.1128/jvi.01614-18 · Cited by 80
“Typically, IL-6 is produced following pathogen stimulation in the initial stage of the inflammation and is the main inducer of an acute-phase response in the liver (47).”
BackgroundHan, R., Zhang, F., Wan, C., Liu, L., Zhong, Q., & Ding, W. (2018) · Chemosphere · doi:10.1016/j.chemosphere.2018.02.137 · Cited by 78
Impact of Lipotoxicity on Tissue “Cross Talk” and Metabolic Regulation
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Interleukin-6: Molecule in the Intersection of Cancer, Ageing and COVID-19
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“It is well known that some types of cancer are associated with the mutation of proteins of the IL-6 axis that can significantly influence IL-6 signalling [13,153,154].”
BackgroundNaseem, S., Hussain, T., & Manzoor, S. (2018) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2018.01.002 · Cited by 72
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“-e progression of fibrogenesis leads to increased synthesis of collagen [33].”
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“The classic IL-6 pathway is known to induce the hepatic acute-phase response (Schmidt-Arras and Rose-John 2016).”
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NAFLD and HBV interplay - related mechanisms underlying liver disease progression
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IL-6 Directed Therapy in Transplantation
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Dynamic human liver proteome atlas reveals functional insights into disease pathways
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Aging of Liver in Its Different Diseases
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Functional role of skeletal muscle-derived interleukin-6 and its effects on lipid metabolism
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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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