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 plays an important role in both the acute-phase response against infections and liver regeneration.
“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]
As a pro-inflammatory cytokine, IL-6 is produced at local tissue sites by various cells.
“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]
IL-6 is a major factor in hepatic regeneration.
“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]
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.
“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]
Deletion of the il6 gene impairs hepatocyte homeostasis and liver regeneration.
“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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Self-citationPossible role for tocilizumab, an anti-interleukin-6 receptor antibody, in treating cancer cachexia.
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Combined interleukin 6 and soluble interleukin 6 receptor accelerates murine liver regeneration
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Self-citationInterleukin-6 and its soluble receptor in patients with liver cirrhosis and hepatocellular carcinoma
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In Vivo and In Vitro Activities of the gp130-Stimulating Designer Cytokine Hyper-IL-6
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Self-citationSTAT3 targets the regulatory regions of gluconeogenic genes in vivo
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Self-citationImpact of interleukin-6 classic- and trans-signaling on liver damage and regeneration
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Self-citationCiliary neurotrophic factor induces acute‐phase protein expression in hepatocytes
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Hyper-IL-6 Gene Therapy Reverses Fulminant Hepatic Failure
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The interleukin 6 pathway and atherosclerosis
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Self-citationNCOA5 Haploinsufficiency Results in Glucose Intolerance and Subsequent Hepatocellular Carcinoma
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Tumoricidal effects of the JAK inhibitor Ruxolitinib (INC424) on hepatocellular carcinoma in vitro
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Role of IL-6 trans-signaling in CCl4 induced liver damage
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Self-citationThe Regenerative Activity of Interleukin-6
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Self-citationMurine Cardiotrophin-1 Stimulates the Acute-Phase Response in Rat Hepatocytes and H35 Hepatoma Cells
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Obesity Promotes Liver Carcinogenesis via Mcl-1 Stabilization Independent of IL-6Rα Signaling
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Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model
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Elevated serum interleukin-6 levels in patients with acute hepatitis
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Assessment of Tocilizumab in the Treatment of Cancer Cachexia
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Oncogenic deletion mutants of gp130 signal from intracellular compartments
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Self-citationAn acute phase protein ready to go therapeutic for sepsis
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gp130 activation is regulated by D2–D3 interdomain connectivity
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Self-citationHepatocyte senescence explains conjugated bilirubinaemia in chronic liver failure
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Chimeric antigen receptor T-cell therapy—assessment and management of toxicities
Neelapu, S. S., Tummala, S., Kebriaei, P., Wierda, W., Gutierrez, C., Locke, F. L., Komanduri, K. V., Lin, Y., Jain, N., Daver, N., et al. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.148 · Cited by 2,438 · see citing works
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Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations
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Interleukin-6 Family CytokinesPreprint
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Self-citationWen, Y., Lambrecht, J., Ju, C., & Tacke, F. (2021) · Cellular & Molecular Immunology · doi:10.1038/s41423-020-00558-8 · Cited by 695 · see citing works
The endocrine function of adipose tissues in health and cardiometabolic disease
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Hepatocytes direct the formation of a pro-metastatic niche in the liver
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Metabolic regulation of the immune system in health and diseases: mechanisms and interventions
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Contribution of Adipose Tissue Inflammation to the Development of Type 2 Diabetes Mellitus
Burhans, M. S., Hagman, D. K., Kuzma, J. N., Schmidt, K. A., & Kratz, M. (2018) · Comprehensive physiology · doi:10.1002/cphy.c170040 · Cited by 427 · see citing works
Regulation of Adipose Tissue Inflammation by Interleukin 6
Han, M. S., White, A., Perry, R. J., Camporez, J.-P., Hidalgo, J., Shulman, G. I., & Davis, R. J. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1920004117 · Cited by 344 · see citing works
“The physiology of IL6 signaling is complex because the effects of IL6 on metabolism requires signal integration between cell types (4) that involve proinflammatory, anti-inflammatory, and noninflammatory mechanisms (5).”
BackgroundInterleukin 6 as an Energy Allocator in Muscle Tissue
Kistner, T. M., Pedersen, B. K., & Lieberman, D. E. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00538-4 · Cited by 295 · see citing works
Pathophysiology of COVID-19: Mechanisms Underlying Disease Severity and Progression
Bohn, M. K., Hall, A., Sepiashvili, L., Jung, B., Steele, S., & Adeli, K. (2020) · Physiology · doi:10.1152/physiol.00019.2020 · Cited by 259 · see citing works
The Role of Complement in Liver Injury, Regeneration, and Transplantation
Thorgersen, E. B., Barratt‐Due, A., Haugaa, H., Harboe, M., Pischke, S. E., Nilsson, P. H., & Mollnes, T. E. (2019) · Hepatology · doi:10.1002/hep.30508 · Cited by 240 · see citing works
“Thus, the prosurvival properties of C3a and C5a seem to be exerted through crosstalk with the cytokine network, in particular local formation of IL-6 and TNF.(36) The versatile cytokine IL-4, produced locally by natural killer T cells, may contribute to liver regeneration, possibly through a regulatory positive feedba…”
BackgroundCosta, D., Simbrunner, B., Jachs, M., Hartl, L., Bauer, D. J. M., Paternostro, R., Schwabl, P., Scheiner, B., Stättermayer, A. F., Pinter, M., et al. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.10.004 · Cited by 211 · see citing works
Hou, X., Yin, S., Ren, R., Liu, S., Yong, L., Liu, Y., Li, Y., Zheng, M., Kunos, G., Gao, B., et al. (2021) · Hepatology · doi:10.1002/hep.31658 · Cited by 223 · see citing works
Deep insight into cytokine storm: from pathogenesis to treatment
Nie, J., Zhou, L., Tian, W., Liu, X., Yang, L., Yang, X., Zhang, Y., Wei, S., Wang, D. W., & Wei, J. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02178-y · Cited by 224 · see citing works
“245 – 247 Hepatic dysfunction disrupts the balance between coagulation and antic-oagulation, potentially leading to DIC in severe cases.”
Relevance of SIRT1-NF-κB Axis as Therapeutic Target to Ameliorate Inflammation in Liver Disease
de Gregorio, E., Colell, A., Morales, A., & Marı́, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21113858 · Cited by 202 · see citing works
“Among these cytokines IL6, a hepatocyte mitogen that is crucial for liver regeneration [91] and IL10, with potent anti-inflammatory and immunoregulatory effects, are key in restoring hepatic homeostasis [92].”
BackgroundRole of C-Reactive Protein in Diabetic Inflammation
Stanimirović, J., Radovanović, J., Banjac, K., Obradovic, M. M., Essack, M., Zafirovic, S. S., Gluvic, Z. M., Gojobori, T., & Isenović, E. R. (2022) · Mediators of Inflammation · doi:10.1155/2022/3706508 · Cited by 214 · see citing works
Liver Regeneration: Analysis of the Main Relevant Signaling Molecules
Tao, Y.-C., Wang, M.-L., Chen, E., & Tang, H. (2017) · Mediators of Inflammation · doi:10.1155/2017/4256352 · Cited by 191 · see citing works
“Surprisingly, either IL-6 or IL-6R alone has no affinity to gp130 and only when the IL-6/IL-6R complex is formed, interaction with gp130 would occur.”
BackgroundInfluentialMosteiro, L., Pantoja, C., de Martino, A., & Serrano, M. (2018) · Aging Cell · doi:10.1111/acel.12711 · Cited by 182 · see citing works
“IL6 has been implicated in several models of cell dedifferentiation and tissue regeneration (see, e.g., Dubois-PotSchneider et al., 2014; Gallucci et al., 2000; Lin, Kondo, Ishida, Takayasu & Mukaida, 2003; Schmidt-Arras & Rose-John, 2016).”
BackgroundLiver Regeneration after Hepatectomy and Partial Liver Transplantation
Yagi, S., Hirata, M., Miyachi, Y., & Uemoto, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218414 · Cited by 192 · see citing works
“Recently, the importance of “IL-6 trans-signaling” on liver regeneration has gained considerable attention [70].”
BackgroundLee, H. L., Jang, J. W., Lee, S. W., Yoo, S. H., Kwon, J. H., Nam, S. W., Bae, S. H., Choi, J. Y., Han, N. I., & Yoon, S. K. (2019) · Scientific Reports · doi:10.1038/s41598-019-40078-8 · Cited by 185 · see citing works
Effects of aging on liver microcirculatory function and sinusoidal phenotype
Maeso‐Díaz, R., Ortega‐Ribera, M., Fernández‐Iglesias, A., Hide, D., Muñoz, L., Hessheimer, A. J., Vila, S., Francés, R., Fondevila, C., Albillos, A., et al. (2018) · Aging Cell · doi:10.1111/acel.12829 · Cited by 175 · see citing works
Rosa, M., Chignon, A., Li, Z., Boulanger, M., Arsenault, B. J., Bossé, Y., Thériault, S., & Mathieu, P. (2019) · npj Genomic Medicine · doi:10.1038/s41525-019-0097-4 · Cited by 167 · see citing works
T lymphocyte membrane-decorated epigenetic nanoinducer of interferons for cancer immunotherapy
Zhai, Y., Wang, J., Lang, T., Kong, Y., Rong, R., Cai, Y., Ran, W., Xiong, F., Zheng, C., Wang, Y., et al. (2021) · Nature Nanotechnology · doi:10.1038/s41565-021-00972-7 · Cited by 170 · see citing works
The gut microbiome and elevated cardiovascular risk in obesity and autoimmunity
Kasselman, L. J., Vernice, N. A., DeLeon, J. R., & Reiss, A. B. (2018) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.02.036 · Cited by 159 · see citing works
Interleukin-6: A Novel Target for Cardio-Cerebrovascular Diseases
Su, J.-H., Luo, M.-Y., Liang, N., Gong, S.-X., Chen, W., Huang, W., Tian, Y., & Wang, A. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.745061 · Cited by 160 · see citing works
“Secretion and Structure of Interleukin-6 IL-6 comes from a wide range of sources, mainly produced by mononuclear macrophages, T helper 2 cells, B cells, vascular endothelial cells (ECs), smooth muscle cells (SMCs) and fibroblasts (Schmidt-Arras and Rose-John, 2016).”
BackgroundLi, Y., Zheng, Q., Zou, L., et al. (2019) · Pediatric Rheumatology · doi:10.1186/s12969-018-0303-4 · Cited by 155 · see citing works
Damania, A., Jaiman, D., Teotia, A. K., & Kumar, A. (2018) · Stem Cell Research & Therapy · doi:10.1186/s13287-017-0752-6 · Cited by 150 · see citing works
“Some studies have shown the prominent role of TNF-α and IL-6 in initiating liver regeneration, with their levels increasing on injury [54, 55].”
BackgroundAcute liver failure is regulated by MYC- and microbiome-dependent programs
Kolodziejczyk, A. A., Federici, S., Zmora, N., Mohapatra, G., Dori-Bachash, M., Hornstein, S., Leshem, A., Reuveni, D., Zigmond, E., Tobar, A., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-1102-2 · Cited by 148 · see citing works
Three-dimensional perfused human in vitro model of non-alcoholic fatty liver disease
Kostrzewski, T. M., Cornforth, T. V., Snow, S., Ouro-Gnao, L., Rowe, C., Large, E. M., & Hughes, D. J. (2017) · World Journal of Gastroenterology · doi:10.3748/wjg.v23.i2.204 · Cited by 149 · see citing works
Leukocytes, Systemic Inflammation and Immunopathology in Acute-on-Chronic Liver Failure
Casulleras, M., Zhang, I. W., López‐Vicario, C., & Clària, J. (2020) · Cells · doi:10.3390/cells9122632 · Cited by 137 · see citing works
“The inhibition of IL-6 for the prevention or treatment of inflammatory diseases has been extensively approached [83].”
BackgroundIL‐6 trans‐signaling is essential for the development of hepatocellular carcinoma in mice
Bergmann, J., Müller, M., Baumann, N., Reichert, M., Heneweer, C., Bolik, J., Lücke, K., Gruber, S., Carambia, A., Boretius, S., et al. (2017) · Hepatology · doi:10.1002/hep.28874 · Cited by 152 · see citing works
“(15) This indicates that IL-6 trans-signaling, rather than IL-6 classic signaling through the membrane-bound IL-6R, is critical for development of HCC. Tumors in both mice were well differentiated and did not show large differences in gene expression of a 16-gene set recently used for assessment of HCC aggressiveness.”
BackgroundInfluentialSelf-citationImmunopathobiology and therapeutic targets related to cytokines in liver diseases
He, Y., Hwang, S., Ahmed, Y. A., Feng, D., Li, N., Ribeiro, M. D. C., Lafdil, F., Kisseleva, T., Szabó, G., & Gao, B. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-00580-w · Cited by 136 · see citing works
Distinct Effects of IL-6 Classic and Trans -Signaling in Bone Fracture Healing
Prystaz, K., Kaiser, K., Kovtun, A., Haffner-Luntzer, M., Fischer, V., Rapp, A. E., Liedert, A., Strauss, G., Waetzig, G. H., Rose-John, S., et al. (2018) · The American Journal of Pathology · doi:10.1016/j.ajpath.2017.10.011 · Cited by 142 · see citing works
“To test the efficacy of IL-6 inhibition, the induction of intracellular IL-6 signaling was analyzed by determining STAT3 phosphorylation in hepatocytes, which express high levels of mIL-6R (31).”
BackgroundResultInfluentialSelf-citationStackIL6: a stacking ensemble model for improving the prediction of IL-6 inducing peptides
Charoenkwan, P., Chiangjong, W., Nantasenamat, C., Hasan, M. M., Manavalan, B., & Shoombuatong, W. (2021) · Briefings in Bioinformatics · doi:10.1093/bib/bbab172 · Cited by 134 · see citing works
Innate Immune Cells in the Adipose Tissue in Health and Metabolic Disease
Michailidou, Z., Gomez-Salazar, M. A., & Alexaki, V. I. (2021) · Journal of Innate Immunity · doi:10.1159/000515117 · Cited by 137 · see citing works
Fibrinogen-like protein 1 (FGL1): the next immune checkpoint target
Qian, W., Zhao, M., Wang, R., & Li, H. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01161-8 · Cited by 136 · see citing works
Dong, J., Viswanathan, S., Adami, E., Singh, B. K., Chothani, S. P., Ng, B., Lim, W., Zhou, J., Tripathi, M., Ko, N. S. J., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20303-z · Cited by 125 · see citing works
Lee, C., Kim, J., & Jung, Y. (2019) · Cells · doi:10.3390/cells8101259 · Cited by 123 · see citing works
Beyer, D., Hoff, J., Sommerfeld, O., Zipprich, A., Gaßler, N., & Press, A. T. (2022) · Molecular Medicine · doi:10.1186/s10020-022-00510-8 · Cited by 122 · see citing works
“The liver sinusoidal endothelial cell (LSEC) is a specialized endothelial cell lining the capillaries of the liver, termed sinusoids.”
BackgroundInfluentialCoperchini, F., Chiovato, L., & Rotondi, M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.668507 · Cited by 116 · see citing works
Pathogenesis of Kupffer Cells in Cholestatic Liver Injury
Sato, K., Hall, C. M., Glaser, S. S., Francis, H., Meng, F., & Alpini, G. D. (2016) · American Journal Of Pathology · doi:10.1016/j.ajpath.2016.06.003 · Cited by 120 · see citing works
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Gender Differences in the Pathogenesis and Risk Factors of Hepatocellular Carcinoma
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“This property of IL-6 trans-signaling might be important for several cellular or tissue responses, which can only be induced by IL-6 trans-signaling but not by IL-6 classic signaling via the membrane-bound IL-6R [18].”
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From Infection to Death: An Overview of the Pathogenesis of Visceral Leishmaniasis
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“Liver-resident neutrophils also secrete IL-6, which enhances liver inflammation in the early phase of liver disease and promotes the final development from cirrhosis to HCC 158 .”
BackgroundCancer-associated fibroblasts promote the stemness of CD24+ liver cells via paracrine signaling
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“Additionally, IL-6 is secreted by neutrophils and macrophages during inflammatory conditions, such as during stimulation of Toll-like receptor- (TLR-) 4 by lipopolysaccharide or stimulation of cells by IL-1 or TNF-α [36].”
BackgroundDifferential regulation of hepcidin in cancer and non-cancer tissues and its clinical implications
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Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2
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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
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“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
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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].”
BackgroundLiver Inflammation and Hepatobiliary Cancers.
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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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“(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.”
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“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.”
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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].”
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“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).”
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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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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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- 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
- Health Sciences › Medicine › Oncology › 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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