Cited by 881Cytokine Signaling Pathways and InteractionsLiver physiology and pathologyHepatitis C virus research

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IL-6 pathway in the liver: From physiopathology to therapy

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Schmidt-Arras, Dirk, Rose-John, Stefan·2016·Journal of Hepatology

DOI 10.1016/j.jhep.2016.02.004

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Abstract

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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BackgroundInfluential
Two phase kinetics of the inflammatory response from hepatocyte-peripheral blood mononuclear cell interactions
Beringer, A., Molle, J., Bartosch, B., & Miossec, P. (2019) · Scientific Reports · doi:10.1038/s41598-019-44840-w · Cited by 11
Interleukin-1 family cytokines in liver cell death: a new therapeutic target for liver diseases
Udomsinprasert, W. (2023) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2023.2285763 · Cited by 10
“The selection of ILs as therapeutic targets in the treatment of liver disease needs careful consideration due to their conflicting functions at different stages of the disease [149, 150].”
Background
IL-2-mediated hepatotoxicity: knowledge gap identification based on the irAOP concept
Roser, L. A., Sakellariou, C. A., Lindstedt, M., Neuhaus, V., Dehmel, S., Sommer, C., Raasch, M., Flandre, T., Roesener, S., Hewitt, P. G., et al. (2024) · Journal of Immunotoxicology · doi:10.1080/1547691x.2024.2332177 · Cited by 10
“IL-6 also has pleiotropic roles in the liver, promoting liver regeneration but also inflammation and cancer (Schmidt-Arras and Rose-John 2016).”
The 40-min HIIT acutely induced bone formation which was likely through the increases in muscle derived interleukin 6 and adiponectin activation: The 16 weeks of HIIT intervention, longitudinal randomized controlled trial
Sasimontonkul, S., & Sirivarasai, J. (2024) · Bone · doi:10.1016/j.bone.2024.117105 · Cited by 10
Gut Microbiota and Liver Regeneration: A Synthesis of Evidence on Structural Changes and Physiological Mechanisms
Kiseleva, Y. V., Zharikova, T. S., Maslennikov, R. V., Temirbekov, S. M., Olsufieva, A. V., Polyakova, O. L., Pontes‐Silva, A., & Zharikov, Y. O. (2024) · Journal of Clinical and Experimental Hepatology · doi:10.1016/j.jceh.2024.101455 · Cited by 11
Endothelin Receptor Down-Regulation Mediated Ligand Regulation Mechanisms Protect Against Cellular Hypoxia Injury in Rat Vascular Endothelial Cells
Li, L., Hu, M., Zheng, L., et al. (2016) · Cellular Physiology and Biochemistry · doi:10.1159/000453196 · Cited by 10
Serum from CCl4-induced acute rat injury model induces differentiation of ADSCs towards hepatic cells and reduces liver fibrosis
Baig, M. T., Ali, G., Awan, S. J., Shehzad, U., Mehmood, A., Mohsin, S., Khan, S. N., & Riazuddin, S. A. (2017) · Growth Factors · doi:10.1080/08977194.2017.1392945 · Cited by 10
“…the acute phase response by hepatocytes during inflammation and other homeostatic disturbances (Castell et al., 1990; Gauldie et al., 1990; Schmidt-Arras & Rose-John, 2016; Streetz et al., 2001) and in our study IL-6 was also elevated though non- significantly in serum isolated from rat…”
Background
Therapeutic potential of root and stem bark of wild medicinal plant Ziziphus mauritiana (Lamk.) against silica induced toxicity in Wistar albino rats
Dutta, R. P., & Patil, M. (2018) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2018.04.045 · Cited by 10
Inflammatory Process and Role of Cytokines in Inflammation: An Overview
Muzamil, A., Tahir, H. M., Ali, S., Liaqat, I., Ali, A., & Summer, M. (2022) · Punjab University journal of zoology · doi:10.17582/journal.pujz/2021.36.2.237.252 · Cited by 14
Baseline clinical features predicting macrophage activation syndrome in patients with systemic adult‐onset Still’s disease receiving interleukin‐6 inhibitor treatment
Naniwa, T., Yamabe, T., Ohmura, S., Uehara, K., Tamechika, S., Maeda, S., Isogai, S., & Wada, J.-I. (2022) · International Journal of Rheumatic Diseases · doi:10.1111/1756-185x.14371 · Cited by 10
Essential Amino Acids-Rich Diet Decreased Adipose Tissue Storage in Adult Mice: A Preliminary Histopathological Study
Corsetti, G., Romano, C., Codenotti, S., Pasini, E., Fanzani, A., & Dioguardi, F. S. (2022) · Nutrients · doi:10.3390/nu14142915 · Cited by 10
“The effects of IL-6 on metabolism need signal integration between many cell types [46].”
Background
Mechanisms of nonalcoholic steatohepatitis-associated cardiomyopathy: key roles for liver–heart crosstalk
Njoku, D. B., Schilling, J. D., & Finck, B. N. (2022) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000845 · Cited by 10
“In the liver, IL-6 drives the acute-phase response to invading pathogens or antigens, and is also required for hepatocyte and metabolic homeostasis [19].”
Background
Early Pathogenesis in Rabbit Hemorrhagic Disease Virus 2
O’Toole, A. D., Mohamed, F. S., Zhang, J., & Brown, C. C. (2022) · Microbial Pathogenesis · doi:10.1016/j.micpath.2022.105814 · Cited by 11
Association of preoperative IL-6 levels with overt HE in patients with cirrhosis after TIPS
Li, J., Liu, Y., Li, M.-B., Rong, X., Yuan, Z., Ren, C., Liu, S., Li, L., Zhao, C., Gao, L., et al. (2023) · Hepatology Communications · doi:10.1097/hc9.0000000000000128 · Cited by 10
“Under physiological conditions, it is very important for the prevention of infection and the regulation of metabolic function.[24] The cause of HE in patients with liver cirrhosis caused by IL-6 may be due to the destruction of intestinal mucosal barrier and the translocation of intestinal bacteria in patients with ci…”
Background
Sclareol ameliorates liver injury by inhibiting nuclear factor-kappa B/NOD-like receptor protein 3-mediated inflammation and lipid metabolism disorder in diabetic mice
Tang, L., Mei, X., Ye, M., Liu, Y., Huang, Y., Yu, J., Zhang, L., Zhuge, S., Jiang, G. Z., & Zhu, J. (2023) · International Journal of Immunopathology and Pharmacology · doi:10.1177/03946320231223644 · Cited by 10
“46,47 Increasing nuclear activation of NF-κ B p65 activated in ﬂ ammation in the livers of STZ-induced diabetic rats.”
Background
Sexually Dimorphic Response to Hepatic Injury in Newborn Suffering from Intrauterine Growth Restriction
Wei, Y., Tang, W., Mao, P., Mao, J., Ni, Z., Hou, K., Valencak, T. G., Liu, D., Ji, J., & Wang, H. (2024) · Advanced Science · doi:10.1002/advs.202403095 · Cited by 9
The Morphopathogenetic Aspects of Intraabdominal Adhesions in Children under One Year of Age
Junga, A., Pilmane, M., Ābola, Z., & Volrāts, O. (2019) · Medicina · doi:10.3390/medicina55090556 · Cited by 10
“IL-1 and TNFα are main activators of IL-6 expression [50].”
Background
Co‐cultured bone marrow mesenchymal stem cells repair thioacetamide‐induced hepatocyte damage
Chen, H., Awale, S., Wu, C., Lee, H., & Wu, H. (2020) · Cell Biology International · doi:10.1002/cbin.11453 · Cited by 10
“Liver fibrosis leads to the production of inflammatory cytokines like tumor growth factor‐β (TGF‐β) and tumor necrosis factor (TNF; Fabregat et al., 2016; Secchi et al., 2017).”
Background
The Novel Coronavirus and Inflammation
George, J. A., & Mayne, E. S. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-59261-5_11 · Cited by 9
Coronavirus disease 2019 severity in obesity: Metabolic dysfunction-associated fatty liver disease in the spotlight
Vasques‐Monteiro, I. M. L., & Souza‐Mello, V. (2021) · World Journal of Gastroenterology · doi:10.3748/wjg.v27.i16.1738 · Cited by 10
Unraveling the Molecular and Cellular Pathogenesis of COVID-19-Associated Liver Injury
Akkız, H. (2023) · Viruses · doi:10.3390/v15061287 · Cited by 10
Serum interleukin-6 level predicts the prognosis for patients with alcohol-related acute-on-chronic liver failure
Murakami, S., Imamura, M., Uchida, T., et al. (2023) · Hepatology International · doi:10.1007/s12072-023-10532-x · Cited by 9
“It is also involved in liver regeneration as well as in metabolic functions of the liver [26].”
Background
Comparison of the effects of BDNF/TRKB signalling on metabolic biomarkers in the liver of sedentary and trained rats with normal and knockout BDNF genotypes
Grzelak, N., Kaczmarek, D., & Mrówczyński, W. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1268648 · Cited by 10
Protective Effect of Artocarpus heterophyllus Lam. (Jackfruit) Polysaccharides on Liver Injury Induced by Cyclophosphamide in Mice
Cheng, M., Zheng, Y., Wu, G., Tan, L., Xu, F., Zhang, Y., Chen, X., & Zhu, K. (2024) · Nutrients · doi:10.3390/nu16010166 · Cited by 9
“Informed Consent Statement: Not applicable.”
An integrated kirigami-patterned skin patch for multiplexed detection of inflammatory biomarkers along with transdermal drug delivery
Noushin, T., Hossain, N. I., Tahrin, R., Islam, M. N., & Tabassum, S. (2025) · Sensing and Bio-Sensing Research · doi:10.1016/j.sbsr.2025.100772 · Cited by 10
Circulating IL6 is involved in the infiltration of M2 macrophages and CD8+ T cells
Huang, J., Xiao, R., Shi, S., Li, Q., Li, M., Xiao, M., Wang, Y., Yang, Y., Li, W., & Tang, Y. (2025) · Scientific Reports · doi:10.1038/s41598-025-92817-9 · Cited by 9
“The extent to which these biological effects are fully realized at a given concentration may be critical in determining differences in patient prognosis 36 .”
Mechanistic insights into the P-coumaric acid protection against bisphenol A-induced hepatotoxicity in in vivo and in silico models
Tekin, S., Bolat, M., Atasever, A., Bolat, İ., Çınar, B., Shadidizaji, A., Dağ, Y., Şengül, E., Yıldırım, S., Hacımüftüoğlu, A., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-87099-0 · Cited by 9
Anticancer Effects of Monacolin X Against Human Liver Cancer Cell Line: Exploring the Apoptosis Using AO/EB and DCFHDA Fluorescent Staining
Jayaraman, V., Arumugam, M. K., Balachandran, S., et al. (2025) · Luminescence · doi:10.1002/bio.70229 · Cited by 9
Clinical Impact of Serum CRP Levels on Advanced HCC Treated With Durvalumab and Tremelimumab: A Multicentre Study
Hatanaka, T., Yata, Y., Hiraoka, A., Tada, T., Hirooka, M., Kariyama, K., Tani, J., Atsukawa, M., Takaguchi, K., Itobayashi, E., et al. (2025) · Liver International · doi:10.1111/liv.70192 · Cited by 9
Cross‐regulation by TLR4 and T cell Ig mucin‐3 determines severity of liver injury in a CCl4‐induced mouse model
Zhao, L., Liang, J., Rao, W., Cui, M., Ren, S., Zhang, L., Xu, D., Han, Q., Zang, Y., & Zhang, B. (2019) · Scandinavian Journal of Immunology · doi:10.1111/sji.12851 · Cited by 9
Association of the IL-6 Rs1800796 SNP with Concentration/dose Ratios of Tacrolimus and Donor Liver Function after Transplantation
Wang, F., Wei, F., Liu, H., et al. (2020) · Immunological Investigations · doi:10.1080/08820139.2020.1793775 · Cited by 9
Human umbilical cord‐derived mesenchymal stem cells affect urea synthesis and the cell apoptosis of human induced hepatocytes by secreting IL‐6 in a serum‐free co‐culture system
Gu, C., Du, W., Chai, M., Jin, Z., Zhou, Y., Guo, P., Zhou, Y., & Tan, W. (2021) · Biotechnology Journal · doi:10.1002/biot.202100096 · Cited by 10
“[32] Therefore, hUMSCs are widely used in clinical research and treatment.[35] Gu et al.”
Background
Interval-Based Secretomics Unravels Acute-Phase Response in Hepatocyte Model Systems
Knecht, S., Eberl, H. C., & Bantscheff, M. (2022) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2022.100241 · Cited by 8
Growth Hormone Signaling in Liver Diseases: Therapeutic Potentials and Controversies
Oxley, M., Francis, H., & Sato, K. (2023) · Seminars in Liver Disease · doi:10.1055/a-2015-1359 · Cited by 5
NCOA5 Haploinsufficiency in Myeloid-Lineage Cells Sufficiently Causes Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma
Zhang, Y., Luo, Y., Liu, X., Kiupel, M., Li, A., Wang, H., Mi, Q., & Xiao, H. (2023) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2023.09.007 · Cited by 9
“17,18 Moreover, the mRNA level of Tnf encoding another proin ﬂ ammatory cytokine, tumor necrosis factor (TNF) a , was signi ﬁ cantly reduced in the intrahepatic macrophages of Ncoa5 D M/ þ male mice, validated by real-time quantitative polymerase chain reaction (RT-qPCR) (Figure5 D ).”
Method
Antirheumatic drugs and the risk of nonalcoholic fatty liver disease in patients with rheumatoid arthritis: A nationwide, population‐based cohort study
Meng, C., Chen, D., Chen, Y., et al. (2023) · International Journal of Rheumatic Diseases · doi:10.1111/1756-185x.15003 · Cited by 9
“14,15 It is posited that bio-logics targeting these cytokines could potentially reduce the prevalence of NAFLD.”
Background
Fibrinogen‐like 1: A hepatokine linking liver physiology to hematology
Personnaz, J., Guillou, H., & Kautz, L. (2024) · HemaSphere · doi:10.1002/hem3.115 · Cited by 8
“53 Treatment of the human hepatoma cell line HepG2 with IL ‐ 6 increased the expression and secretion of FGL1 in conditioned media concomitantly with other canonical acute phase response proteins, such as serum amyloid A1 or fibrinogen alpha chain.”
Background
Effects of Aerobic Exercise Protocol on Genes Related to Insulin Resistance and Inflammation in the Pancreas of ob/ob Mice with NAFLD
Silva, L. D. L. S. E., Fernandes, M. S. D. S., Kubrusly, M. S., Muller, C. R., Américo, A. L. V., Stefano, J. T., Evangelista, F. S., de Oliveira, C. P. M. S., & Jukemura, J. (2020) · Clinical and Experimental Gastroenterology · doi:10.2147/ceg.s242393 · Cited by 11
Serum Amyloid Beta42 Is Not Eliminated by the Cirrhotic Liver: A Pilot Study
Wiest, R., Weiß, T. S., Danielyan, L., & Buechler, C. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10122669 · Cited by 9
“Permanently high IL-6 is, nevertheless, detrimental to liver health [32].”
Background
Relationship Between Immunoinflammation and Coronary Physiology Evaluated by Quantitative Flow Ratio in Patients With Coronary Artery Disease
Liu, C., Yu, Z., Chen, H., Wang, J., Liu, W. Y., Zhou, L., Wang, Y., Chen, H., Zhou, H., Liu, Z., et al. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.714276 · Cited by 9
“In addition, IL-6 induces liver cells to synthesize fibrinogen and CRP (23).”
BackgroundInfluential
Interleukin-6 mediates lipopolysaccharide-inhibited irisin secretion in Nile tilapia (Oreochromis niloticus)
Yan, Y., Dong, R., Zhang, C., & Jiang, Q. (2021) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2021.12.039 · Cited by 9
Physical Exercise and Liver Autophagy: Potential Roles of IL-6 and Irisin
Pinto, A. P., Ropelle, E. R., Quadrilatero, J., & da Silva, A. S. R. (2021) · Exercise and Sport Sciences Reviews · doi:10.1249/jes.0000000000000278 · Cited by 10
“The complex of IL-6/IL-6R recruits the signaling b-subunit gp130 and induces downstream signaling (62).”
Background

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)
DOI: 10.1016/j.jhep.2016.02.004
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: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
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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IL-6 pathway in the liver: From physiopathology to therapy

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