Tumor Biology

, Volume 37, Issue 1, pp 105–114 | Cite as

IL-22: a promising candidate to inhibit viral-induced liver disease progression and hepatocellular carcinoma

  • Muhammad Saalim
  • Saleha Resham
  • Sobia Manzoor
  • Hassam Ahmad
  • Shahla Jaleel
  • Javed Ashraf
  • Muhammad Imran
  • Sidrah Naseem
Review

Abstract

Hepatocellular carcinoma (HCC) is a growing concern all over the world. With the number of patients rising exponentially with each passing day, HCC is a problem that needs immediate attention. Currently, available treatment strategies focus on controlling the damage after the development of HCC. The options available from chemo- and radio-embolization to surgical resection and transplantation are not efficacious as required due to the complex nature of the disease. Liver regeneration and tissue healing are the subject of great interest today. Interleukin-22 (IL-22) is a cytokine with the ability to regenerate and therefore reverse the injuries caused by a wide range of agents. IL-22 acts via STAT molecule and controls the activity of a wide variety of cell survival and proliferation genes. Experimental data has given a positive insight into the role of IL-22 in inhibition of viral and alcohol-induced hepatocellular carcinoma. A further insight into the nature of IL-22 and the factors that can be manipulated in controlling the activity of IL-22 can help to counter the menace caused by the devastating effects of HCC.

Keywords

Hepatocellular carcinoma IL-22 Liver regeneration 

Notes

Authors’ contributions

Muhammad Saalim and Saleha Resham performed the conception and design, acquisition of data, analysis and interpretation of data, and drafting of the article. Sobia Manzoor is the principal investigator and did the conception and design, analysis and interpretation of data, critical revision of the article, and final approval of the version to be published. Shahla Jaleel, Hassam Ahmad and Javed Ashraf participated in the critical revision of the article. Javed Ashraf, Muhammad Imran and Sidrah Naseem contributed in drafting the article.

Compliance with ethical standards

Conflicts of interest

None

References

  1. 1.
    Society AC. What are the key statistics about liver cancer? 2014. http://www.cancer.org/cancer/livercancer/detailedguide/liver-cancer-what-is-key-statistics.
  2. 2.
    Hassan MM, Hwang LY, Hatten CJ, Swaim M, Li D, Abbruzzese JL, et al. Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology. 2002;36(5):1206–13.CrossRefPubMedGoogle Scholar
  3. 3.
    Marrero JA, Fontana RJ, Fu S, Conjeevaram HS, Su GL, Lok AS. Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma. J Hepatol. 2005;42(2):218–24.CrossRefPubMedGoogle Scholar
  4. 4.
    Cougot D, Neuveut C, Buendia MA. HBV induced carcinogenesis. J Clin Virol. 2005;34:S75–S8.CrossRefPubMedGoogle Scholar
  5. 5.
    Anthony P. Hepatocellular carcinoma: an overview. Histopathology. 2001;39(2):109–18.CrossRefPubMedGoogle Scholar
  6. 6.
    Block TM, Mehta AS, Fimmel CJ, Jordan R. Molecular viral oncology of hepatocellular carcinoma. Oncogene. 2003;22(33):5093–107.CrossRefPubMedGoogle Scholar
  7. 7.
    Lindenbach BD, Rice CM. Unravelling hepatitis C virus replication from genome to function. Nature. 2005;436(7053):933–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Levrero M. Viral hepatitis and liver cancer: the case of hepatitis C. Oncogene. 2006;25(27):3834–47.CrossRefPubMedGoogle Scholar
  9. 9.
    Rehermann B. Hepatitis C, virus versus innate and adaptive immune responses: a tale of coevolution and coexistence. J Clin Invest. 2009;119(7):1745–54.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Dumoutier L, Louahed J, Renauld J-C. Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9. J Immunol. 2000;164(4):1814–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Radaeva S, Sun R, Pan H, Hong F, Gao B, Interleukin 22. (IL‐22) plays a protective role in T cell‐mediated murine hepatitis: IL‐22 is a survival factor for hepatocytes via STAT3 activation. Hepatology. 2004;39(5):1332–42.CrossRefPubMedGoogle Scholar
  12. 12.
    Dumoutier L, de Meester C, Tavernier J, Renauld J-C. New activation modus of STAT3 a tyrosine-less region of the interleukin-22 receptor recruits STAT3 by interacting with its coiled-coil domain. J Biol Chem. 2009;284(39):26377–84.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci. 2004;117(8):1281–3.CrossRefPubMedGoogle Scholar
  14. 14.
    Bromberg J, Darnell Jr JE. The role of STATs in transcriptional control and their impact on cellular function. Oncogene. 2000;19(21):2468–73.CrossRefPubMedGoogle Scholar
  15. 15.
    Yoshida T, Hanada T, Tokuhisa T, Kosai K-I, Sata M, Kohara M. Activation of STAT3 by the hepatitis C virus core protein leads to cellular transformation. J Exp Med. 2002;196(5):641–53.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Gao B. Cytokines, STATs and liver disease. Cell Mol Immunol. 2005;2(2):92–100.PubMedGoogle Scholar
  17. 17.
    Michalopoulos GK, DeFrances MC. Liver regeneration. Science. 1997;276(5309):60–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Wang H, Lafdil F, Kong X, Gao B. Signal transducer and activator of transcription 3 in liver diseases: a novel therapeutic target. Int J Biol Sci. 2011;7(5):536.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Nagem RAP, Colau D, Dumoutier L, Renauld J-C, Ogata C, Polikarpov I. Crystal structure of recombinant human interleukin-22. Structure. 2002;10(8):1051–62.CrossRefPubMedGoogle Scholar
  20. 20.
    de Oliveira NM, Ferreira Jr JR, Colau D, Fischer H, Nascimento AS, Craievich AF, et al. Interleukin-22 forms dimers that are recognized by two interleukin-22R1 receptor chains. Biophys J. 2008;94(5):1754–65.CrossRefGoogle Scholar
  21. 21.
    Foster RG, Golden-Mason L, Rutebemberwa A, Rosen HR. Interleukin (IL)-17/IL-22-producing T cells enriched within the liver of patients with chronic hepatitis C viral (HCV) infection. Dig Dis Sci. 2012;57(2):381–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Okuhara S, Umemura T, Joshita S, Shibata S, Kimura T, Morita S et al. Serum levels of interleukin‐22 and hepatitis B core‐related antigen are associated with treatment response to entecavir therapy in chronic hepatitis B. Hepatology Research. 2014.Google Scholar
  23. 23.
    Dambacher J, Beigel F, Zitzmann K, Heeg MH, Göke B, Diepolder HM, et al. The role of interleukin-22 in hepatitis C virus infection. Cytokine. 2008;41(3):209–16.CrossRefPubMedGoogle Scholar
  24. 24.
    Ki SH, Park O, Zheng M, Morales‐Ibanez O, Kolls JK, Bataller R, et al. Interleukin‐22 treatment ameliorates alcoholic liver injury in a murine model of chronic‐binge ethanol feeding: role of signal transducer and activator of transcription 3. Hepatology. 2010;52(4):1291–300.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Støy S, Sandahl TD, Dige AK, Agnholt J, Rasmussen TK, Grønbæk H, et al. Highest frequencies of interleukin-22-producing T helper cells in alcoholic hepatitis patients with a favourable short-term course. PLoS One. 2013;8(1), e55101.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ashour TH. Therapy with interleukin-22 alleviates hepatic injury and hemostasis dysregulation in rat model of acute liver failure. Advances in hematology. 2014; 2014.Google Scholar
  27. 27.
    Brault C, Lévy PL, Bartosch B. Hepatitis C virus-induced mitochondrial dysfunctions. Viruses. 2013;5(3):954–80.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Gurtsevitch V. Human oncogenic viruses: hepatitis B and hepatitis C viruses and their role in hepatocarcinogenesis. Biochem Mosc. 2008;73(5):504–13.CrossRefGoogle Scholar
  29. 29.
    Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006;6(9):674–87.CrossRefPubMedGoogle Scholar
  30. 30.
    Kitaoka S, Shiota G, Kawasaki H. Serum levels of interleukin-10, interleukin-12 and soluble interleukin-2 receptor in chronic liver disease type C. Hepato-Gastroenterology. 2002;50(53):1569–74.Google Scholar
  31. 31.
    Huang Y, Hwang S, Chan C, Wu J, Chao Y, Chang F, et al. Serum levels of cytokines in hepatitis C-related liver disease: a longitudinal study. Zhonghua yi xue za zhi = Chinese medical journal. Free China ed. 1999;62(6):327–33.Google Scholar
  32. 32.
    Sato T, Asanuma Y, Masaki Y, Sato Y, Hatakeyama Y, Kusano T, et al. Changes in tumor necrosis factor-a and interleukin-1 beta production following liver surgery on cirrhotic patients. Hepato-Gastroenterology. 1995;43(11):1148–53.Google Scholar
  33. 33.
    Lejeune D, Dumoutier L, Constantinescu S, Kruijer W, Schuringa JJ, Renauld J-C. Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line pathways that are shared with and distinct from IL-10. J Biol Chem. 2002;277(37):33676–82.CrossRefPubMedGoogle Scholar
  34. 34.
    Boniface K, Bernard F-X, Garcia M, Gurney AL, Lecron J-C, Morel F. IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes. J Immunol. 2005;174(6):3695–702.CrossRefPubMedGoogle Scholar
  35. 35.
    Wolk K, Witte E, Wallace E, Döcke WD, Kunz S, Asadullah K, et al. IL‐22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur J Immunol. 2006;36(5):1309–23.CrossRefPubMedGoogle Scholar
  36. 36.
    Pan H, Hong F, Radaeva S, Gao B. Hydrodynamic gene delivery of interleukin-22 protects the mouse liver from concanavalin A-, carbon tetrachloride-, and Fas ligand-induced injury via activation of STAT3. Cell Mol Immunol. 2004;1(1):43–9.PubMedGoogle Scholar
  37. 37.
    Andoh A, Zhang Z, Inatomi O, Fujino S, Deguchi Y, Araki Y, et al. Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology. 2005;129(3):969–84.CrossRefPubMedGoogle Scholar
  38. 38.
    Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Karow M, Flavell RA. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity. 2007;27(4):647–59.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Park O, Wang H, Weng H, Feigenbaum L, Li H, Yin S, et al. In vivo consequences of liver‐specific interleukin‐22 expression in mice: implications for human liver disease progression. Hepatology. 2011;54(1):252–61.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Kong X, Feng D, Wang H, Hong F, Bertola A, Wang FS, et al. Interleukin‐22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Hepatology. 2012;56(3):1150–9.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Kong X, Feng D, Mathews S, Gao B. Hepatoprotective and anti‐fibrotic functions of interleukin‐22: therapeutic potential for the treatment of alcoholic liver disease. J Gastroenterol Hepatol. 2013;28(S1):56–60.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    W-w X, M-j Z, Liu S, Xu T, Gao J, Wang J-x, et al. Hepatoprotective effects of IL-22 on fulminant hepatic failure induced by d-galactosamine and lipopolysaccharide in mice. Cytokine. 2011;56(2):174–9.CrossRefGoogle Scholar
  43. 43.
    Liang SC, Nickerson-Nutter C, Pittman DD, Carrier Y, Goodwin DG, Shields KM, et al. IL-22 induces an acute-phase response. J Immunol. 2010;185(9):5531–8.CrossRefPubMedGoogle Scholar
  44. 44.
    Ho HH, Ivashkiv LB. Role of STAT3 in type I interferon responses negative regulation of STAT1-dependent inflammatory gene activation. J Biol Chem. 2006;281(20):14111–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Zhang Y, Ji H, Liu Y, Shen X, Gao F, Fong C et al., editors. The immunomodulatory role of IL-22 in mouse liver ischemia and reperfusion injury (IRI): enhancement of autophagy by STAT3-c-myc signaling. American Journal of Transplantation; 2013: Wiley-Blackwell 111 River ST, Hoboken 07030-5774, NJ USA.Google Scholar
  46. 46.
    Zhao J, Zhang Z, Luan Y, Zou Z, Sun Y, Li Y, et al. Pathological functions of interleukin‐22 in chronic liver inflammation and fibrosis with hepatitis B virus infection by promoting T helper 17 cell recruitment. Hepatology. 2014;59(4):1331–42.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Zhang Y, Cobleigh MA, Lian JQ, Huang CX, Booth CJ, Bai XF, et al. A proinflammatory role for interleukin-22 in the immune response to hepatitis B virus. Gastroenterology. 2011;141(5):1897–906.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Chestovich PJ, Uchida Y, Chang W, Ajalat M, Lassman C, Sabat R, et al. IL-22: implications for liver ischemia/reperfusion injury. Transplantation. 2012;93(5):485.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Feng D, Wang Y, Wang H, Weng H, Kong X, Martin-Murphy BV, et al. Acute and chronic effects of IL-22 on acetaminophen-induced liver injury. J Immunol. 2014;193(5):2512–8.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Zhang Z, Zhao J, Fu Y, Wang F-S. Increased IL-22-producing cells contribute to liver fibrosis through promoting Th17 migration in chronic HBV patients (P3363). The Journal of Immunology. 2013;190 (meeting abstracts 1):202.4.Google Scholar
  51. 51.
    Jiang R, Tan Z, Deng L, Chen Y, Xia Y, Gao Y, et al. Interleukin‐22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology. 2011;54(3):900–9.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Muhammad Saalim
    • 1
  • Saleha Resham
    • 1
  • Sobia Manzoor
    • 1
  • Hassam Ahmad
    • 2
  • Shahla Jaleel
    • 3
  • Javed Ashraf
    • 4
  • Muhammad Imran
    • 1
  • Sidrah Naseem
    • 1
  1. 1.Atta-ur-Rahman School of Applied Bio-Sciences, Department of Healthcare BiotechnologyNational University of Sciences and TechnologyIslamabadPakistan
  2. 2.Hepatopancreatobiliary Liver Transplant UnitShaikh Zayd HospitalLahorePakistan
  3. 3.Department of HistopathologyShaikh Zayd HospitalLahorePakistan
  4. 4.Islam Dental CollegeSialkotPakistan

Personalised recommendations