Download PDF
CC BY-NC-ND 4.0 · Semin Liver Dis 2023; 43(03): 336-350
DOI: 10.1055/a-2153-8836
Review Article

Research Progress on the Role and Mechanism of IL-37 in Liver Diseases

Baoyi Jiang
1   Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
,
Yulin Zhou
2   Department of Clinical Laboratory, Shunde New Rongqi Hospital, Foshan, China
,
Yanting Liu
1   Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
,
Siqi He
1   Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
,
Baojian Liao
1   Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
,
Tieli Peng
1   Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
,
Leyi Yao
1   Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
,
Ling Qi
1   Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
› Author Affiliations Funding The study is supported in part by grant no. 20211458 from the Foundation of Traditional Chinese Medicine Bureau of Guangdong Province; no. 2022108 from the Foundation of Student Innovation Ability Promotion Plan of Guangzhou Medical University; no. 20190220 from the Foundation of Qingyuan People's Hospital (Qingyuan, Guangdong; to Prof. Ling Qi).
› Further Information
   Permissions and Reprints


Abstract

Cytokines are important components of the immune system that can predict or influence the development of liver diseases. IL-37, a new member of the IL-1 cytokine family, exerts potent anti-inflammatory and immunosuppressive effects inside and outside cells. IL-37 expression differs before and after liver lesions, suggesting that it is associated with liver disease; however, its mechanism of action remains unclear. This article mainly reviews the biological characteristics of IL-37, which inhibits hepatitis, liver injury, and liver fibrosis by inhibiting inflammation, and inhibits the development of hepatocellular carcinoma (HCC) by regulating the immune microenvironment. Based on additional evidence, combining IL-37 with liver disease markers for diagnosis and treatment can achieve more significant effects, suggesting that IL-37 can be developed into a powerful tool for the clinical adjuvant treatment of liver diseases, especially HCC.

Keywords

IL-37 - hepatitis - liver injury - liver fibrosis - HCC

Authors' Contribution

B.J. and Y.Z. contributed to manuscript writing; Y.L., B.L., and T.P. conducted literature retrieval; and L.Y. and L.Q. revised the manuscript.




Publication History

Accepted Manuscript online:
15 August 2023

Article published online:
11 September 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Wang FS, Fan JG, Zhang Z, Gao B, Wang HY. The global burden of liver disease: the major impact of China. Hepatology 2014; 60 (06) 2099-2108
    CrossrefPubMedGoogle Scholar
  • 2 Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol 2019; 16 (10) 589-604
    CrossrefPubMedGoogle Scholar
  • 3 Wang H, Lu Z, Zhao X. Tumorigenesis, diagnosis, and therapeutic potential of exosomes in liver cancer. J Hematol Oncol 2019; 12 (01) 133
    CrossrefPubMedGoogle Scholar
  • 4 Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet 2018; 391 (10127): 1301-1314
    CrossrefPubMedGoogle Scholar
  • 5 Yang YM, Kim SY, Seki E. Inflammation and liver cancer: molecular mechanisms and therapeutic targets. Semin Liver Dis 2019; 39 (01) 26-42
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 He Y, Hwang S, Ahmed YA. et al. Immunopathobiology and therapeutic targets related to cytokines in liver diseases. Cell Mol Immunol 2021; 18 (01) 18-37
    CrossrefPubMedGoogle Scholar
  • 7 Rico Montanari N, Anugwom CM, Boonstra A, Debes JD. The role of cytokines in the different stages of hepatocellular carcinoma. Cancers (Basel) 2021; 13 (19) 13
    CrossrefPubMedGoogle Scholar
  • 8 Catalan-Dibene J, McIntyre LL, Zlotnik A. Interleukin 30 to interleukin 40. J Interferon Cytokine Res 2018; 38 (10) 423-439
    CrossrefPubMedGoogle Scholar
  • 9 Kumar S, McDonnell PC, Lehr R. et al. Identification and initial characterization of four novel members of the interleukin-1 family. J Biol Chem 2000; 275 (14) 10308-10314
    CrossrefPubMedGoogle Scholar
  • 10 Kumar S, Hanning CR, Brigham-Burke MR. et al. Interleukin-1F7B (IL-1H4/IL-1F7) is processed by caspase-1 and mature IL-1F7B binds to the IL-18 receptor but does not induce IFN-gamma production. Cytokine 2002; 18 (02) 61-71
    CrossrefPubMedGoogle Scholar
  • 11 Nold MF, Nold-Petry CA, Zepp JA, Palmer BE, Bufler P, Dinarello CA. IL-37 is a fundamental inhibitor of innate immunity. Nat Immunol 2010; 11 (11) 1014-1022
    CrossrefPubMedGoogle Scholar
  • 12 Gao B. Hepatoprotective and anti-inflammatory cytokines in alcoholic liver disease. J Gastroenterol Hepatol 2012; 27 (Suppl. 02) 89-93
    CrossrefPubMedGoogle Scholar
  • 13 Jia H, Liu J, Han B. Reviews of interleukin-37: functions, receptors, and roles in diseases. BioMed Res Int 2018; 3058640
    PubMedGoogle Scholar
  • 14 Boraschi D, Lucchesi D, Hainzl S. et al. IL-37: a new anti-inflammatory cytokine of the IL-1 family. Eur Cytokine Netw 2011; 22 (03) 127-147
    CrossrefPubMedGoogle Scholar
  • 15 Keller M, Rüegg A, Werner S, Beer HD. Active caspase-1 is a regulator of unconventional protein secretion. Cell 2008; 132 (05) 818-831
    CrossrefPubMedGoogle Scholar
  • 16 Gritsenko A, Díaz-Pino R, López-Castejón G. NLRP3 inflammasome triggers interleukin-37 release from human monocytes. Eur J Immunol 2022; 52 (07) 1141-1157
    CrossrefPubMedGoogle Scholar
  • 17 Cavalli G, Dinarello CA. Suppression of inflammation and acquired immunity by IL-37. Immunol Rev 2018; 281 (01) 179-190
    CrossrefPubMedGoogle Scholar
  • 18 Gao W, Kumar S, Lotze MT, Hanning C, Robbins PD, Gambotto A. Innate immunity mediated by the cytokine IL-1 homologue 4 (IL-1H4/IL-1F7) induces IL-12-dependent adaptive and profound antitumor immunity. J Immunol 2003; 170 (01) 107-113
    CrossrefPubMedGoogle Scholar
  • 19 Bufler P, Gamboni-Robertson F, Azam T, Kim SH, Dinarello CA. Interleukin-1 homologues IL-1F7b and IL-18 contain functional mRNA instability elements within the coding region responsive to lipopolysaccharide. Biochem J 2004; 381 (Pt 2): 503-510
    CrossrefPubMedGoogle Scholar
  • 20 Rudloff I, Cho SX, Lao JC. et al. Monocytes and dendritic cells are the primary sources of interleukin 37 in human immune cells. J Leukoc Biol 2017; 101 (04) 901-911
    CrossrefPubMedGoogle Scholar
  • 21 Hong JT, Son DJ, Lee CK, Yoon DY, Lee DH, Park MH. Interleukin 32, inflammation and cancer. Pharmacol Ther 2017; 174: 127-137
    CrossrefPubMedGoogle Scholar
  • 22 Del Campo JA, Gallego P, Grande L. Role of inflammatory response in liver diseases: therapeutic strategies. World J Hepatol 2018; 10 (01) 1-7
    CrossrefPubMedGoogle Scholar
  • 23 Bulau AM, Fink M, Maucksch C. et al. In vivo expression of interleukin-37 reduces local and systemic inflammation in concanavalin A-induced hepatitis. ScientificWorldJournal 2011; 11: 2480-2490
    CrossrefPubMedGoogle Scholar
  • 24 Sharaf N, Nicklin MJ, di Giovine FS. Long-range DNA interactions at the IL-1/IL-36/IL-37 gene cluster (2q13) are induced by activation of monocytes. Cytokine 2014; 68 (01) 16-22
    CrossrefPubMedGoogle Scholar
  • 25 Abulkhir A, Samarani S, Amre D. et al. A protective role of IL-37 in cancer: a new hope for cancer patients. J Leukoc Biol 2017; 101 (02) 395-406
    CrossrefPubMedGoogle Scholar
  • 26 Bufler P, Azam T, Gamboni-Robertson F. et al. A complex of the IL-1 homologue IL-1F7b and IL-18-binding protein reduces IL-18 activity. Proc Natl Acad Sci U S A 2002; 99 (21) 13723-13728
    CrossrefPubMedGoogle Scholar
  • 27 Tsutsumi N, Kimura T, Arita K. et al. The structural basis for receptor recognition of human interleukin-18. Nat Commun 2014; 5: 5340
    CrossrefPubMedGoogle Scholar
  • 28 Schröder A, Lunding LP, Zissler UM. et al. IL-37 regulates allergic inflammation by counterbalancing pro-inflammatory IL-1 and IL-33. Allergy 2022; 77 (03) 856-869
    CrossrefPubMedGoogle Scholar
  • 29 Mariotti FR, Supino D, Landolina N. et al. IL-1R8: a molecular brake of anti-tumor and anti-viral activity of NK cells and ILC. Semin Immunol 2023; 66: 101712
    CrossrefPubMedGoogle Scholar
  • 30 Nold-Petry CA, Lo CY, Rudloff I. et al. IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction. Nat Immunol 2015; 16 (04) 354-365
    CrossrefPubMedGoogle Scholar
  • 31 Harms RZ, Creer AJ, Lorenzo-Arteaga KM, Ostlund KR, Sarvetnick NE. Interleukin (IL)-18 binding protein deficiency disrupts natural killer cell maturation and diminishes circulating IL-18. Front Immunol 2017; 8: 1020
    CrossrefPubMedGoogle Scholar
  • 32 Allam G, Gaber AM, Othman SI, Abdel-Moneim A. The potential role of interleukin-37 in infectious diseases. Int Rev Immunol 2020; 39 (01) 3-10
    CrossrefPubMedGoogle Scholar
  • 33 Kuipery A, Gehring AJ, Isogawa M. Mechanisms of HBV immune evasion. Antiviral Res 2020; 179: 104816
    CrossrefPubMedGoogle Scholar
  • 34 Fisicaro P, Barili V, Rossi M. et al. Pathogenetic mechanisms of T cell dysfunction in chronic HBV infection and related therapeutic approaches. Front Immunol 2020; 11: 849
    CrossrefPubMedGoogle Scholar
  • 35 Robinson MW, Harmon C, O'Farrelly C. Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol 2016; 13 (03) 267-276
    CrossrefPubMedGoogle Scholar
  • 36 Li C, Ji H, Cai Y. et al. Serum interleukin-37 concentrations and HBeAg seroconversion in chronic HBV patients during telbivudine treatment. J Interferon Cytokine Res 2013; 33 (10) 612-618
    CrossrefPubMedGoogle Scholar
  • 37 Zhong S, Zhang T, Tang L, Li Y. Cytokines and chemokines in HBV infection. Front Mol Biosci 2021; 8: 805625
    CrossrefPubMedGoogle Scholar
  • 38 Sakai N, Van Sweringen HL, Belizaire RM. et al. Interleukin-37 reduces liver inflammatory injury via effects on hepatocytes and non-parenchymal cells. J Gastroenterol Hepatol 2012; 27 (10) 1609-1616
    CrossrefPubMedGoogle Scholar
  • 39 Feng XX, Chi G, Wang H. et al. IL-37 suppresses the sustained hepatic IFN-γ/TNF-α production and T cell-dependent liver injury. Int Immunopharmacol 2019; 69: 184-193
    CrossrefPubMedGoogle Scholar
  • 40 Lin SJ, Shu PY, Chang C, Ng AK, Hu CP. IL-4 suppresses the expression and the replication of hepatitis B virus in the hepatocellular carcinoma cell line Hep3B. J Immunol 2003; 171 (09) 4708-4716
    CrossrefPubMedGoogle Scholar
  • 41 Yao Y, Li J, Lu Z. et al. Proteomic analysis of the interleukin-4 (IL-4) response in hepatitis B virus-positive human hepatocelluar carcinoma cell line HepG2.2.15. Electrophoresis 2011; 32 (15) 2004-2012
    CrossrefPubMedGoogle Scholar
  • 42 Palumbo GA, Scisciani C, Pediconi N. et al. Correction: IL6 inhibits HBV transcription by targeting the epigenetic control of the nuclear cccDNA minichromosome. PLoS One 2015; 10 (12) e0145555
    CrossrefPubMedGoogle Scholar
  • 43 Chang TS, Wu YC, Chi CC. et al. Activation of IL6/IGFIR confers poor prognosis of HBV-related hepatocellular carcinoma through induction of OCT4/NANOG expression. Clin Cancer Res 2015; 21 (01) 201-210
    CrossrefPubMedGoogle Scholar
  • 44 Zhou X, Yang F, Yang Y. et al. HBV facilitated hepatocellular carcinoma cells proliferation by up-regulating angiogenin expression through IL-6. Cell Physiol Biochem 2018; 46 (02) 461-470
    CrossrefPubMedGoogle Scholar
  • 45 Wang B, Zhao XP, Fan YC, Zhang JJ, Zhao J, Wang K. IL-17A but not IL-22 suppresses the replication of hepatitis B virus mediated by over-expression of MxA and OAS mRNA in the HepG2.2.15 cell line. Antiviral Res 2013; 97 (03) 285-292
    CrossrefPubMedGoogle Scholar
  • 46 Xiong SQ, Lin BL, Gao X, Tang H, Wu CY. IL-12 promotes HBV-specific central memory CD8+ T cell responses by PBMCs from chronic hepatitis B virus carriers. Int Immunopharmacol 2007; 7 (05) 578-587
    CrossrefPubMedGoogle Scholar
  • 47 Wu JF, Hsu HY, Chiu YC, Chen HL, Ni YH, Chang MH. The effects of cytokines on spontaneous hepatitis B surface antigen seroconversion in chronic hepatitis B virus infection. J Immunol 2015; 194 (02) 690-696
    CrossrefPubMedGoogle Scholar
  • 48 Zeng Z, Kong X, Li F, Wei H, Sun R, Tian Z. IL-12-based vaccination therapy reverses liver-induced systemic tolerance in a mouse model of hepatitis B virus carrier. J Immunol 2013; 191 (08) 4184-4193
    CrossrefPubMedGoogle Scholar
  • 49 Carreño V, Zeuzem S, Hopf U. et al. A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis B. J Hepatol 2000; 32 (02) 317-324
    CrossrefPubMedGoogle Scholar
  • 50 Wang H, Luo H, Wan X. et al. TNF-α/IFN-γ profile of HBV-specific CD4 T cells is associated with liver damage and viral clearance in chronic HBV infection. J Hepatol 2020; 72 (01) 45-56
    CrossrefPubMedGoogle Scholar
  • 51 Xia Y, Cheng X, Li Y, Valdez K, Chen W, Liang TJ. Hepatitis B virus deregulates the cell cycle to promote viral replication and a premalignant phenotype. J Virol 2018; 92 (19) 92
    CrossrefPubMedGoogle Scholar
  • 52 Liu R, Tang C, Shen A. et al. IL-37 suppresses hepatocellular carcinoma growth by converting pSmad3 signaling from JNK/pSmad3L/c-Myc oncogenic signaling to pSmad3C/P21 tumor-suppressive signaling. Oncotarget 2016; 7 (51) 85079-85096
    CrossrefPubMedGoogle Scholar
  • 53 Liu Q, Zhou Q, Wang M, Pang B. Interleukin-37 suppresses the cytotoxicity of hepatitis B virus peptides-induced CD8+ T cells in patients with acute hepatitis B. Bosn J Basic Med Sci 2023; 23 (03) 527-534
    PubMedGoogle Scholar
  • 54 Al-Anazi MR, Matou-Nasri S, Al-Qahtani AA. et al. Association between IL-37 gene polymorphisms and risk of HBV-related liver disease in a Saudi Arabian population. Sci Rep 2019; 9 (01) 7123
    CrossrefPubMedGoogle Scholar
  • 55 Wong MCS, Huang JLW, George J. et al. The changing epidemiology of liver diseases in the Asia-Pacific region. Nat Rev Gastroenterol Hepatol 2019; 16 (01) 57-73
    CrossrefPubMedGoogle Scholar
  • 56 Saraceni C, Birk J. A review of hepatitis B virus and hepatitis C virus immunopathogenesis. J Clin Transl Hepatol 2021; 9 (03) 409-418
    PubMedGoogle Scholar
  • 57 Heydtmann M, Shields P, McCaughan G, Adams D. Cytokines and chemokines in the immune response to hepatitis C infection. Curr Opin Infect Dis 2001; 14 (03) 279-287
    CrossrefPubMedGoogle Scholar
  • 58 Ding SX, Ma JB, Hu YR, Hu AR, Shen Q, Gao GS. Outcomes of interferon/ribavirin therapy in patients with HCV defined by expression of plasma soluble human leukocyte antigen-G but not IL-37. Med Sci Monit 2016; 22: 1398-1402
    CrossrefPubMedGoogle Scholar
  • 59 Wen Y, Lambrecht J, Ju C, Tacke F. Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities. Cell Mol Immunol 2021; 18 (01) 45-56
    CrossrefPubMedGoogle Scholar
  • 60 Roberts RA, Ganey PE, Ju C, Kamendulis LM, Rusyn I, Klaunig JE. Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis. Toxicol Sci 2007; 96 (01) 2-15
    CrossrefPubMedGoogle Scholar
  • 61 Xu Z, Li K, Pan X, Tan J, Li Y, Li M. Protective effects of interleukin-37 expression against acetaminophen-induced hepatotoxicity in mice. Evid Based Complement Alternat Med 2022; 6468299
    PubMedGoogle Scholar
  • 62 Li G, Kong D, Qin Y. et al. IL-37 overexpression enhances the therapeutic effect of endometrial regenerative cells in concanavalin A-induced hepatitis. Cytotherapy 2021; 23 (07) 617-626
    CrossrefPubMedGoogle Scholar
  • 63 Zhou P, Li Q, Su S. et al. Interleukin 37 suppresses M1 macrophage Polarization through inhibition of the Notch1 and nuclear factor kappa B pathways. Front Cell Dev Biol 2020; 8: 56
    CrossrefPubMedGoogle Scholar
  • 64 Liew PX, Kubes P. The neutrophil's role during health and disease. Physiol Rev 2019; 99 (02) 1223-1248
    CrossrefPubMedGoogle Scholar
  • 65 Wang Y, Liu Y. Neutrophil-induced liver injury and interactions between neutrophils and liver sinusoidal endothelial cells. Inflammation 2021; 44 (04) 1246-1262
    CrossrefPubMedGoogle Scholar
  • 66 Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A. Neutrophil function: from mechanisms to disease. Annu Rev Immunol 2012; 30: 459-489
    CrossrefPubMedGoogle Scholar
  • 67 Seitz HK, Bataller R, Cortez-Pinto H. et al. Alcoholic liver disease. Nat Rev Dis Primers 2018; 4 (01) 16
    CrossrefPubMedGoogle Scholar
  • 68 Grabherr F, Grander C, Adolph TE. et al. Ethanol-mediated suppression of IL-37 licenses alcoholic liver disease. Liver Int 2018; 38 (06) 1095-1101
    CrossrefPubMedGoogle Scholar
  • 69 Schuppan D, Kim YO. Evolving therapies for liver fibrosis. J Clin Invest 2013; 123 (05) 1887-1901
    CrossrefPubMedGoogle Scholar
  • 70 Higashi T, Friedman SL, Hoshida Y. Hepatic stellate cells as key target in liver fibrosis. Adv Drug Deliv Rev 2017; 121: 27-42
    CrossrefPubMedGoogle Scholar
  • 71 Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005; 115 (02) 209-218
    CrossrefPubMedGoogle Scholar
  • 72 Lindquist JN, Marzluff WF, Stefanovic B. Fibrogenesis. III. Posttranscriptional regulation of type I collagen. Am J Physiol Gastrointest Liver Physiol 2000; 279 (03) G471-G476
    CrossrefPubMedGoogle Scholar
  • 73 Yoshida K, Matsuzaki K, Mori S. et al. Transforming growth factor-beta and platelet-derived growth factor signal via c-Jun N-terminal kinase-dependent Smad2/3 phosphorylation in rat hepatic stellate cells after acute liver injury. Am J Pathol 2005; 166 (04) 1029-1039
    CrossrefPubMedGoogle Scholar
  • 74 Kluwe J, Pradere JP, Gwak GY. et al. Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition. Gastroenterology 2010; 138 (01) 347-359
    CrossrefPubMedGoogle Scholar
  • 75 Dooley S, ten Dijke P. TGF-β in progression of liver disease. Cell Tissue Res 2012; 347 (01) 245-256
    CrossrefPubMedGoogle Scholar
  • 76 Matsuzaki K. Smad phospho-isoforms direct context-dependent TGF-β signaling. Cytokine Growth Factor Rev 2013; 24 (04) 385-399
    CrossrefPubMedGoogle Scholar
  • 77 Matsuzaki K, Murata M, Yoshida K. et al. Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor beta signaling, promoting cirrhosis and hepatocellular carcinoma. Hepatology 2007; 46 (01) 48-57
    CrossrefPubMedGoogle Scholar
  • 78 Mountford S, Effenberger M, Noll-Puchta H. et al. Modulation of liver inflammation and fibrosis by interleukin-37. Front Immunol 2021; 12: 603649
    CrossrefPubMedGoogle Scholar
  • 79 Griessmair L, Pirringer L, Mountford S. et al. Expression of IL-37 correlates with immune cell infiltrate and fibrosis in pediatric autoimmune liver diseases. J Pediatr Gastroenterol Nutr 2022; 74 (06) 742-749
    CrossrefPubMedGoogle Scholar
  • 80 Sung H, Ferlay J, Siegel RL. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71 (03) 209-249
    Google Scholar
  • 81 Wong MC, Jiang JY, Goggins WB. et al. International incidence and mortality trends of liver cancer: a global profile. Sci Rep 2017; 7: 45846
    CrossrefPubMedGoogle Scholar
  • 82 Chen J, Gingold JA, Su X. Immunomodulatory TGF-β signaling in hepatocellular carcinoma. Trends Mol Med 2019; 25 (11) 1010-1023
    CrossrefPubMedGoogle Scholar
  • 83 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
    CrossrefPubMedGoogle Scholar
  • 84 Khemlina G, Ikeda S, Kurzrock R. The biology of hepatocellular carcinoma: implications for genomic and immune therapies. Mol Cancer 2017; 16 (01) 149
    CrossrefPubMedGoogle Scholar
  • 85 Dimri M, Satyanarayana A. Molecular signaling pathways and therapeutic targets in hepatocellular carcinoma. Cancers (Basel) 2020; 12 (02) 12
    CrossrefPubMedGoogle Scholar
  • 86 Budhu A, Wang XW. The role of cytokines in hepatocellular carcinoma. J Leukoc Biol 2006; 80 (06) 1197-1213
    CrossrefPubMedGoogle Scholar
  • 87 Zhao JJ, Pan QZ, Pan K. et al. Interleukin-37 mediates the antitumor activity in hepatocellular carcinoma: role for CD57+ NK cells. Sci Rep 2014; 4: 5177
    CrossrefPubMedGoogle Scholar
  • 88 Mei Y, Zhu Y, Teo HY. et al. The indirect antiangiogenic effect of IL-37 in the tumor microenvironment. J Leukoc Biol 2020; 107 (05) 783-796
    CrossrefPubMedGoogle Scholar
  • 89 Ding VA, Zhu Z, Xiao H, Wakefield MR, Bai Q, Fang Y. The role of IL-37 in cancer. Med Oncol 2016; 33 (07) 68
    CrossrefPubMedGoogle Scholar
  • 90 Johnson DE, O'Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol 2018; 15 (04) 234-248
    CrossrefPubMedGoogle Scholar
  • 91 Pan T, Zhang F, Li F. et al. Shikonin blocks human lung adenocarcinoma cell migration and invasion in the inflammatory microenvironment via the IL–6/STAT3 signaling pathway. Oncol Rep 2020; 44 (03) 1049-1063
    CrossrefPubMedGoogle Scholar
  • 92 Won C, Kim BH, Yi EH. et al. Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma. Hepatology 2015; 62 (04) 1160-1173
    CrossrefPubMedGoogle Scholar
  • 93 Wu J, Zhang J, Shen B. et al. Long noncoding RNA lncTCF7, induced by IL-6/STAT3 transactivation, promotes hepatocellular carcinoma aggressiveness through epithelial-mesenchymal transition. J Exp Clin Cancer Res 2015; 34: 116
    CrossrefPubMedGoogle Scholar
  • 94 Kao JT, Feng CL, Yu CJ. et al. IL-6, through p-STAT3 rather than p-STAT1, activates hepatocarcinogenesis and affects survival of hepatocellular carcinoma patients: a cohort study. BMC Gastroenterol 2015; 15: 50
    CrossrefPubMedGoogle Scholar
  • 95 Pu XY, Zheng DF, Shen A. et al. IL-37b suppresses epithelial mesenchymal transition in hepatocellular carcinoma by inhibiting IL-6/STAT3 signaling. Hepatobiliary Pancreat Dis Int 2018; 17 (05) 408-415
    CrossrefPubMedGoogle Scholar
  • 96 Russell SJ, Peng KW, Bell JC. Oncolytic virotherapy. Nat Biotechnol 2012; 30 (07) 658-670
    CrossrefPubMedGoogle Scholar
  • 97 Zhang Z, Zhang J, Zhang Y, Xing J, Yu Z. Vaccinia virus expressing IL-37 promotes antitumor immune responses in hepatocellular carcinoma. Cell Biochem Funct 2019; 37 (08) 618-624
    CrossrefPubMedGoogle Scholar
  • 98 Zhang Z, Zhang J, He P, Han J, Sun C. Interleukin-37 suppresses hepatocellular carcinoma growth through inhibiting M2 polarization of tumor-associated macrophages. Mol Immunol 2020; 122: 13-20
    CrossrefPubMedGoogle Scholar
  • 99 Dang J, He Z, Cui X. et al. The role of IL-37 and IL-38 in colorectal cancer. Front Med (Lausanne) 2022; 9: 811025
    CrossrefPubMedGoogle Scholar
  • 100 Macias MJ, Martin-Malpartida P, Massagué J. Structural determinants of Smad function in TGF-β signaling. Trends Biochem Sci 2015; 40 (06) 296-308
    CrossrefPubMedGoogle Scholar
  • 101 Budi EH, Duan D, Derynck R. Transforming growth factor-β receptors and Smads: regulatory complexity and functional versatility. Trends Cell Biol 2017; 27 (09) 658-672
    CrossrefPubMedGoogle Scholar
  • 102 Wu MZ, Yuan YC, Huang BY. et al. Identification of a TGF-β/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis. Signal Transduct Target Ther 2021; 6 (01) 395
    CrossrefPubMedGoogle Scholar
  • 103 Chen J, Zaidi S, Rao S. et al. Analysis of genomes and transcriptomes of hepatocellular carcinomas identifies mutations and gene expression changes in the transforming growth factor-β pathway. Gastroenterology 2018; 154 (01) 195-210
    CrossrefPubMedGoogle Scholar
  • 104 Gupta DK, Singh N, Sahu DK. TGF-β mediated crosstalk between malignant hepatocyte and tumor microenvironment in hepatocellular carcinoma. Cancer Growth Metastasis 2014; 7: 1-8
    CrossrefPubMedGoogle Scholar
  • 105 Achyut BR, Yang L. Transforming growth factor-β in the gastrointestinal and hepatic tumor microenvironment. Gastroenterology 2011; 141 (04) 1167-1178
    CrossrefPubMedGoogle Scholar
  • 106 Fabregat I, Caballero-Díaz D. Transforming growth factor-β-induced cell plasticity in liver fibrosis and hepatocarcinogenesis. Front Oncol 2018; 8: 357
    CrossrefPubMedGoogle Scholar
  • 107 Dituri F, Mancarella S, Cigliano A, Chieti A, Giannelli G. TGF-β as multifaceted orchestrator in HCC progression: signaling, EMT, immune microenvironment, and novel therapeutic perspectives. Semin Liver Dis 2019; 39 (01) 53-69
    Article in Thieme ConnectPubMedGoogle Scholar
  • 108 Coulouarn C, Factor VM, Thorgeirsson SS. Transforming growth factor-beta gene expression signature in mouse hepatocytes predicts clinical outcome in human cancer. Hepatology 2008; 47 (06) 2059-2067
    CrossrefPubMedGoogle Scholar
  • 109 Gough NR, Xiang X, Mishra L. TGF-β signaling in liver, pancreas, and gastrointestinal diseases and cancer. Gastroenterology 2021; 161 (02) 434-452.e15
    CrossrefPubMedGoogle Scholar
  • 110 Fabregat I, Moreno-Càceres J, Sánchez A. et al; IT-LIVER Consortium. TGF-β signalling and liver disease. FEBS J 2016; 283 (12) 2219-2232
    CrossrefPubMedGoogle Scholar
  • 111 Tu S, Huang W, Huang C, Luo Z, Yan X. Contextual regulation of TGF-β signaling in liver cancer. Cells 2019; 8 (10) 8
    CrossrefPubMedGoogle Scholar
  • 112 Reichl P, Dengler M, van Zijl F. et al. Axl activates autocrine transforming growth factor-β signaling in hepatocellular carcinoma. Hepatology 2015; 61 (03) 930-941
    CrossrefPubMedGoogle Scholar
  • 113 Qin G, Luo M, Chen J. et al. Reciprocal activation between MMP-8 and TGF-β1 stimulates EMT and malignant progression of hepatocellular carcinoma. Cancer Lett 2016; 374 (01) 85-95
    CrossrefPubMedGoogle Scholar
  • 114 Yu W, Huang C, Wang Q. et al. MEF2 transcription factors promotes EMT and invasiveness of hepatocellular carcinoma through TGF-β1 autoregulation circuitry. Tumour Biol 2014; 35 (11) 10943-10951
    CrossrefPubMedGoogle Scholar
  • 115 Ferrín G, Guerrero M, Amado V, Rodríguez-Perálvarez M, De la Mata M. Activation of mTOR signaling pathway in hepatocellular carcinoma. Int J Mol Sci 2020; 21 (04) 21
    CrossrefPubMedGoogle Scholar
  • 116 Yang H, Ni HM, Ding WX. The double-edged sword of MTOR in autophagy deficiency induced-liver injury and tumorigenesis. Autophagy 2019; 15 (09) 1671-1673
    CrossrefPubMedGoogle Scholar
  • 117 Huang F, Wang BR, Wang YG. Role of autophagy in tumorigenesis, metastasis, targeted therapy and drug resistance of hepatocellular carcinoma. World J Gastroenterol 2018; 24 (41) 4643-4651
    CrossrefPubMedGoogle Scholar
  • 118 Qu X, Yu J, Bhagat G. et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 2003; 112 (12) 1809-1820
    CrossrefPubMedGoogle Scholar
  • 119 Karantza-Wadsworth V, Patel S, Kravchuk O. et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev 2007; 21 (13) 1621-1635
    CrossrefPubMedGoogle Scholar
  • 120 Rabinowitz JD, White E. Autophagy and metabolism. Science 2010; 330 (6009) 1344-1348
    CrossrefPubMedGoogle Scholar
  • 121 Liu EY, Ryan KM. Autophagy and cancer – issues we need to digest. J Cell Sci 2012; 125 (Pt 10): 2349-2358
    PubMedGoogle Scholar
  • 122 Liu K, Lee J, Ou JJ. Autophagy and mitophagy in hepatocarcinogenesis. Mol Cell Oncol 2018; 5 (02) e1405142
    CrossrefPubMedGoogle Scholar
  • 123 Yun CW, Lee SH. The roles of autophagy in cancer. Int J Mol Sci 2018; 19 (11) 19
    CrossrefPubMedGoogle Scholar
  • 124 Li TT, Zhu D, Mou T. et al. IL-37 induces autophagy in hepatocellular carcinoma cells by inhibiting the PI3K/AKT/mTOR pathway. Mol Immunol 2017; 87: 132-140
    CrossrefPubMedGoogle Scholar
  • 125 Ringelhan M, Pfister D, O'Connor T, Pikarsky E, Heikenwalder M. The immunology of hepatocellular carcinoma. Nat Immunol 2018; 19 (03) 222-232
    CrossrefPubMedGoogle Scholar
  • 126 Rizvi S, Wang J, El-Khoueiry AB. Liver cancer immunity. Hepatology 2021; 73 (Suppl. 01) 86-103
    CrossrefPubMedGoogle Scholar
  • 127 Wu X, Gu Z, Chen Y. et al. Application of PD-1 blockade in cancer immunotherapy. Comput Struct Biotechnol J 2019; 17: 661-674
    CrossrefPubMedGoogle Scholar
  • 128 Mizukoshi E, Kaneko S. Immune cell therapy for hepatocellular carcinoma. J Hematol Oncol 2019; 12 (01) 52
    CrossrefPubMedGoogle Scholar
  • 129 Han C, Jiang Y, Wang Z, Wang H. Natural killer cells involved in tumour immune escape of hepatocellular carcinoma. Int Immunopharmacol 2019; 73: 10-16
    CrossrefPubMedGoogle Scholar
  • 130 Liu Y, Zhao JJ, Zhou ZQ. et al. IL-37 induces anti-tumor immunity by indirectly promoting dendritic cell recruitment and activation in hepatocellular carcinoma. Cancer Manag Res 2019; 11: 6691-6702
    CrossrefPubMedGoogle Scholar
  • 131 Huo J, Hu J, Liu G, Cui Y, Ju Y. Elevated serum interleukin-37 level is a predictive biomarker of poor prognosis in epithelial ovarian cancer patients. Arch Gynecol Obstet 2017; 295 (02) 459-465
    CrossrefPubMedGoogle Scholar
  • 132 Wang Z, Zeng FL, Hu YW. et al. Interleukin-37 promotes colitis-associated carcinogenesis via SIGIRR-mediated cytotoxic T cells dysfunction. Signal Transduct Target Ther 2022; 7 (01) 19
    CrossrefPubMedGoogle Scholar
  • 133 Osborne DG, Domenico J, Luo Y. et al. Interleukin-37 is highly expressed in regulatory T cells of melanoma patients and enhanced by melanoma cell secretome. Mol Carcinog 2019; 58 (09) 1670-1679
    CrossrefPubMedGoogle Scholar
  • 134 Bodzin AS, Busuttil RW. Hepatocellular carcinoma: advances in diagnosis, management, and long term outcome. World J Hepatol 2015; 7 (09) 1157-1167
    CrossrefPubMedGoogle Scholar
  • 135 Guo H, Li P, Su L. et al. Low expression of IL-37 protein is correlated with high Oct4 protein expression in hepatocellular carcinoma. Gene 2020; 737: 144445
    CrossrefPubMedGoogle Scholar
  • 136 Li P, Guo H, Wu K. et al. Decreased IL-37 expression in hepatocellular carcinoma tissues and liver cancer cell lines. Oncol Lett 2020; 19 (04) 2639-2648
    PubMedGoogle Scholar
  • 137 Yang Z, Zhang Q, Xu K. et al. Combined therapy with cytokine-induced killer cells and oncolytic adenovirus expressing IL-12 induce enhanced antitumor activity in liver tumor model. PLoS One 2012; 7 (09) e44802
    CrossrefPubMedGoogle Scholar