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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 is secreted by T cells and macrophages to enhance the immune reaction (25), to aid the differentiation and proliferation of T and B cells, and to advance the development of plasma cells from B cells (26).”
Heidarian, E., Keloushadi, M., Samani, K. G., et al. (2017) · International Journal of Cancer Management · doi:10.5812/ijcm.9163 · Cited by 8
“IL-6 is a pleiotropic cytokine that plays several physiological roles in cells (4).”
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“IL-6 signaling is harmful to liver and ultimately leads to hepatic tumors and its level increase in fibrosis and cirrhosis (Schmidt-Arras and Rose-John 2016).”
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“IL-6 is a primary inducer of the hepatic acute-phase response; exogenous IL-6 entering the liver acts on hepatocytes, increasing acute-phase protein synthesis, including C-reactive protein (Schmidt-Arras and Rose-John 2016; Huang et al. 2019).”
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“IL-6 is a cytokine produced by macrophages, endothelial cells, T cells and fibroblasts upon stimulation of Toll-like receptor 4, IL1 or tumor necrosis factor-a.(16) IL-6 signaling involves classical cis-signaling as well as trans-signaling pathways.”
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“The trigger for increased IL-6 gene expression could be due to the HFF diet-induced dysbiosis, which stimulates the release of gut-derived endotoxin-like lipopolysaccharide (LPS) and activation of resident Kupffer cells, resulting in a TNF α -dependent regulation of IL-6 in the liver [62].”
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IL-6 trans-Signaling Regulates Neutrophilic Inflammation in Alcohol-Associated Hepatitis
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“Nevertheless, its persistent activation is detrimental to the liver [109].”
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“IL-6 and the above-mentioned growth factors have also been described in the context of the premetastatic niche, a concept that describes tissue alterations facilitating the engraftment of circulating tumor cells in the target organ, thus leading to successful implantation of metastases (10, 11).”
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“10,42 Concordantly, IL-1b is a known activator of HSCs and is increased in hepatic venous blood in patients with ALCD.”
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“TCZblocks IL-6, which has an important role in acute phase response and CRP production [32].”
BackgroundCLASSIC IL-6 SIGNALING IS ASSOCIATED WITH POOR OUTCOMES IN BURN PATIENTS
Rehou, S., Abdullahi, A., & Jeschke, M. G. (2022) · Shock · doi:10.1097/shk.0000000000002051 · Cited by 6
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“Previous studies have reported higher serum levels of IL-6 in several hepatic diseases (Schmidt-Arras and Rose-John, 2016), as well as a positive correlation between IL-6 and AST levels in hospitalized COVID-19 patients (Effenberger et al., 2021).”
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“IL-6 has a crucial role in triggering the acute-phase response and defending against infections in the liver [22].”
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“IL-6 trans-signaling has been shown to play a decisive role in the regulation of liver regeneration (Scheller et al., 2011; Schmidt-Arras and Rose-John, 2016).”
Founder cells for hepatocytes during liver regeneration: from identification to application
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“At 24 h post-RFA, interleukin (IL)-6, an important mediator of the acute phase response that has both pro-and anti-inflammatory properties [33 – 35] was significantly increased (4 h vs 24 h, p value = 0.012).”
BackgroundInfluentialPerricone, C., Castellucci, A., Cafaro, G., Calvacchi, S., Bruno, L., Pozzolo, R. D., Tromby, F., Colangelo, A., Gerli, R., & Bartoloni, E. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1398314 · Cited by 5
“IL-6 IL-6 inhibitors turn out to be related to certain contraindications in patients with altered liver enzymes; likewise JAKi appear to have some contraindications too (10 – 13, 122 – 124).”
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“Many studies have illustrated that immune-related molecules, such as interleukin-6 [24, 25], lymphotoxin-α [26], and tumor necrosis factor [27, 28], can accelerate the occurrence of liver cancer and affect the aggressiveness of tumors; however, the immune response also limits the progression of…”
BackgroundSalt Sensitivity of Blood Pressure and the Role of the Immune System in Hypertension
Flores, J., Peña, C., & NUGENT, K. M. (2024) · Cardiology in Review · doi:10.1097/crd.0000000000000834 · Cited by 5
IL-6 decodes sex and diet-dependent circadian and metabolic rhythms
González-Vila, A., Ibrahim-Alasoufi, A. M., Luengo-Mateos, M., Pardo-García, V., Diaz-López, A., Fernández-Rodríguez, B., POUTANEN, M. H., Ohlsson, C., Tena‐Sempere, M., Diéguez-González, C., et al. (2025) · Molecular Metabolism · doi:10.1016/j.molmet.2025.102171 · Cited by 5
Part I: Acute Lower Limb Ischemia-Reperfusion Injury: Pathophysiology and Experimental Interventions
Carmon, L., Peters, A. A., Laban, N., Langert, K. A., Maier, K. G., & Gahtan, V. (2025) · Vascular and Endovascular Surgery · doi:10.1177/15385744251387771 · Cited by 7
Liver Regeneration: Polyploidy and Cellular Senescence as Potential Regulators
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“…such as hepatocyte growth factor (HGF), transforming growth factor-beta (TGF-β), epidermal growth factor (EGF), and cytokines such as interleukin-6 ● Cytokines (IL-6 and TNF-α): These cytokines are in - volved in the priming phase and prepare hepatocytes to respond to growth factors [19].”
Oxidative Stress and Alcohol-Related Hepatitis: A Role for Future Therapies
D’Arcangelo, F., Rajoriya, N., & Lalor, P. F. (2026) · Antioxidants · doi:10.3390/antiox15040493 · Cited by 6
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IL-6 Promotes Hepatocellular Carcinoma Invasion by Releasing Exosomal miR-133a-3p
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“Interleukin-6 (IL-6) is a critical mediator of HCC development [2] and is involved in the regulation of cancer stem cell proliferation, differentiation, invasion, metastasis, and angiogenesis through a number of signaling pathways, such as STAT3 signaling, which drives cancer progression and metastasis [3].”
BackgroundCarvalho, M. L. G., Falcão, L. F. M., Lopes, J. D. C., Mendes, C. C. H., Olímpio, F. A., Miranda, V. D. S. C., dos Santos, L. C., de de Moraes, D. D. P., Filho, M. V. B., da Costa, L. D., et al. (2022) · Cells · doi:10.3390/cells11132053 · Cited by 7
“This may be directly related to the participation of IL-6, a cytokine included in our study that, in addition to participating together with TGF-β in the differentiation process of the Th17 pro le, can also stimulate myo broblasts and hepatocytes to synthesise collagen, which is important for the formation of the reti…”
BackgroundMyofibroblasts: A key promoter of tumorigenesis following radiofrequency tumor ablation
Moussa, M., Mwin, D., Liao, H., Atac, M. F., Markezana, A., Galun, E., Goldberg, S. N., & Ahmed, M. (2022) · PLoS ONE · doi:10.1371/journal.pone.0266522 · Cited by 5
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gp130 Activates Mitochondrial Dynamics for Hepatocyte Survival in a Model of Steatohepatitis
Shunkina, D., Dakhnevich, A. Y., Shunkin, E. O., Хазиахматова, О. Г., Shupletsova, V. V., Vulf, M. A., Komar, A., Кириенкова, Е. В., & Litvinova, L. S. (2023) · Biomedicines · doi:10.3390/biomedicines11020396 · Cited by 5
Stress-inducible IL-6 is regulated by KLF7 in brown adipocytes
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Endotheliopathy of liver sinusoidal endothelial cells in liver disease
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“IL‐1β, IL‐6, TNFα), and induces the production of acute inflammatory proteins such as CRP and fibrinogen in hepatocytes.(94,95) IL‐6 trans‐signaling is thought to be the major route of IL‐6 signaling in LSECs because they don't have the membrane‐bound IL‐6Rα.”
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“In the liver, IL-6 is synthesized mainly by KCs upon stimulation of TLRs or tissue injury, providing the induction of acute phase response [49] and hence, early protection against infection [50].”
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“HGF induces mitosis in hepatocytes by activating the tyrosine kinase receptor c-Met, which is the predominant mitogen in hepatocytes 26 .”
BackgroundInflammatory mechanisms of abused drugs
Mitchell, C. M., Jordi, O. E., & Yamamoto, B. K. (2018) · Advances in neurotoxicology · doi:10.1016/bs.ant.2018.10.006 · Cited by 5
Development and Validation of a Reporter-Cell-Line-Based Bioassay for Therapeutic Soluble gp130-Fc
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The Peculiar Trialogue between Pediatric Obesity, Systemic Inflammatory Status, and Immunity
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“Moreover, the obesity-resident immune cells were also proved to secrete certain adipokines like: C-X-C motif chemokine ligand 14, released from brown adipose tissue, seems to be involved in the stimulation of thermogenic differentiation in white adipose tissue via M2 macrophage polarization [75]; IL 6 which might expr…”
BackgroundIL6 Signaling in Cancer: Not Always Bad News
Huynh, J., & Ernst, M. (2021) · Cancer Research · doi:10.1158/0008-5472.can-21-2137 · Cited by 5
“Indeed, studies indicate that blockade of IL6/IL6R binding leads to an increase in systemic IL6 (7).”
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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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