Digestive Diseases and Sciences

, Volume 64, Issue 3, pp 773–780 | Cite as

BATF Interference Blocks Th17 Cell Differentiation and Inflammatory Response in Hepatitis B Virus Transgenic Mice

  • Long-Yan Chen
  • Xiao-Peng Fan
  • Yu-Chen Fan
  • Jing Zhao
  • Shuai Gao
  • Feng Li
  • Zhao-Xia Qi
  • Kai WangEmail author
Original Article



B cell-activating transcription factor (BATF) contributes to Th17 cell differentiation and pathological inflammatory responses.


This study explored BATF as a regulator of Th17 differentiation in normal and hepatitis B virus (HBV) transgenic mice.


Normal mice were divided into control, short hairpin RNA (shRNA) scramble, and shRNA BATF groups. HBV transgenic mice were divided into control, entecavir, shRNA scramble, entecavir + vector control, entecavir + shRNA scramble, shRNA BATF, and entecavir + shRNA BATF groups. Serum concentrations of AST, ALT, HBV-DNA, BATF, IL-17, and IL-22 and Th17 cell frequencies in the liver were compared among the groups. Correlations of serum HBV surface antigen (HBsAg), e-antigen (HBeAg), and core antigen (HBcAg) concentrations with BATF mRNA expression and the proportion of Th17 cells in the livers of HBV transgenic mice were also analyzed.


Serum AST, ALT, BATF, IL-17, and IL-22 concentrations and Th17 cell proportions were higher in HBV transgenic mice relative to normal controls. Positive correlations of the HBcAg concentration with BATF mRNA and the proportion of Th17 cells were observed in HBV transgenic mice. BATF interference reduced the proportion of Th17 cells and serum IL-17 and IL-22 concentrations and led to obvious downregulation of AST, ALT, BATF, IL-17, and IL-22 expression and a reduced proportion of Th17 cells when combined with entecavir.


HBV markedly upregulated BATF expression and promoted Th17 cell activation. By contrast, BATF interference significantly impeded the proliferation of Th17 cells and secretion of IL-17 and IL-22 while alleviating hepatic lesions.


HBV Transgenic mice BATF Th17 



This work was supported by the grants from National Natural Science Foundation of China (81171579, 81201287, 81300318, and 81371832), Key Project of Chinese Ministry of Science and Technology (2012ZX10002007 and 2013ZX10002001), and Science and Technology Development Plan of Shandong Province (2014GSF118068).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All mouse experiments were approved by the Institutional Animal Care and Use Committee (KYLL-2017(KS)-076).


  1. 1.
    Seeger C, Mason WS. Hepatitis B virus biology. Microbiol Mol Biol Rev. 2000;64:51–68.CrossRefGoogle Scholar
  2. 2.
    Cui Y, Jia J. Update on epidemiology of hepatitis B and C in China. J Gastroenterol Hepatol. 2013;28:7–10.CrossRefGoogle Scholar
  3. 3.
    Yang S, Yu C, Chen P, et al. Protective immune barrier against hepatitis B is needed in individuals born before infant HBV vaccination program in China. Sci Rep. 2015;5:18334.CrossRefGoogle Scholar
  4. 4.
    Zhao RR, Yang XF, Dong J, et al. Toll-like receptor 2 promotes T helper 17 cells response in hepatitis B virus infection. Int J Clin Exp Med. 2015;8:7315–7323.Google Scholar
  5. 5.
    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. 2010;30:60–67.CrossRefGoogle Scholar
  6. 6.
    Williams KL, Nanda I, Lyons GE, et al. Characterization of murine BATF: a negative regulator of activator protein-1 activity in the thymus. Eur J Immunol. 2001;31:1620–1627.CrossRefGoogle Scholar
  7. 7.
    Martinez GJ, Dong C. BATF: bringing (in) another Th17-regulating factor. J Mol Cell Biol. 2009;1:66–68.CrossRefGoogle Scholar
  8. 8.
    Miao T, Raymond M, Bhullar P, et al. Early growth response gene-2 controls IL-17 expression and Th17 differentiation by negatively regulating Batf. J Immunol. 2013;190:58–65.CrossRefGoogle Scholar
  9. 9.
    Zhang Z, Pan Q, Duan XY, et al. Fatty liver reduces hepatitis B virus replication in a genotype B hepatitis B virus transgenic mice model. J Gastroenterol Hepatol. 2012;27:1858–1864.CrossRefGoogle Scholar
  10. 10.
    Guidotti LG, Matzke B, Schaller H, Chisari FV. High-level hepatitis B virus replication in transgenic mice. J Virol. 1995;69:6158–6169.Google Scholar
  11. 11.
    Pan CQ, Zhang JX. Natural history and clinical consequences of hepatitis B virus infection. Int J Med Sci. 2005;2:36–40.CrossRefGoogle Scholar
  12. 12.
    Te HS, Jensen DM. Epidemiology of hepatitis B and C viruses: a global overview. Clin Liver Dis. 2010;14:1–21.CrossRefGoogle Scholar
  13. 13.
    Butt AA. Hepatitis C virus infection: the new global epidemic. Expert Rev Anti Infect Ther. 2005;3:241–249.CrossRefGoogle Scholar
  14. 14.
    Yu R, Fan R, Hou J. Chronic hepatitis B virus infection: epidemiology, prevention, and treatment in China. Front Med. 2014;8:135–144.CrossRefGoogle Scholar
  15. 15.
    Yan YP, Su HX, Ji ZH, Shao ZJ, Pu ZS. Epidemiology of hepatitis B virus infection in China: current status and challenges. J Clin Transl Hepatol. 2014;2:15–22.Google Scholar
  16. 16.
    Busca A, Kumar A. Innate immune responses in hepatitis B virus (HBV) infection. Virol J. 2014;11:22.CrossRefGoogle Scholar
  17. 17.
    Yousfi N, Hattaf K, Tridane A. Modeling the adaptive immune response in HBV infection. J Math Biol. 2011;63:933–957.CrossRefGoogle Scholar
  18. 18.
    Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6:1133–1141.CrossRefGoogle Scholar
  19. 19.
    Zhang Z, Zhang JY, Wang LF, Wang FS. Immunopathogenesis and prognostic immune markers of chronic hepatitis B virus infection. J Gastroenterol Hepatol. 2012;27:223–230.CrossRefGoogle Scholar
  20. 20.
    Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity. 2008;28:454–467.CrossRefGoogle Scholar
  21. 21.
    Zhang JY, Zhang Z, Lin F, 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.CrossRefGoogle Scholar
  22. 22.
    Meng F, Wang K, Aoyama T, et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology. 2012;143:e761–e763.CrossRefGoogle Scholar
  23. 23.
    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;97:285–292.CrossRefGoogle Scholar
  24. 24.
    Kurachi M, Barnitz RA, Yosef N, et al. The transcription factor BATF operates as an essential differentiation checkpoint in early effector CD8+T cells. Nat Immunol. 2014;15:373–383.CrossRefGoogle Scholar
  25. 25.
    Dunsford HA, Sell S, Chisari FV. Hepatocarcinogenesis due to chronic liver cell injury in hepatitis B virus transgenic mice. Cancer Res. 1990;50:3400–3407.Google Scholar
  26. 26.
    Galli A, Ceni E, Mello T, et al. Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus-transgenic mice by peroxisome proliferator-activated receptor gamma-independent regulation of nucleophosmin. Hepatology. 2010;52:493–505.CrossRefGoogle Scholar
  27. 27.
    Feng H, Yin J, Han YP, et al. Regulatory T cells and IL-17(+) T helper cells enhanced in patients with chronic hepatitis B virus infection. Int J Clin Exp Med. 2015;8:8674–8685.Google Scholar
  28. 28.
    Zhang JY, Song CH, Shi F, Zhang Z, Fu JL, Wang FS. Decreased ratio of Treg cells to Th17 cells correlates with HBV DNA suppression in chronic hepatitis B patients undergoing entecavir treatment. PLoS ONE. 2010;5:e13869.CrossRefGoogle Scholar
  29. 29.
    Meyer NP, Johansen LM, Tae HJ, Budde PP, Williams KL, Taparowsky EJ. Genomic organization of human B-ATF, a target for regulation by EBV and HTLV-1. Mamm Genome. 1998;9:849–852.CrossRefGoogle Scholar
  30. 30.
    Grusdat M, McIlwain DR, Xu HC, et al. IRF4 and BATF are critical for CD8(+) T-cell function following infection with LCMV. Cell Death Differ. 2014;21:1050–1060.CrossRefGoogle Scholar
  31. 31.
    Tian ZF, You ZL, Yi H, Kuang XM, Wang YM. Effect of entecavir on CD4+T-cell subpopulations in patients with chronic hepatitis B. Ann Hepatol. 2016;15:174–182.Google Scholar
  32. 32.
    Niu YH, Yin DL, Liu HL, et al. Restoring the Treg cell to Th17 cell ratio may alleviate HBV-related acute-on-chronic liver failure. World J Gastroenterol. 2013;19:4146–4154.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Long-Yan Chen
    • 1
  • Xiao-Peng Fan
    • 1
  • Yu-Chen Fan
    • 1
  • Jing Zhao
    • 1
  • Shuai Gao
    • 1
  • Feng Li
    • 1
  • Zhao-Xia Qi
    • 1
  • Kai Wang
    • 1
    • 2
    Email author
  1. 1.Department of HepatologyQilu Hospital of Shandong UniversityJinanChina
  2. 2.Institute of HepatologyShandong UniversityJinanChina

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