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Cited by 84Cytokine Signaling Pathways and InteractionsLiver physiology and pathologyAlcohol Consumption and Health Effects

The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases

Open access
Wang, Min-Jun, Zhang, Hai-Ling, Chen, Fei, Guo, Xiao-Jing, Liu, Qing-Gui, Hou, Jin·2024·Experimental Hematology & Oncology
DOI 10.1186/s40164-024-00527-1PMC PMC11184755
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Abstract

Interleukin-6 (IL-6) is a pleiotropic cytokine and exerts its complex biological functions mainly through three different signal modes, called cis-,trans-, and cluster signaling. When IL-6 binds to its membrane or soluble receptors, the co-receptor gp130 is activated to initiate downstream signaling and induce the expression of target genes. In the liver, IL-6 can perform its anti-inflammatory activities to promote hepatocyte reprogramming and liver regeneration. On the contrary, IL-6 also exerts the pro-inflammatory functions to induce liver aging, fibrosis, steatosis, and carcinogenesis. However, understanding the roles and underlying mechanisms of IL-6 in liver physiological and pathological processes is still an ongoing process. So far, therapeutic agents against IL‑6, IL‑6 receptor (IL‑6R), IL-6-sIL-6R complex, or IL-6 downstream signal transducers have been developed, and determined to be effective in the intervention of inflammatory diseases and cancers. In this review, we summarized and highlighted the understanding of the double-edged effects of IL-6 in liver homeostasis, aging, inflammation, and chronic diseases, for better shifting the “negative” functions of IL-6 to the “beneficial” actions, and further discussed the potential therapeutic effects of targeting IL-6 signaling in the clinics.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review argues that interleukin-6 (IL-6) acts as a double-edged cytokine in the liver, driving regeneration and hepatocyte reprogramming through its pro-regenerative and anti-inflammatory actions while also promoting steatosis, fibrosis, aging, and carcinogenesis when chronically elevated. It surveys the three IL-6 signaling modes (cis/classic, trans, and cluster), their downstream JAK-STAT, MAPK, PI3K, and YAP cascades, and the therapeutic case for selectively blocking IL-6 trans-signaling rather than global IL-6 blockade.

Key findings

  • IL-6 is a 184-amino-acid glycoprotein of 21–28 kDa that signals via three modes; because gp130 is widely expressed while membrane IL-6R is largely restricted to hepatocytes, immune cells, and some endothelial cells, trans- and cluster signaling greatly expand the range of IL-6-responsive cells.
  • In liver regeneration, IL-6 trans-signaling is described as more important than classic signaling: hyper-IL-6 (an IL-6/sIL-6R fusion protein) produced stronger and earlier hepatocyte regeneration after 70% hepatectomy, and IL-6/sIL-6R double transgenic mice showed massive hepatocyte proliferation even without hepatectomy, whereas IL-6 single transgenic mice did not. IL-6 combined with EGF and HGF supported long-term expansion of primary mouse hepatocytes in vitro (>30 passages in ~150 days, theoretical expansion of ~10^35 times).
  • In aging and disease, serum IL-6 is normally <2 pg/mL or undetectable but rises with age; in a cohort of end-stage liver disease, no patients with IL-6 <5.3 pg/mL died within one year, while more than half of aged patients with IL-6 >11.6 pg/mL died within one year. Hepatic IL-6 can exceed 100 ng/mL during inflammation, and elevated IL-6/STAT3 signaling is associated with early tumor recurrence and poor prognosis in HCC.
  • IL-6 also has protective/anti-inflammatory roles: in mdr2−/− mice, il6 deletion or soluble gp130 blockade exacerbated steatosis, inflammation, chronic hepatitis, and hepatocarcinogenesis; IL-6 from liver stromal cells skews monocyte differentiation toward tissue-resident Kupffer cells and away from scar-associated macrophages.
  • On therapy, the review reports that selective trans-signaling blockade (e.g., sgp130Fc/olamkicept) avoids impairing classic-signaling host defense, and that in a phase II trial 47% of Crohn's disease patients on filgotinib achieved clinical remission versus 23% on tofacitinib; over 20% of active IBD patients treated with olamkicept had complete alleviation of clinical symptoms and inflammatory markers.

Methods

  • Narrative review (no primary data collection); the paper synthesizes mechanistic and preclinical literature plus clinical trial evidence on IL-6 signaling in liver homeostasis, regeneration, aging, inflammation, and chronic disease.
  • Evidence cited spans knockout and transgenic mouse models (il6−/−, hepatocyte-specific gp130 or STAT3 knockout, IL-6R-deficient, IL-6/sIL-6R double transgenic, DEN-induced HCC, mdr2−/−, NASH models), humanized liver and hPSC-derived liver culture models, patient cohorts, and a table of clinical trials (Table 1) listing agents targeting IL-6, IL-6R, sIL-6R, JAK, and STAT across phases I–IV.
  • No systematic search strategy, inclusion criteria, or quantitative synthesis is described.

Limitations

  • The paper states no formal limitations section; it acknowledges that "understanding the roles and underlying mechanisms of IL-6 in liver physiological and pathological processes is still an ongoing process," and that global IL-6 inhibition produces adverse effects (e.g., abdominal pain in IBD) that limit clinical use.
  • Evident from the text: as a narrative review it presents no systematic search or quality appraisal, and much of the mechanistic evidence derives from mouse models and in vitro systems, with the authors themselves noting that conclusions such as the primacy of trans-signaling need confirmation and that timing, location, and mechanism of IL-6 action must be better defined before accurate intervention.
  • Several cited findings are attributed to other groups' studies without independent verification, and the clinical trial table lists trial phases and identifiers without reporting efficacy outcomes for most agents.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1186/s40164-024-00527-1

Cites

114 of 114 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

35 of 59 cited sources checked · 8 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    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].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [3] Blindenbacher A, Wang X, Langer I, Savino R, Terracciano L, Heim MH. Interleukin 6 is important for survival after partial hepatectomy in mice. Hepatology. 2003;38:674–82. source

      The Discussion (page unavailable) reports that IL-6-deficient mice had much poorer survival after partial hepatectomy, supporting a role for IL-6 in recovery. But the Liver Regeneration section (page unavailable) says surviving knockout mice restored liver mass as well as controls, and the paper does not establish impaired baseline hepatocyte homeostasis. The unqualified claim that deletion impairs liver regeneration therefore overstates the findings. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [4] Cressman DE, Greenbaum LE, DeAngelis RA, Ciliberto G, Furth EE, Poli V, et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science. 1996;274:1379–83. source
    • cites [5] Schmidt-Arras D, Rose-John S. IL-6 pathway in the liver: from physiopathology to therapy. J Hepatol. 2016;64:1403–15. source
  • Premisecitation

    Specific blockade of IL-6 trans-signaling using recombinant sgp130Fc does not interfere with functions in defense against pathogens.

    “However, the specific blockade of IL-6 trans-signaling using the recombinant sgp130Fc did not interfere with its functions in the defense against pathogens [80].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [80] Jones SA, Jenkins BJ. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat Rev Immunol. 2018;18:773–89. source

      The Therapeutic strategies section identifies an engineered sgp130 protein that selectively inhibits IL-6 trans-signalling. It does not report that this blockade leaves pathogen defence unaffected. Indeed, the Critical modulators of innate immunity section describes IL-6 trans-signalling as contributing to neutrophil phagocytosis and killing, so the claimed lack of interference is not established by this review. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    Specific inhibition of IL-6 trans-signaling, rather than total inhibition of IL-6 signaling, is sufficient to suppress tumor progression.

    “Only the specific inhibition of IL-6 trans-signaling, rather than total inhibition of IL-6 signaling, is sufficient to suppress tumor progression [71, 72].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [71] Bergmann J, Müller M, Baumann N, Reichert M, Heneweer C, Bolik J, et al. IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice. Hepatology. 2017;65:89–103. source
    • cites [72] Reeh H, Rudolph N, Billing U, Christen H, Streif S, Bullinger E, et al. Response to IL-6 trans- and IL-6 classic signalling is determined by the ratio of the IL-6 receptor α to gp130 expression: fusing experimental insights and dynamic modelling. Cell Commun Signal. 2019;17:46. source

      The Discussion (page unavailable) describes selective inhibition of IL-6 trans-signalling while preserving classic signalling, and reports its use in animal models of Crohn’s disease. It does not report that selective inhibition suppresses tumor progression or establish that it is sufficient to do so rather than total IL-6 inhibition. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    Global blockade of IL-6 signaling may reduce induction of hepatic acute-phase proteins upon infection, such as Listeria monocytogenes.

    “As IL-6 classic signaling plays crucial roles in the initiation of inflammation and the host defense against pathogen infection, global blockade of IL-6 signaling may reduce the induction of hepatic acute-phase proteins upon infection, such as Listeria monocytogenes [79].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [79] Rose-John S, Jenkins BJ, Garbers C, Moll JM, Scheller J. Targeting IL-6 trans-signalling: past, present and future prospects. Nat Rev Immunol. 2023;23:666–81. source
  • Premisecitation

    In a mouse model of NASH, knockout of IL-6 or IL-6R reduces signs of inflammation during NASH progression.

    “In a mouse model of non-alcoholic steatohepatitis (NASH), knockout of IL-6 or IL-6R also reduced the signs of inflammation during NASH progression [59].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [59] Hou X, Yin S, Ren R, Liu S, Yong L, Liu Y, et al. Myeloid-cell-specific IL-6 signaling promotes MicroRNA-223-enriched exosome production to attenuate NAFLD-associated fibrosis. Hepatology. 2021;74:116–32. source
  • May combine two claims. 29
  • Classified as probably not a substantial claim. 1

  • May combine two claims.

    Premisecitation

    Deletion of il6 in mice impairs compensatory hepatocyte proliferation by reducing STAT3 activation, promoting liver failure, which can be corrected by IL-6 treatment.

    “The IL-6-promoted liver regeneration was determined in IL-6 knockout mice, as the deletion of il6 impaired the compensatory proliferation of hepatocytes by reducing the downstream STAT3 activation [3, 4], thus promoting liver failure, which could be corrected by the treatment of IL-6.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [3] Blindenbacher A, Wang X, Langer I, Savino R, Terracciano L, Heim MH. Interleukin 6 is important for survival after partial hepatectomy in mice. Hepatology. 2003;38:674–82. source

      The Discussion says that surviving IL-6 knockout mice restored liver mass without a significant growth difference and concludes that IL-6 is not required for liver cell proliferation—contrary to the claimed impairment of compensatory proliferation. The paper does report increased mortality after partial hepatectomy and rescue with subcutaneous IL-6, but attributes the survival benefit to a sustained acute-phase response, not to correction of a STAT3-mediated proliferation defect. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [4] Cressman DE, Greenbaum LE, DeAngelis RA, Ciliberto G, Furth EE, Poli V, et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science. 1996;274:1379–83. source

  • May combine two claims.

    Premisecitation

    During aging, inflammation, or other pathological conditions, especially in the liver, IL-6 levels are significantly increased and are crucial for the progression of inflammation, fibrosis and carcinogenesis.

    “During aging, inflammation, or other pathological conditions, especially in the liver, IL-6 levels are significantly increased and are crucial for the progression of inflammation, fibrosis and carcinogenesis [1, 2].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [1] Forcina L, Franceschi C, Musarò A. The hormetic and hermetic role of IL-6. Ageing Res Rev. 2022;80:101697. source

      Section 4 says IL-6 levels increase with advancing age and in concomitant pathologies. The Introduction says circulating levels rise significantly in diseases associated with inflammation and fibrosis, and describes how IL-6 signaling can sustain inflammation and lead to inflammation-related fibrosis. The paper does not establish that these effects occur especially in the liver or that IL-6 is crucial to carcinogenesis; section 3.1 only hypothesizes a role in sustaining cancer proliferation. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [2] Giraldez MD, Carneros D, Garbers C, Rose-John S, Bustos M. New insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology. Nat Rev Gastroenterol Hepatol. 2021;18:787–803. source

  • May combine two claims.

    Premisecitation

    Increased serum IL-6 level and activated IL-6/STAT3 signaling are highly associated with early tumor recurrence and poor prognosis of HCC patients.

    “In the event of hepatocarcinogenesis and progression, increased serum IL-6 level and activated IL-6/STAT3 signaling is highly associated with early tumor recurrence and poor prognosis of HCC patients [61].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [61] Lai SC, Su YT, Chi CC, Kuo YC, Lee KF, Wu YC, et al. DNMT3b/OCT4 expression confers sorafenib resistance and poor prognosis of hepatocellular carcinoma through IL-6/STAT3 regulation. J Exp Clin Cancer Res. 2019;38:474. source

      The Results section reports that, among 144 HCC patients, higher serum IL-6 was associated with poorer overall survival and more early tumor recurrence. The paper also links IL-6/STAT3 activation to OCT4 expression, but the cited passages do not establish a direct association between measured STAT3 activation in patients and those clinical outcomes. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Although IL-6 classic signaling promotes compensatory hepatocyte proliferation, IL-6 trans-signaling is more important in liver regeneration.

    “Although the classic or cis-signaling of IL-6 is determined to promote the compensatory proliferation of hepatocytes, its trans-signaling in liver regeneration is more important [19, 25–27].”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [19] Fazel Modares N, Polz R, Haghighi F, Lamertz L, Behnke K, Zhuang Y, et al. IL-6 trans-signaling controls liver regeneration after partial hepatectomy. Hepatology. 2019;70:2075–91. source
    • cites [25] Peters M, Blinn G, Jostock T, Schirmacher P, Meyer zum Büschenfelde KH, Galle PR, et al. Combined interleukin 6 and soluble interleukin 6 receptor accelerates murine liver regeneration. Gastroenterology. 2000;119:1663–71. source

      The Discussion (page unavailable) reports that IL-6 combined with soluble IL-6R accelerated hepatocyte proliferation and liver regeneration after partial hepatectomy in mice, whereas IL-6 alone did not significantly accelerate either outcome. This supports the comparison favoring trans-signaling in that model, but the paper does not establish that classic signaling itself promotes compensatory hepatocyte proliferation or that trans-signaling is generally more important across liver regeneration settings. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [26] Galun E, Zeira E, Pappo O, Peters M, Rose-John S. Liver regeneration induced by a designer human IL-6/sIL-6R fusion protein reverses severe hepatocellular injury. FASEB J. 2000;14:1979–87. source
    • cites [27] Galun E, Rose-John S. The regenerative activity of interleukin-6. Methods Mol Biol. 2013;982:59–77. source

  • May combine two claims.

    Premisecitation

    In the serum of healthy adults, IL-6 is normally lower than 2 pg/mL or undetectable, and serum IL-6 gradually increases with advancing age.

    “In the serum of healthy adults, IL-6 is normally lower than 2 pg/mL or undetectable, while a gradual increment of serum IL-6 amounts with advancing ages (Fig. 3) [39, 40].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [39] Puzianowska-Kuźnicka M, Owczarz M, Wieczorowska-Tobis K, Nadrowski P, Chudek J, Slusarczyk P, et al. Interleukin-6 and C-reactive protein, successful aging, and mortality: the PolSenior study. Immun Ageing. 2016;13:21. source

      The Results section’s Table 1 shows median serum IL-6 rising across age groups from 65–69 to 90+, including among successfully aging participants. It does not establish that IL-6 is normally below 2 pg/mL or undetectable in healthy adults generally; even in the 65–69 successfully aging group, 2 pg/mL is not an upper limit. No page numbers are provided in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [40] Lustgarten MS, Fielding RA. Metabolites Associated with circulating Interleukin-6 in older adults. J Gerontol Biol Sci Med Sci. 2017;72:1277–83. source

      The introductory passage in the paper’s Abstract section says IL-6 is often undetectable in young individuals and increases with advancing age. The Results report a median of 1.9 pg/mL in a cohort of overweight older adults, but do not establish that serum IL-6 is normally below 2 pg/mL in healthy adults. Page numbers were not available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In a mouse model mimicking human NASH-driven HCC, treatment with olamkicept significantly regresses NASH and markedly reduces NASH-driven HCC.

    “In addition, in a mouse model that mimics human NASH-driven HCC, treatment of olamkicept can significantly regress NASH and markedly reduce NASH-driven HCC [98].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [98] Boslem E, Reibe S, Carlessi R, Smeuninx B, Tegegne S, Egan CL, et al. Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC. Sci Adv. 2023;9:eadh0831. source

      The Introduction identifies the HFD-fed MUP-uPA mouse as a model of human NASH-to-HCC progression. But the Results section on monotherapies reports only mild benefits from sgp130Fc (olamkicept): it improved tumor incidence but did not reduce tumor number or volume. The reported NASH regression and marked HCC reduction came from combining sgp130Fc with BGP-15, not from olamkicept alone. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In mdr2−/− mice, deletion of il6 or blockade of IL-6 trans-signaling by soluble gp130 exacerbates hepatic steatosis, inflammation, chronic hepatitis, and hepatocarcinogenesis, suggesting a protective role of IL-6 signaling.

    “In the mdr2−/− mouse model, the deletion of il6 gene or blockade of IL-6 trans-signaling by the soluble gp130 form exacerbated hepatic steatosis, inflammation, chronic hepatitis, and hepatocarcinogenesis, suggesting the protective role of IL-6 signaling [74].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [74] Shriki A, Lanton T, Sonnenblick A, Levkovitch-Siany O, Eidelshtein D, Abramovitch R, et al. Multiple roles of IL6 in hepatic injury, steatosis, and senescence aggregate to suppress tumorigenesis. Cancer Res. 2021;81:4766–77. source

  • May combine two claims.

    Premisecitation

    IL-6 trans-signaling, but not IL-6 classic signaling, is essential to promote HCC carcinogenesis and progression; activation of membrane-bound IL-6R and gp130 in hepatocytes alone seems not sufficient for tumor formation.

    “In addition, evidences suggest that IL-6 trans-signaling, but not IL-6 classic signaling, is essential to promote HCC carcinogenesis and progression, and only the activation of membrane-bound IL-6R and gp130 in hepatocytes seems not sufficient for tumor formation [71, 72].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [71] Bergmann J, Müller M, Baumann N, Reichert M, Heneweer C, Bolik J, et al. IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice. Hepatology. 2017;65:89–103. source
    • cites [72] Reeh H, Rudolph N, Billing U, Christen H, Streif S, Bullinger E, et al. Response to IL-6 trans- and IL-6 classic signalling is determined by the ratio of the IL-6 receptor α to gp130 expression: fusing experimental insights and dynamic modelling. Cell Commun Signal. 2019;17:46. source

      The Results section ('IL-6-induced trans-signalling is more potent than classic signalling in human hepatoma cells'; page unavailable) reports stronger STAT3 activation with trans-signalling in HepG2 cells. It does not establish that trans-signalling is essential for HCC carcinogenesis or progression, or that activation of membrane-bound IL-6R and gp130 in hepatocytes is insufficient for tumor formation. The separate proliferation experiments used murine pre-B cells, not a tumor-formation model. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Olamkicept (sgp130Fc) consists of two soluble human gp130 proteins fused with Fc of human IgG and selectively targets the IL-6-sIL-6R complex.

    “Soluble gp130Fc, named olamkicept or TJ301, is consists of two soluble human gp130 proteins fused with the Fc of human IgG, and selectively targets the IL-6-sIL-6R complex [79].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [79] Rose-John S, Jenkins BJ, Garbers C, Moll JM, Scheller J. Targeting IL-6 trans-signalling: past, present and future prospects. Nat Rev Immunol. 2023;23:666–81. source

      The ‘Preclinical and clinical development of olamkicept’ section identifies olamkicept as sgp130Fc. Figure 6 describes soluble gp130 fused to a human IgG1 Fc, and ‘An IL-6 trans-signalling inhibitor: sgp130Fc’ says the fusion protein interacts with IL-6–sIL-6R complexes. The passages do not establish the claimed count of two soluble gp130 proteins; the paper also notes interaction with IL-6–membrane IL-6R complexes, so binding is not exclusive to the soluble-receptor complex. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In COVID-19 patients, both sgp130Fc and the JAK inhibitor ruxolitinib can block IL-6 trans-signaling, decreasing phosphorylation of JAK1 and STAT1/3, inhibiting proinflammatory factor production, and alleviating liver injury.

    “As reported in COVID-19 patients, both sgp130Fc and JAK inhibitors ruxolitinib can block IL-6 trans-signaling with decreased phosphorylation of JAK1 and STAT1/3, resulting in the inhibition of proinflammatory factors production and the alleviation of liver injury [60].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [60] McConnell MJ, Kawaguchi N, Kondo R, Sonzogni A, Licini L, Valle C, et al. Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy. J Hepatol. 2021;75:647–58. source

      The Results sections on soluble gp130 and ruxolitinib (page not provided) report that both blocked IL-6 trans-signaling-induced JAK1 and STAT1/3 phosphorylation and proinflammatory-factor expression in liver sinusoidal endothelial cells. The patient data link IL-6 and endotheliopathy with liver injury, but the paper does not show that either treatment alleviated liver injury in COVID-19 patients. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • Rests on an assumption: IL-6 binding to IL-6R and gp130 activates intercellular signal transducers, including phosphorylation of JAK, Src, and STAT3.

  • May combine two claims.

    Premisecitation

    Clazakizumab and siltuximab directly target site I of IL-6, interfering with formation of IL-6 and IL-6R complex, and have been approved for effectiveness in rheumatoid arthritis and Castleman's disease in clinical trials.

    “Clazakizumab and siltuximab directly target the site I of IL-6 for interfering the formation of IL-6 and IL-6R complex, and have been approved for the effectiveness in the treatment of rheumatoid arthritis (RA) and Castleman’s disease in clinical trials [81, 82].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [81] van Rhee F, Rosenthal A, Kanhai K, Martin R, Nishimura K, Hoering A, et al. Siltuximab is associated with improved progression-free survival in idiopathic multicentric Castleman disease. Blood Adv. 2022;6:4773–81. source

      The Introduction states that siltuximab targets IL-6, is approved for idiopathic multicentric Castleman disease, and showed benefit in clinical trials. The copy does not establish site I binding, interference with IL-6–IL-6R complex formation, or the claim about clazakizumab and rheumatoid arthritis. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [82] Aletaha D, Bingham CO, Karpouzas GA, Takeuchi T, Thorne C, Bili A, et al. Long-term safety and efficacy of sirukumab for patients with rheumatoid arthritis who previously received sirukumab in randomised controlled trials (SIRROUND-LTE). RMD Open. 2021;7:e001465. source

      The Introduction describes sirukumab as an IL-6-targeting antibody studied for rheumatoid arthritis, not clazakizumab or siltuximab. Searches for those drugs, IL-6 site I, and Castleman’s disease found no passage addressing their mechanism, clinical effectiveness, or approval in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Ruxolitinib effectively inhibits the JAK/STAT signaling pathway in HCC cells and significantly reduces their proliferation and colony formation.

    “Ruxolitinib also effectively inhibits the JAK/STAT signaling pathway in HCC cells and significantly reduces their proliferation and colony formation [103].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [103] Xu J, Lin H, Wu G, Zhu M, Li M. IL-6/STAT3 is a promising therapeutic target for hepatocellular carcinoma. Front Oncol. 2021;11:760971. source
    • Rests on an assumption: IL-6 binding to IL-6R and gp130 activates intercellular signal transducers, including phosphorylation of JAK, Src, and STAT3.

  • May combine two claims.

    Premisecitation

    IL-6 or gp130 knockout mice develop significantly fewer tumors in DEN-induced HCC model and have prolonged survival.

    “Indeed, IL-6 or gp130 knockout mice developed significantly less tumors in the diethylnitrosamine (DEN)-induced HCC model and prolonged survival [63, 64]”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [63] Mittenbühler MJ, Sprenger HG, Gruber S, Wunderlich CM, Kern L, Brüning JC, et al. Hepatic leptin receptor expression can partially compensate for IL-6Rα deficiency in DEN-induced hepatocellular carcinoma. Mol Metab. 2018;17:122–33. source

      The Results section reports reduced DEN-induced tumor burden in IL-6Rα-deficient mice. It does not establish the same result for IL-6 or gp130 knockout mice, and the study ended at eight months rather than measuring prolonged survival. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [64] Hatting M, Spannbauer M, Peng J, Al Masaoudi M, Sellge G, Nevzorova YA, et al. Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model. Cell Death Dis. 2015;6:e1667. source

      The Results section ('Ablation of gp130 in hepatocytes reduces HCC progression in male and female mice'; page unavailable) reports significantly fewer tumor nodules in male mice with hepatocyte-specific gp130 deletion 40 weeks after DEN treatment. The reduction in female mice was not statistically significant. The paper does not report prolonged survival, and its own experiment did not test IL-6 knockout mice. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In hPSC-derived liver culture mimicking genetic variant-derived NAFLD, IL-6 expression and IL-6/STAT3 activity are elevated during NAFLD development, and dampening IL-6/STAT3 activity alleviates genetic variant-mediated susceptibility to NAFLD.

    “A recent study used hPSC-derived liver culture to mimic genetic variant-derived NAFLD, and found that IL-6 expression and IL-6/STAT3 activity was elevated during NAFLD development. The dampening of IL-6/STAT3 activity could alleviate the genetic variant-mediated susceptibility to NAFLD [58].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [58] Park J, Zhao Y, Zhang F, Zhang S, Kwong AC, Zhang Y, et al. IL-6/STAT3 axis dictates the PNPLA3-mediated susceptibility to non-alcoholic fatty liver disease. J Hepatol. 2023;78:45–56. source

  • May combine two claims.

    Premisecitation

    Tocilizumab binds the IL-6 binding site of both membrane and soluble IL-6R, blocking classic, trans-, and cluster signaling.

    “Tocilizumab, a humanized monoclonal antibody, is determined to bind to the IL-6 binding site of both membrane and soluble IL-6R, thus blocking classic, trans-, as well as cluster signaling [84, 85].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [84] Avci AB, Feist E, Burmester GR. Targeting IL-6 or IL-6 receptor in rheumatoid arthritis: what have we learned? BioDrugs. 2024;38:61–71. source

      The Introduction identifies tocilizumab as an IL-6R inhibitor and explains that membrane-bound and soluble IL-6R mediate classic and trans-signaling, respectively. It also says anti-IL-6Rα antibodies can neutralize trans-presentation, but does not specify tocilizumab’s binding site or state that it binds both receptor forms and blocks all three pathways. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [85] Kishimoto T, Kang S. IL-6 revisited: from rheumatoid arthritis to CAR T cell therapy and COVID-19. Annu Rev Immunol. 2022;40:323–48. source

  • May combine two claims.

    Premisecitation

    Olamkicept selectively targets sIL-6R but not IL-6 or IL-6R, and can effectively discriminate between IL-6 classic and trans-signaling.

    “olamkicept, selectively targeting sIL-6R but not IL-6 or IL-6R, can effectively discriminate between IL-6 classic and trans-signaling”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [111] Prystaz K, Kaiser K, Kovtun A, Haffner-Luntzer M, Fischer V, Rapp AE, et al. Distinct efects of IL-6 classic and trans-signaling in bone fracture healing. Am J Pathol. 2018;188:474–90. source

      The Discussion (page unavailable) says sgp130Fc selectively binds the IL-6/sIL-6R complex and inhibits trans-signaling, supporting the distinction from classic signaling. Our copy does not name olamkicept or establish that it targets sIL-6R alone rather than the IL-6/sIL-6R complex. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [112] George MJ, Jasmin NH, Cummings VT, Richard-Loendt A, Launchbury F, Woollard K, et al. Selective interleukin-6 trans-signaling blockade is more effective than panantagonism in reperfused myocardial infarction. JACC Basic Transl Sci. 2021;6:431–43. source

      The Conclusions identify olamkicept as sgp130Fc, and the Results and Discussion show that sgp130Fc blocks trans-signaling without antagonizing free IL-6, distinguishing it from blockade of both classic and trans-signaling. The paper describes its target as the IL-6/sIL-6R complex, however, not sIL-6R alone; it does not establish the claim’s precise receptor-binding distinction. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • Rests on an assumption: IL-6 binding to IL-6R and gp130 activates intercellular signal transducers, including phosphorylation of JAK, Src, and STAT3.

  • May combine two claims.

    Premisecitation

    IL-6 is a pleiotropic cytokine that exerts its complex biological functions mainly through three signal modes: cis-, trans-, and cluster signaling.

    “The effector signaling of IL-6 contains three modes (Fig. 1) [6].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Garbers C, Heink S, Korn T, Rose-John S. Interleukin-6: designing specific therapeutics for a complex cytokine. Nat Rev Drug Discov. 2018;17:395–412. source

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Therapeutic agents against IL-6, IL-6R, IL-6-sIL-6R complex, or IL-6 downstream signal transducers have been developed and are effective in the intervention of inflammatory diseases and cancers.

    “So far, therapeutic agents against IL‑6, IL‑6 receptor (IL‑6R), IL-6-sIL-6R complex, or IL-6 downstream signal transducers have been developed, and determined to be effective in the intervention of inflammatory diseases and cancers.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    IL-6 exerts pro-inflammatory functions to induce liver aging, fibrosis, steatosis, and carcinogenesis.

    “On the contrary, IL-6 also exerts the pro-inflammatory functions to induce liver aging, fibrosis, steatosis, and carcinogenesis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Local IL-6 level is decreased in early-stage human liver diseases compared to healthy liver tissues, suggesting a protective role for local IL-6 in the healthy liver.

    “Additionally, local IL-6 level is decreased in early-stage human liver diseases as compared to healthy liver tissues, suggesting a protective role for local IL-6 in the healthy liver [78].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Buonomo EL, Mei S, Guinn SR, Leo IR, Peluso MJ, Nolan MA, et al. Liver stromal cells restrict macrophage maturation and stromal IL-6 limits the differentiation of cirrhosis-linked macrophages. J Hepatol. 2022;76:1127–37. source

  • May combine two claims.

    Premisecitation

    Blocking IL-6 trans-signaling using soluble gp130, clearing senescent cells using a senolytic agent, or depleting hepatic progenitor cells results in significant reduction of hepatocellular-cholangiocarcinoma tumors.

    “Blocking IL-6 trans-signaling using soluble gp130 or clearing senescent cells using a senolytic agent, as well as the depletion of hepatic progenitor cells, result in a significant reduction of hepatocellular-cholangiocarcinoma tumors [44, 45].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [44] Rosenberg N, Van Haele M, Lanton T, Brashi N, Bromberg Z, Adler H, et al. Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL-6 trans-signaling. J Hepatol. 2022;77:1631–41. source
    • cites [45] Arechederra M, Fernández-Barrena MG. Hepatic progenitor cells, senescence and IL-6 as the main players in combined hepatocellular-cholangiocarcinoma development. J Hepatol. 2022;77:1479–81. source

  • May combine two claims.

    Premisenone given

    Neutralization of IL-6 inhibits both classic and trans-signaling, and targeting IL-6R blocks all three modes of IL-6 effects.

    “Neutralization of IL-6 inhibits both classic and trans-signaling, and targeting IL-6R blocks all the three modes of IL-6 effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Elevated IL-6 levels are highly predictive for mortality in a cohort of end-stage liver diseases; none of the patients with lower IL-6 level (<5.3 pg/mL) died within one year, but more than half of aged patients died within one year under higher IL-6 level (>11.6 pg/mL).

    “As the data shown in the cohort of end-stage liver diseases, elevated IL-6 levels were highly predictive for mortality. None of the patients with lower IL-6 level (< 5.3 pg/mL) died within one year, but more than half of aged patients died within one year under higher IL-6 level (> 11.6 pg/mL) [41].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Remmler J, Schneider C, Treuner-Kaueroff T, Bartels M, Seehofer D, Scholz M, et al. Increased level of interleukin 6 associates with increased 90-day and 1-year mortality in patients with end-stage liver disease. Clin Gastroenterol Hepatol. 2018;16:730–37. source

  • May combine two claims.

    Interpretationnone given

    High IL-6 levels produced by senescent cells can lead to reprogramming of hepatocytes and have a protective effect on development of liver diseases with anti-inflammatory activities.

    “However, on the other side, high IL-6 level produced by senescent cells can also lead to the reprogramming of hepatocytes, and performs its protective effect on the development of liver diseases with anti-inflammatory activities.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Membrane IL-6R are mainly expressed in hepatocytes, immune cells, and some endothelial cells, limiting IL-6 classic signaling.

  • May combine two claims.

    Interpretationnone given

    During aging progression, IL-6 levels gradually increase, enhancing pro-inflammatory effects and promoting development of inflammation-associated liver diseases.

    “During aging progression, the IL-6 level was gradually increased, which enhances its pro-inflammatory effects and even promotes the development of inflammation-associated liver diseases.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Membrane IL-6R are mainly expressed in hepatocytes, immune cells, and some endothelial cells, limiting IL-6 classic signaling.

  • May combine two claims.

    Premisecitation

    The gp130 protein is widely expressed in tissues, representing extensive responses to IL-6 via trans-signaling activated by the IL-6/sIL-6R/gp130 complex.

    “However, the gp130 protein is widely expressed in tissues [78], representing the extensive responses to IL-6 via the trans-signaling activated by IL-6/sIL-6R/gp130 complex.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Buonomo EL, Mei S, Guinn SR, Leo IR, Peluso MJ, Nolan MA, et al. Liver stromal cells restrict macrophage maturation and stromal IL-6 limits the differentiation of cirrhosis-linked macrophages. J Hepatol. 2022;76:1127–37. source
    • Rests on an assumption: Membrane IL-6R are mainly expressed in hepatocytes, immune cells, and some endothelial cells, limiting IL-6 classic signaling.

  • May combine two claims.

    Interpretationnone given

    Under physiological conditions, IL-6 signaling is critical for liver regeneration and hepatocyte proliferation, reflecting its pro-regenerative effect.

    “Under physiological conditions, IL-6 signal is critical for liver regeneration and the proliferation of hepatocytes as to its pro-regenerative effect.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Membrane IL-6R are mainly expressed in hepatocytes, immune cells, and some endothelial cells, limiting IL-6 classic signaling.

  • May combine two claims.

    Premisenone given

    IL-6 is a well-investigated pleiotropic cytokine with three different signal modes.

    “IL-6 is a well investigated pleiotropic cytokine with three different signal modes.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Membrane IL-6R are mainly expressed in hepatocytes, immune cells, and some endothelial cells, limiting IL-6 classic signaling.

  • May combine two claims.

    Interpretationreasoning

    The adverse effects of global IL-6 inhibition may be due to the diverse biological effects of global inhibition, and selective targeting of IL-6 or its downstream effectors may be more important.

    “This problem may be due to the diverse biological effects of the global inhibition of IL-6, and the selective targeting of IL-6 or its downstream effectors may be more important.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: IL-6 binding to IL-6R and gp130 activates intercellular signal transducers, including phosphorylation of JAK, Src, and STAT3.
29 of 29

  • The paper relies on this without support.

    Findings from mouse models of liver injury, regeneration, and cancer are relevant to human liver physiology and disease.

    “Thus, the clinic use of hyper-IL-6 would be more effective to promote liver regeneration in patients post partial liver resection.”

  • The paper relies on this without support.

    IL-6 binding to IL-6R and gp130 activates intercellular signal transducers, including phosphorylation of JAK, Src, and STAT3.

    “IL-6 binding to IL-6R and gp130 results in the activation of intercellular signal transducers including the phosphorylation of JAK, Src, and STAT3.”

  • The paper relies on this without support.

    Membrane IL-6R are mainly expressed in hepatocytes, immune cells, and some endothelial cells, limiting IL-6 classic signaling.

    “Membrane IL-6R are mainly expressed in hepatocytes, immune cells, and some endothelial cells, leading to the limit of IL-6 classic signaling.”
3 of 3

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • IL-6-GP130 effect on lipid accumulation is reversed

    Minor

    The text says IL-6/GP130 signaling promoted hepatic lipid accumulation in the humanized liver model, but the title of the cited study says the signaling protects human hepatocytes against lipid droplet accumulation.

  • Filgotinib comparator conflicts with the cited trial

    Minor

    The text identifies the 23% remission group as receiving tofacitinib, whereas the cited filgotinib trial is described as placebo-controlled.

  • Insulin-resistance result contradicts the cited study

    Minor

    The text reports improved insulin resistance after sgp130Fc treatment in high-fat-diet-fed mice. The cited study's title says that blocking IL-6 trans-signaling did not improve insulin resistance.

3 of 3

Cites

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Related

Authors
Wang, M.-J., Zhang, H.-L., Chen, F., Guo, X.-J., Liu, Q.-G., & Hou, J.
Affiliations
Second Military Medical University (CN)
Corresponding author
Hou, Jin
ORCID
Venue
Experimental Hematology & Oncology
Publisher
Springer Science and Business Media LLC
Published
2024-06-18
Volume
13
Issue
1
Pages
62-62
ISSN
2162-3619 (ISSN-L)
DOI
10.1186/s40164-024-00527-1
PMC
PMC11184755
OpenAlex
W4399788031
Semantic Scholar
2af1b063b3b7a8add5dca944ef132946c9490a03
Cited by
84
References
114
Citations by year
2026: 38 · 2025: 42 · 2024: 4
FWCI
12.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Experimental Hematology and Oncology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (32070732, 92269204, 82171755)
  • Shanghai Rising-Star Program (21QA1411400)
  • National Key Research and Development Program of China (2023YFC2505900)
  • Military Outstanding Youth Program (2020QN06119, 01-SWKJYCJJ07)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
Keywords
interleukin-6, liver regeneration, liver aging, hepatocyte reprogramming, liver fibrosis, hepatic steatosis, hepatocarcinogenesis, IL-6 signaling, gp130, IL-6 receptor, anti-inflammatory activity, pro-inflammatory effects, chronic liver disease

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-23.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-23.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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