Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Th17 cells and their associated cytokines in liver diseases

Cellular & Molecular Immunology volume 7, pages 250–254 (2010)Cite this article

Abstract

T helper 17 (Th17) cells are a newly identified subset of T helper cells that play important roles in host defense against extracellular bacteria as well as in the pathogenesis of autoimmune disease. The functions of Th17 cells are mediated via the production of several cytokines including interleukin (IL)-17 and IL-22. Recent studies show that the frequency of IL-17+ cells is significantly elevated in a variety of chronic liver diseases including alcoholic liver disease, viral hepatitis and hepatocellular carcinoma. IL-17 receptor is expressed virtually on all types of liver cells, while IL-22 receptor expression is restricted to epithelial cells including hepatocytes in the liver. IL-17 seems to play an important role in inducing liver inflammation via stimulating multiple types of liver nonparenchymal cells to produce proinflammatory cytokines and chemokines, while IL-22 appears to be an important factor in promoting hepatocyte survival and proliferation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. O'Shea RS, Dasarathy S, McCullough AJ . Alcoholic liver disease. Hepatology 2010; 51: 307–328.

    Article  Google Scholar 

  2. Torres DM, Harrison SA . Diagnosis and therapy of nonalcoholic steatohepatitis. Gastroenterology 2008; 134: 1682–1698.

    Article  CAS  Google Scholar 

  3. Vuppalanchi R, Chalasani N . Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: selected practical issues in their evaluation and management. Hepatology 2009; 49: 306–317.

    Article  Google Scholar 

  4. Di Bisceglie AM . Hepatitis B and hepatocellular carcinoma. Hepatology 2009; 49: S56–S60.

    Article  Google Scholar 

  5. Chang KM . Immunopathogenesis of hepatitis C virus infection. Clin Liver Dis 2003; 7: 89–105.

    Article  Google Scholar 

  6. Rehermann B . Intrahepatic T cells in hepatitis B: viral control versus liver cell injury. J Exp Med 2000; 191: 1263–1268.

    Article  CAS  Google Scholar 

  7. Ichiki Y, Aoki CA, Bowlus CL, Shimoda S, Ishibashi H, Gershwin ME . T cell immunity in autoimmune hepatitis. Autoimmun Rev 2005; 4: 315–321.

    Article  CAS  Google Scholar 

  8. Thiele GM, Freeman TL, Klassen LW . Immunologic mechanisms of alcoholic liver injury. Semin Liver Dis 2004; 24: 273–287.

    Article  CAS  Google Scholar 

  9. Caldwell CC, Tschoep J, Lentsch AB . Lymphocyte function during hepatic ischemia/reperfusion injury. J Leukoc Biol 2007; 82: 457–464.

    Article  CAS  Google Scholar 

  10. Alatrakchi N, Koziel M . Regulatory T cells and viral liver disease. J Viral Hepat 2009; 16: 223–229.

    Article  Google Scholar 

  11. Dolganiuc A, Szabo G . T cells with regulatory activity in hepatitis C virus infection: what we know and what we don't. J Leukoc Biol 2008; 84: 614–622.

    Article  CAS  Google Scholar 

  12. Dolganiuc A, Paek E, Kodys K, Thomas J, Szabo G . Myeloid dendritic cells of patients with chronic HCV infection induce proliferation of regulatory T lymphocytes. Gastroenterology 2008; 135: 2119–2127.

    Article  CAS  Google Scholar 

  13. Longhi MS, Mitry RR, Samyn M, Scalori A, Hussain MJ, Quaglia A et al. Vigorous activation of monocytes in juvenile autoimmune liver disease escapes the control of regulatory T-cells. Hepatology 2009; 50: 130–142.

    Article  CAS  Google Scholar 

  14. Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 2007; 132: 2328–2339.

    Article  Google Scholar 

  15. Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Kruger C, Manns MP et al. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 2008; 135: 234–243.

    Article  CAS  Google Scholar 

  16. TrehanPati N, Geffers R, Sukriti, Hissar S, Riese P, Toepfer T et al. Gene expression signatures of peripheral CD4+ T cells clearly discriminate between patients with acute and chronic hepatitis B infection. Hepatology 2009; 49: 781–790.

    Article  CAS  Google Scholar 

  17. Zhang W, Sharma R, Ju ST, He XS, Tao Y, Tsuneyama K et al. Deficiency in regulatory T cells results in development of antimitochondrial antibodies and autoimmune cholangitis. Hepatology 2009; 49: 545–552.

    Article  CAS  Google Scholar 

  18. Kido M, Watanabe N, Okazaki T, Akamatsu T, Tanaka J, Saga K et al. Fatal autoimmune hepatitis induced by concurrent loss of naturally arising regulatory T cells and PD-1-mediated signaling. Gastroenterology 2008; 135: 1333–1343.

    Article  CAS  Google Scholar 

  19. Stockinger B, Veldhoen M . Differentiation and function of Th17 T cells. Curr Opin Immunol 2007; 19: 281–286.

    Article  CAS  Google Scholar 

  20. Chen Z, O'Shea JJ . Th17 cells: a new fate for differentiating helper T cells. Immunol Res 2008; 41: 87–102.

    Article  CAS  Google Scholar 

  21. Ouyang W, Kolls JK, Zheng Y . The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 2008; 28: 454–467.

    Article  CAS  Google Scholar 

  22. Dong C . Regulation and pro-inflammatory function of interleukin-17 family cytokines. Immunol Rev 2008; 226: 80–86.

    Article  CAS  Google Scholar 

  23. Zhou L, Littman DR . Transcriptional regulatory networks in Th17 cell differentiation. Curr Opin Immunol 2009; 21: 146–152.

    Article  Google Scholar 

  24. Chen Z, Laurence A, O'Shea JJ . Signal transduction pathways and transcriptional regulation in the control of Th17 differentiation. Semin Immunol 2007; 19: 400–408.

    Article  CAS  Google Scholar 

  25. Ge D, You Z . Expression of interleukin-17RC protein in normal human tissues. Int Arch Med 2008; 1: 19.

    Article  Google Scholar 

  26. Lafdil F, Wang H, Park O, Zhang W, Moritoki Y, Yin S et al. Myeloid STAT3 inhibits T cell-mediated hepatitis by regulating T helper 1 cytokine and interleukin-17 production. Gastroenterology 2009; 137: 2125-35 e1-2.

    Article  CAS  Google Scholar 

  27. Lemmers A, Moreno C, Gustot T, Marechal R, Degre D, Demetter P et al. The interleukin-17 pathway is involved in human alcoholic liver disease. Hepatology 2009; 49: 646–657.

    Article  CAS  Google Scholar 

  28. Harada K, Shimoda S, Sato Y, Isse K, Ikeda H, Nakanuma Y . Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosis. Clin Exp Immunol 2009; 157: 261–270.

    Article  CAS  Google Scholar 

  29. Patel DN, King CA, Bailey SR, Holt JW, Venkatachalam K, Agrawal A et al. Interleukin-17 stimulates C-reactive protein expression in hepatocytes and smooth muscle cells via p38 MAPK and ERK1/2-dependent NF-kappaB and C/EBPbeta activation. J Biol Chem 2007; 282: 27229–27238.

    Article  CAS  Google Scholar 

  30. Toy D, Kugler D, Wolfson M, Vanden Bos T, Gurgel J, Derry J et al. Cutting edge: interleukin 17 signals through a heteromeric receptor complex. J Immunol 2006; 177: 36–39.

    Article  CAS  Google Scholar 

  31. Gaffen SL . An overview of IL-17 function and signaling. Cytokine 2008; 43: 402–407.

    Article  CAS  Google Scholar 

  32. Tiegs G, Hentschel J, Wendel A . A T cell-dependent experimental liver injury in mice inducible by concanavalin A. J Clin Invest 1992; 90: 196–203.

    Article  CAS  Google Scholar 

  33. Tiegs G . Cellular and cytokine-mediated mechanisms of inflammation and its modulation in immune-mediated liver injury. Z Gastroenterol 2007; 45: 63–70.

    Article  CAS  Google Scholar 

  34. Jaruga B, Hong F, Sun R, Radaeva S, Gao B . Crucial role of IL-4/STAT6 in T cell-mediated hepatitis: up-regulating eotaxins and IL-5 and recruiting leukocytes. J Immunol 2003; 171: 3233–3244.

    Article  CAS  Google Scholar 

  35. Hong F, Jaruga B, Kim WH, Radaeva S, El-Assal ON, Tian Z et al. Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS. J Clin Invest 2002; 110: 1503–1513.

    Article  CAS  Google Scholar 

  36. 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: 647–659.

    Article  CAS  Google Scholar 

  37. Nagata T, McKinley L, Peschon JJ, Alcorn JF, Aujla SJ, Kolls JK . Requirement of IL-17RA in Con A induced hepatitis and negative regulation of IL-17 production in mouse T cells. J Immunol 2008; 181: 7473–7479.

    Article  CAS  Google Scholar 

  38. Bautista AP . Neutrophilic infiltration in alcoholic hepatitis. Alcohol 2002; 27: 17–21.

    Article  CAS  Google Scholar 

  39. Zhang JY, Zhang Z, Lin F, Zou ZS, Xu RN, Jin L et al. Interleukin-17-producing CD4(+) T cells increase with severity of liver damage in patients with chronic hepatitis B. Hepatology 2010; 51: 81–91.

    Article  Google Scholar 

  40. Ge J, Wang K, Meng QH, Qi ZX, Meng FL, Fan YC . Implication of Th17 and Th1 cells in patients with chronic active hepatitis B. J Clin Immunol 2009; in press.

  41. Lan RY, Salunga TL, Tsuneyama K, Lian ZX, Yang GX, Hsu W et al. Hepatic IL-17 responses in human and murine primary biliary cirrhosis. J Autoimmun 2009; 32: 43–51.

    Article  CAS  Google Scholar 

  42. Rowan AG, Fletcher JM, Ryan EJ, Moran B, Hegarty JE, O'Farrelly C et al. Hepatitis C virus-specific Th17 cells are suppressed by virus-induced TGF-beta. J Immunol 2008; 181: 4485–4494.

    Article  CAS  Google Scholar 

  43. Fouser LA, Wright JF, Dunussi-Joannopoulos K, Collins M . Th17 cytokines and their emerging roles in inflammation and autoimmunity. Immunol Rev 2008; 226: 87–102.

    Article  CAS  Google Scholar 

  44. Hsu W, Zhang W, Tsuneyama K, Moritoki Y, Ridgway WM, Ansari AA et al. Differential mechanisms in the pathogenesis of autoimmune cholangitis versus inflammatory bowel disease in interleukin-2Ralpha(-/-) mice. Hepatology 2009; 49: 133–140.

    Article  CAS  Google Scholar 

  45. Zhang JP, Yan J, Xu J, Pang XH, Chen MS, Li L et al. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol 2009; 50: 980–989.

    Article  CAS  Google Scholar 

  46. Kuang DM, Peng C, Zhao Q, Wu Y, Chen MS, Zheng L . Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells. Hepatology 2010; 51: 154–164.

    Article  CAS  Google Scholar 

  47. Murugaiyan G, Saha B . Protumor vs antitumor functions of IL-17. J Immunol 2009; 183: 4169–4175.

    Article  CAS  Google Scholar 

  48. Radaeva S, Sun R, Pan HN, 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: 1332–1342.

    Article  CAS  Google Scholar 

  49. Hamada S, Umemura M, Shiono T, Tanaka K, Yahagi A, Begum MD et al. IL-17A produced by gammadelta T cells plays a critical role in innate immunity against listeria monocytogenes infection in the liver. J Immunol 2008; 181: 3456–3463.

    Article  CAS  Google Scholar 

  50. Kobayashi E, Kobayashi M, Tsuneyama K, Fukami T, Nakajima M, Yokoi T . Halothane-induced liver injury is mediated by interleukin-17 in mice. Toxicol Sci 2009; 111: 302–310.

    Article  CAS  Google Scholar 

  51. Yasumi Y, Takikawa Y, Endo R, Suzuki K . Interleukin-17 as a new marker of severity of acute hepatic injury. Hepatol Res 2007; 37: 248–54.

    Article  CAS  Google Scholar 

  52. Fabrega E, Lopez-Hoyos M, San Segundo D, Casafont F, Pons-Romero F . Changes in the serum levels of interleukin-17/interleukin-23 during acute rejection in liver transplantation. Liver Transpl 2009; 15: 629–633.

    Article  Google Scholar 

  53. Wolk K, Witte E, Hoffmann U, Doecke WD, Endesfelder S, Asadullah K et al. IL-22 induces lipopolysaccharide-binding protein in hepatocytes: a potential systemic role of IL-22 in Crohn's disease. J Immunol 2007; 178: 5973–5981.

    Article  CAS  Google Scholar 

  54. Lejeune D, Dumoutier L, Constantinescu S, Kruijer W, Schuringa JJ, Renauld JC . 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: 33676–33682.

    Article  CAS  Google Scholar 

  55. Brand S, Dambacher J, Beigel F, Zitzmann K, Heeg MH, Weiss TS et al. IL-22-mediated liver cell regeneration is abrogated by SOCS-1/3 overexpression in vitro. Am J Physiol Gastrointest Liver Physiol 2007; 292: G1019–G1028.

    Article  CAS  Google Scholar 

  56. Wahl C, Wegenka UM, Leithauser F, Schirmbeck R, Reimann J . IL-22-dependent attenuation of T cell-dependent (ConA) hepatitis in herpes virus entry mediator deficiency. J Immunol 2009; 182: 4521–4528.

    Article  CAS  Google Scholar 

  57. 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: 43–49.

    CAS  PubMed  Google Scholar 

  58. Ren X, Hu B, Colletti LM . IL-22 is involved in liver regeneration after hepatectomy. Am J Physiol Gastrointest Liver Physiol 2010; 298: G74–G80.

    Article  CAS  Google Scholar 

  59. Dambacher J, Beigel F, Zitzmann K, Heeg MH, Goke B, Diepolder HM et al. The role of interleukin-22 in hepatitis C virus infection. Cytokine 2008; 41: 209–216.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the intramural program of NIAAA, NIH.

Author information

Authors and Affiliations

  1. Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA

    Fouad Lafdil, Andrew M Miller, Sung Hwan Ki & Bin Gao

  2. INSERM, U955, Créteil, France

    Fouad Lafdil

  3. Faculté de Médecine, Université Paris 12, Créteil, France

    Fouad Lafdil

Authors
  1. Fouad Lafdil
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew M Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sung Hwan Ki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bin Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bin Gao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lafdil, F., Miller, A., Ki, S. et al. Th17 cells and their associated cytokines in liver diseases. Cell Mol Immunol 7, 250–254 (2010). https://doi.org/10.1038/cmi.2010.5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2010.5

Keywords

This article is cited by

Search

Advanced search

Quick links