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

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.

[1]  C. Garlanda,et al.  IL-1R8: A molecular brake of anti-tumor and anti-viral activity of NK cells and ILC. , 2023, Seminars in immunology.

[2]  Qi Zhou,et al.  Interleukin-37 suppresses the cytotoxicity of hepatitis B virus peptides-induced CD8+ T cells in patients with acute hepatitis B , 2022, Bosnian journal of basic medical sciences.

[3]  G. López-Castejón,et al.  NLRP3 inflammasome triggers interleukin‐37 release from human monocytes , 2022, European journal of immunology.

[4]  Xiuhe Pan,et al.  Protective Effects of Interleukin-37 Expression against Acetaminophen-Induced Hepatotoxicity in Mice , 2022, Evidence-based complementary and alternative medicine : eCAM.

[5]  A. Sendelhofert,et al.  Expression of IL-37 Correlates With Immune Cell Infiltrate and Fibrosis in Pediatric Autoimmune Liver Diseases , 2022, Journal of pediatric gastroenterology and nutrition.

[6]  Jingchun Fan,et al.  The Role of IL-37 and IL-38 in Colorectal Cancer , 2022, Frontiers in Medicine.

[7]  X. Zhou,et al.  Interleukin-37 promotes colitis-associated carcinogenesis via SIGIRR-mediated cytotoxic T cells dysfunction , 2022, Signal Transduction and Targeted Therapy.

[8]  Mingyue Zhu,et al.  IL-6/STAT3 Is a Promising Therapeutic Target for Hepatocellular Carcinoma , 2021, Frontiers in Oncology.

[9]  Yongyin Li,et al.  Cytokines and Chemokines in HBV Infection , 2021, Frontiers in Molecular Biosciences.

[10]  Shi‐Mei Zhuang,et al.  Identification of a TGF-β/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis , 2021, Signal Transduction and Targeted Therapy.

[11]  A. Boonstra,et al.  The Role of Cytokines in the Different Stages of Hepatocellular Carcinoma , 2021, Cancers.

[12]  H. Schiller,et al.  IL‐37 regulates allergic inflammation by counterbalancing pro‐inflammatory IL‐1 and IL‐33 , 2021, Allergy.

[13]  J. Birk,et al.  A Review of Hepatitis B Virus and Hepatitis C Virus Immunopathogenesis , 2021, Journal of clinical and translational hepatology.

[14]  L. Mishra,et al.  TGF-β Signaling in Liver, Pancreas, and Gastrointestinal Diseases and Cancer , 2021, Gastroenterology.

[15]  H. Tilg,et al.  Modulation of Liver Inflammation and Fibrosis by Interleukin-37 , 2021, Frontiers in Immunology.

[16]  Yulan Liu,et al.  Neutrophil-Induced Liver Injury and Interactions Between Neutrophils and Liver Sinusoidal Endothelial Cells , 2021, Inflammation.

[17]  Hao Wang,et al.  IL-37 overexpression enhances therapeutic effect of endometrial regenerative cells in concanavalin A-induced hepatitis. , 2021, Cytotherapy.

[18]  A. Jemal,et al.  Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries , 2021, CA: a cancer journal for clinicians.

[19]  G. Szabo,et al.  Immunopathobiology and therapeutic targets related to cytokines in liver diseases , 2020, Cellular & Molecular Immunology.

[20]  F. Tacke,et al.  Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities , 2020, Cellular & molecular immunology.

[21]  Tao Pan,et al.  Shikonin blocks human lung adenocarcinoma cell migration and invasion in the inflammatory microenvironment via the IL-6/STAT3 signaling pathway , 2020, Oncology reports.

[22]  A. El-Khoueiry,et al.  Liver Cancer Immunity , 2020, Hepatology.

[23]  G. Missale,et al.  Pathogenetic Mechanisms of T Cell Dysfunction in Chronic HBV Infection and Related Therapeutic Approaches , 2020, Frontiers in Immunology.

[24]  A. Gehring,et al.  Mechanisms of HBV immune evasion. , 2020, Antiviral research.

[25]  P. He,et al.  Interleukin-37 suppresses hepatocellular carcinoma growth through inhibiting M2 polarization of tumor-associated macrophages. , 2020, Molecular immunology.

[26]  V. Angeli,et al.  The indirect antiangiogenic effect of IL‐37 in the tumor microenvironment , 2020, Journal of leukocyte biology.

[27]  Xianzhong Meng,et al.  Interleukin 37 Suppresses M1 Macrophage Polarization Through Inhibition of the Notch1 and Nuclear Factor Kappa B Pathways , 2020, Frontiers in Cell and Developmental Biology.

[28]  Kai Huang,et al.  Decreased IL-37 expression in hepatocellular carcinoma tissues and liver cancer cell lines , 2020, Oncology letters.

[29]  Yan Wang,et al.  Low expression of IL-37 protein is correlated with high Oct4 protein expression in hepatocellular carcinoma. , 2020, Gene.

[30]  M. L. de la Mata,et al.  Activation of mTOR Signaling Pathway in Hepatocellular Carcinoma , 2020, International journal of molecular sciences.

[31]  A. Satyanarayana,et al.  Molecular Signaling Pathways and Therapeutic Targets in Hepatocellular Carcinoma , 2020, Cancers.

[32]  S. Othman,et al.  The potential role of interleukin-37 in infectious diseases , 2020, International reviews of immunology.

[33]  Xiangxuan Zhao,et al.  Tumorigenesis, diagnosis, and therapeutic potential of exosomes in liver cancer , 2019, Journal of Hematology & Oncology.

[34]  Zujiang Yu,et al.  Vaccinia virus expressing IL‐37 promotes antitumor immune responses in hepatocellular carcinoma , 2019, Cell biochemistry and function.

[35]  Zhijun Luo,et al.  Contextual Regulation of TGF-β Signaling in Liver Cancer , 2019, Cells.

[36]  J. Gingold,et al.  Immunomodulatory TGF-β Signaling in Hepatocellular Carcinoma. , 2019, Trends in molecular medicine.

[37]  J. Xia,et al.  IL-37 induces anti-tumor immunity by indirectly promoting dendritic cell recruitment and activation in hepatocellular carcinoma , 2019, Cancer management and research.

[38]  W. Ding,et al.  The double-edged sword of MTOR in autophagy deficiency induced-liver injury and tumorigenesis , 2019, Autophagy.

[39]  S. Kaneko,et al.  Immune cell therapy for hepatocellular carcinoma , 2019, Journal of Hematology & Oncology.

[40]  Xiaomo Wu,et al.  Application of PD-1 Blockade in Cancer Immunotherapy , 2019, Computational and structural biotechnology journal.

[41]  D. G. Osborne,et al.  Interleukin‐37 is highly expressed in regulatory T cells of melanoma patients and enhanced by melanoma cell secretome , 2019, Molecular carcinogenesis.

[42]  P. Kubes,et al.  The Neutrophil's Role During Health and Disease. , 2019, Physiological reviews.

[43]  E. Seki,et al.  Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets , 2019, Seminars in Liver Disease.

[44]  G. Giannelli,et al.  TGF-β as Multifaceted Orchestrator in HCC Progression: Signaling, EMT, Immune Microenvironment, and Novel Therapeutic Perspectives , 2018, Seminars in Liver Disease.

[45]  Yigang Wang,et al.  Role of autophagy in tumorigenesis, metastasis, targeted therapy and drug resistance of hepatocellular carcinoma , 2018, World journal of gastroenterology.

[46]  C. Yun,et al.  The Roles of Autophagy in Cancer , 2018, International journal of molecular sciences.

[47]  A. Zlotnik,et al.  Interleukin 30 to Interleukin 40. , 2018, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[48]  I. Fabregat,et al.  Transforming Growth Factor-β-Induced Cell Plasticity in Liver Fibrosis and Hepatocarcinogenesis , 2018, Front. Oncol..

[49]  Jian-bo Zhang,et al.  IL-37b suppresses epithelial mesenchymal transition in hepatocellular carcinoma by inhibiting IL-6/STAT3 signaling. , 2018, Hepatobiliary & pancreatic diseases international : HBPD INT.

[50]  S. Ng,et al.  The changing epidemiology of liver diseases in the Asia–Pacific region , 2018, Nature Reviews Gastroenterology & Hepatology.

[51]  T. Liang,et al.  Hepatitis B Virus Deregulates the Cell Cycle To Promote Viral Replication and a Premalignant Phenotype , 2018, Journal of Virology.

[52]  H. Tilg,et al.  Ethanol‐mediated suppression of IL‐37 licenses alcoholic liver disease , 2018, Liver international : official journal of the International Association for the Study of the Liver.

[53]  Bo Han,et al.  Reviews of Interleukin-37: Functions, Receptors, and Roles in Diseases , 2018, BioMed research international.

[54]  Ying Yang,et al.  HBV Facilitated Hepatocellular Carcinoma Cells Proliferation by Up-Regulating Angiogenin Expression Through IL-6 , 2018, Cellular Physiology and Biochemistry.

[55]  Jennifer R. Grandis,et al.  Targeting the IL-6/JAK/STAT3 signalling axis in cancer , 2018, Nature Reviews Clinical Oncology.

[56]  J. D. del Campo,et al.  Role of inflammatory response in liver diseases: Therapeutic strategies , 2018, World journal of hepatology.

[57]  Jiyoung Lee,et al.  Autophagy and mitophagy in hepatocarcinogenesis , 2018, Molecular & cellular oncology.

[58]  G. Cavalli,et al.  Suppression of inflammation and acquired immunity by IL‐37 , 2018, Immunological reviews.

[59]  S. Friedman,et al.  Hepatic stellate cells as key target in liver fibrosis. , 2017, Advanced drug delivery reviews.

[60]  R. Derynck,et al.  Transforming Growth Factor-b Receptors and Smads : Regulatory Complexity and Functional Versatility , 2017 .

[61]  S. Ikeda,et al.  The biology of Hepatocellular carcinoma: implications for genomic and immune therapies , 2017, Molecular Cancer.

[62]  N. Sarvetnick,et al.  Interleukin (IL)-18 Binding Protein Deficiency Disrupts Natural Killer Cell Maturation and Diminishes Circulating IL-18 , 2017, Front. Immunol..

[63]  Zhongjun Wu,et al.  IL‐37 induces autophagy in hepatocellular carcinoma cells by inhibiting the PI3K/AKT/mTOR pathway , 2017, Molecular immunology.

[64]  D. Yoon,et al.  Interleukin 32, inflammation and cancer , 2017, Pharmacology & therapeutics.

[65]  Jason C Lao,et al.  Monocytes and dendritic cells are the primary sources of interleukin 37 in human immune cells , 2017, Journal of leukocyte biology.

[66]  Miaoyin Liang,et al.  International incidence and mortality trends of liver cancer: a global profile , 2017, Scientific Reports.

[67]  D. Sinnett,et al.  A protective role of IL‐37 in cancer: a new hope for cancer patients , 2017, Journal of leukocyte biology.

[68]  Ying Ju,et al.  Elevated serum interleukin-37 level is a predictive biomarker of poor prognosis in epithelial ovarian cancer patients , 2017, Archives of Gynecology and Obstetrics.

[69]  R. Liu,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 , 2016, Oncotarget.

[70]  Yujiang Fang,et al.  The role of IL-37 in cancer , 2016, Medical Oncology.

[71]  S. Dooley,et al.  TGF‐β signalling and liver disease , 2016, The FEBS journal.

[72]  Yi Lu,et al.  Reciprocal activation between MMP-8 and TGF-β1 stimulates EMT and malignant progression of hepatocellular carcinoma. , 2016, Cancer letters.

[73]  A. Hu,et al.  Outcomes of Interferon/Ribavirin Therapy in Patients with HCV Defined by Expression of Plasma Soluble Human Leukocyte Antigen-G but Not IL-37 , 2016, Medical science monitor : international medical journal of experimental and clinical research.

[74]  C. O’Farrelly,et al.  Liver immunology and its role in inflammation and homeostasis , 2016, Cellular & Molecular Immunology.

[75]  J. Schneider,et al.  Autophagy and Metabolism , 2016 .

[76]  L. Calvo,et al.  Correction: IL6 Inhibits HBV Transcription by Targeting the Epigenetic Control of the Nuclear cccDNA Minichromosome , 2015, PloS one.

[77]  B. Shen,et al.  Long noncoding RNA lncTCF7, induced by IL-6/STAT3 transactivation, promotes hepatocellular carcinoma aggressiveness through epithelial-mesenchymal transition , 2015, Journal of Experimental & Clinical Cancer Research.

[78]  S. Thorgeirsson,et al.  Signal transducer and activator of transcription 3‐mediated CD133 up‐regulation contributes to promotion of hepatocellular carcinoma , 2015, Hepatology.

[79]  J. Massagué,et al.  Structural determinants of Smad function in TGF-β signaling. , 2015, Trends in biochemical sciences.

[80]  R. Busuttil,et al.  Hepatocellular carcinoma: Advances in diagnosis, management, and long term outcome. , 2015, World journal of hepatology.

[81]  C. Feng,et al.  IL-6, through p-STAT3 rather than p-STAT1, activates hepatocarcinogenesis and affects survival of hepatocellular carcinoma patients: a cohort study , 2015, BMC Gastroenterology.

[82]  J. Whisstock,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 , 2015, Nature Immunology.

[83]  H. Huber,et al.  Axl activates autocrine transforming growth factor‐β signaling in hepatocellular carcinoma , 2015, Hepatology.

[84]  H. Hsu,et al.  The Effects of Cytokines on Spontaneous Hepatitis B Surface Antigen Seroconversion in Chronic Hepatitis B Virus Infection , 2015, The Journal of Immunology.

[85]  T. Tung,et al.  Activation of IL6/IGFIR Confers Poor Prognosis of HBV-Related Hepatocellular Carcinoma through Induction of OCT4/NANOG Expression , 2015, Clinical Cancer Research.

[86]  M. Shirakawa,et al.  The structural basis for receptor recognition of human interleukin-18 , 2014, Nature Communications.

[87]  Zheng Zhang,et al.  The global burden of liver disease: The major impact of China , 2014, Hepatology.

[88]  Weiyu Chen,et al.  MEF2 transcription factors promotes EMT and invasiveness of hepatocellular carcinoma through TGF-β1 autoregulation circuitry , 2014, Tumor Biology.

[89]  M. Nicklin,et al.  Long-range DNA interactions at the IL-1/IL-36/IL-37 gene cluster (2q13) are induced by activation of monocytes. , 2014, Cytokine.

[90]  K. Pan,et al.  Interleukin-37 Mediates the Antitumor Activity in Hepatocellular Carcinoma: Role for CD57+ NK Cells , 2014, Scientific Reports.

[91]  D. Sahu,et al.  TGF-β Mediated Crosstalk Between Malignant Hepatocyte and Tumor Microenvironment in Hepatocellular Carcinoma , 2014, Cancer growth and metastasis.

[92]  Zhutian Zeng,et al.  IL-12–Based Vaccination Therapy Reverses Liver-Induced Systemic Tolerance in a Mouse Model of Hepatitis B Virus Carrier , 2013, The Journal of Immunology.

[93]  Yanfang Jiang,et al.  Serum interleukin-37 concentrations and HBeAg seroconversion in chronic HBV patients during telbivudine treatment. , 2013, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[94]  K. Matsuzaki Smad phospho-isoforms direct context-dependent TGF-β signaling. , 2013, Cytokine & growth factor reviews.

[95]  D. Schuppan,et al.  Evolving therapies for liver fibrosis. , 2013, The Journal of clinical investigation.

[96]  Jing Zhao,et al.  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. , 2013, Antiviral research.

[97]  R. Schuster,et al.  Interleukin‐37 reduces liver inflammatory injury via effects on hepatocytes and non‐parenchymal cells , 2012, Journal of gastroenterology and hepatology.

[98]  Limei Liu,et al.  Combined Therapy with Cytokine-Induced Killer Cells and Oncolytic Adenovirus Expressing IL-12 Induce Enhanced Antitumor Activity in Liver Tumor Model , 2012, PloS one.

[99]  K. Ryan,et al.  Autophagy and cancer – issues we need to digest , 2012, Journal of Cell Science.

[100]  A. Zychlinsky,et al.  Neutrophil function: from mechanisms to disease. , 2012, Annual review of immunology.

[101]  B. Gao,et al.  Hepatoprotective and anti‐inflammatory cytokines in alcoholic liver disease , 2012, Journal of gastroenterology and hepatology.

[102]  R. Kappler,et al.  In Vivo Expression of Interleukin-37 Reduces Local and Systemic Inflammation in Concanavalin A-Induced Hepatitis , 2011, TheScientificWorldJournal.

[103]  C. Dinarello,et al.  IL-37: a new anti-inflammatory cytokine of the IL-1 family. , 2011, European cytokine network.

[104]  S. Dooley,et al.  TGF-β in progression of liver disease , 2011, Cell and Tissue Research.

[105]  Li Yang,et al.  Transforming growth factor-β in the gastrointestinal and hepatic tumor microenvironment. , 2011, Gastroenterology.

[106]  Yuquan Wei,et al.  Proteomic analysis of the interleukin‐4 (IL‐4) response in hepatitis B virus‐positive human hepatocelluar carcinoma cell line HepG2.2.15 , 2011, Electrophoresis.

[107]  S. Thorgeirsson,et al.  Transforming growth factor‐β gene expression signature in mouse hepatocytes predicts clinical outcome in human cancer , 2008, Hepatology.

[108]  S. Werner,et al.  Active Caspase-1 Is a Regulator of Unconventional Protein Secretion , 2008, Cell.

[109]  Katsunori Yoshida,et al.  Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor β signaling, promoting cirrhosis and hepatocellular carcinoma , 2007, Hepatology.

[110]  E. White,et al.  Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. , 2007, Genes & development.

[111]  Xiang Gao,et al.  IL-12 promotes HBV-specific central memory CD8+ T cell responses by PBMCs from chronic hepatitis B virus carriers. , 2007, International immunopharmacology.

[112]  X. Wang,et al.  The role of cytokines in hepatocellular carcinoma , 2006, Journal of leukocyte biology.

[113]  Ivan Rusyn,et al.  Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[114]  C. Dinarello,et al.  Interleukin-1 homologues IL-1F7b and IL-18 contain functional mRNA instability elements within the coding region responsive to lipopolysaccharide. , 2004, The Biochemical journal.

[115]  Govind Bhagat,et al.  Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. , 2003, The Journal of clinical investigation.

[116]  Sue-Jane Lin,et al.  IL-4 Suppresses the Expression and the Replication of Hepatitis B Virus in the Hepatocellular Carcinoma Cell Line Hep3B 1 , 2003, The Journal of Immunology.

[117]  C. Dinarello,et al.  A complex of the IL-1 homologue IL-1F7b and IL-18-binding protein reduces IL-18 activity , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[118]  John C. Lee,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. , 2002, Cytokine.

[119]  G. McCaughan,et al.  Cytokines and chemokines in the immune response to hepatitis C infection , 2001, Current opinion in infectious diseases.

[120]  M. Doyle,et al.  Identification and Initial Characterization of Four Novel Members of the Interleukin-1 Family* , 2000, The Journal of Biological Chemistry.

[121]  P. Marcellin,et al.  A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis B. , 2000, Journal of hepatology.

[122]  Y. Chawla,et al.  Immunology of hepatocellular carcinoma. , 1991, The Italian journal of gastroenterology.

[123]  Guohong Deng,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. , 2019, Journal of hepatology.

[124]  Raja Mazumder,et al.  Analysis of Genomes and Transcriptomes of Hepatocellular Carcinomas Identifies Mutations and Gene Expression Changes in the Transforming Growth Factor-β Pathway. , 2018, Gastroenterology.

[125]  R. Brůha,et al.  Alcoholic liver disease. , 2012, World journal of hepatology.

[126]  R. Schwabe,et al.  Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition. , 2010, Gastroenterology.

[127]  R. Ortíz-López,et al.  Oncolytic virotherapy. , 2008, Annals of hepatology.

[128]  Katsunori Yoshida,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. , 2005, The American journal of pathology.

[129]  M. Pinzani Liver fibrosis , 2004, Springer Seminars in Immunopathology.

[130]  B. Stefanovic,et al.  Fibrogenesis. III. Posttranscriptional regulation of type I collagen. , 2000, American journal of physiology. Gastrointestinal and liver physiology.

[131]  D. Woodfield Hepatocellular carcinoma. , 1986, The New Zealand medical journal.