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Increased BATF expression is associated with the severity of liver damage in patients with chronic hepatitis B

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Abstract

T helper (Th) 17 cells have a critical role in the pathogenesis of chronic hepatitis B virus (HBV) infection, and basic leucine zipper transcription factor, ATF-like (BATF) is a newly identified transcriptional factor regulating the differentiation of Th17 cells. However, its precise role in patients with chronic hepatitis B remains unclear. Sixty chronic hepatitis B (CHB) patients, twenty-two acute-on-chronic hepatitis B liver failure (ACHBLF) patients and seventeen healthy controls were included in our study. Both peripheral and intrahepatic expressions of BATF were analyzed by flow cytometry, quantitative real-time polymerase chain reaction and immunohistochemical staining. Peripheral BATF mRNA and protein expression levels were higher in CHB patients than those in healthy controls. Particularly in ACHBLF patients, the BATF mRNA and protein levels were further increased over those in CHB patients. Intrahepatic BATF-positive infiltrating cells were enriched in portal area of CHB patients, and more positive cells were found in patients with higher inflammation grade. Peripheral BATF expression was positively correlated with serum parameters of liver injury and plasma HBV DNA load. Furthermore, a positive correlation was found between the frequency of BATF-positive CD3+ T cells and the increased Th17 response in chronic HBV-infected patients. BATF over-expression might augment Th17 cell response and relate to the disease progression of CHB.

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References

  1. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661–2.

    Article  PubMed  Google Scholar 

  2. 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.

    Article  CAS  PubMed  Google Scholar 

  3. Feng H, Yin J, Han YP, et al. Sustained changes of Treg and Th17 cells during interferon-α therapy in patients with chronic hepatitis B. Viral Immunol. 2015;28(8):412–7.

    Article  CAS  PubMed  Google Scholar 

  4. 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;30:60–7.

    Article  CAS  PubMed  Google Scholar 

  5. 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(765–76):e1–3.

    Google Scholar 

  6. 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;97:285–92.

    Article  CAS  PubMed  Google Scholar 

  7. Dorsey MJ, Tae HJ, Sollenberger KG, Mascarenhas NT, Johansen LM, Taparowsky EJ. B-ATF: a novel human bZIP protein that associates with members of the AP-1 transcription factor family. Oncogene. 1995;11:2255–65.

    CAS  PubMed  Google Scholar 

  8. Hasegawa H, Utsunomiya Y, Kishimoto K, Tange Y, Yasukawa M, Fujita S. SFA-2, a novel bZIP transcription factor induced by human T-cell leukemia virus type I, is highly expressed in mature lymphocytes. Biochem Biophys Res Commun. 1996;222:164–70.

    Article  CAS  PubMed  Google Scholar 

  9. Echlin DR, Tae HJ, Mitin N, Taparowsky EJ. B-ATF functions as a negative regulator of AP-1 mediated transcription and blocks cellular transformation by Ras and Fos. Oncogene. 2000;19:1752–63.

    Article  CAS  PubMed  Google Scholar 

  10. 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;31:1620–7.

    Article  CAS  PubMed  Google Scholar 

  11. 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;9:849–52.

    Article  CAS  PubMed  Google Scholar 

  12. Betz BC, Jordan-Williams KL, Wang C, et al. Batf coordinates multiple aspects of B and T cell function required for normal antibody responses. J Exp Med. 2010;207:933–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sopel N, Graser A, Mousset S, Finotto S. The transcription factor BATF modulates cytokine-mediated responses in T cells. Cytokine Growth Factor Rev. 2016;. https://doi.org/10.1016/j.cytogfr.2016.03.004.

    PubMed  Google Scholar 

  14. Kuroda S, Yamazaki M, Abe M, Sakimura K, Takayanagi H, Iwai Y. Basic leucine zipper transcription factor, ATF-like (BATF) regulates epigenetically and energetically effector CD8 T-cell differentiation via Sirt1 expression. Proc Natl Acad Sci USA. 2011;108:14885–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Xin G, Schauder DM, Lainez B, et al. A critical role of IL-21-induced BATF in sustaining CD8-T-cell-mediated chronic viral control. Cell Rep. 2015;13(6):1118–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Schraml BU, Hildner K, Ise W, et al. The AP-1 transcription factor Batf controls T(H)17 differentiation. Nature. 2009;460:405–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Glasmacher E, Agrawal S, Chang AB, et al. A genomic regulatory element that directs assembly and function of immune-specific AP-1-IRF complexes. Science. 2012;338:975–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yang B, He F, Dai C, et al. BATF inhibition prevent acute allograft rejection after cardiac transplantation. Am J Transl Res. 2016;8(8):3603–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Punkenburg E, Vogler T, Büttner M, et al. Batf-dependent Th17 cells critically regulate IL-23 driven colitis-associated colon cancer. Gut. 2016;65(7):1139–50.

    Article  CAS  PubMed  Google Scholar 

  20. Smith PM, Jacque B, Conner JR, Poltorak A, Stadecker MJ. IRAK-2 regulates IL-1-mediated pathogenic Th17 cell development in helminthic infection. PLoS Pathog. 2011;7:e1002272. https://doi.org/10.1371/journal.ppat.1002272.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. EASL Clinical Practice Guidelines. Management of chronic hepatitis B virus infection. J Hepatol. 2012;57:167–85.

    Article  Google Scholar 

  22. Liaw YF, Leung N, Kao JH, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int. 2008;2:263–83.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Sarin SK, Kumar A, Almeida JA, et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL). Hepatol Int. 2009;3:269–82.

    Article  PubMed  Google Scholar 

  24. Scheuer PJ. Classification of chronic viral hepatitis: a need for reassessment. J Hepatol. 1991;13:372–4.

    Article  CAS  PubMed  Google Scholar 

  25. Lorenzo Y, Provencio M, Lombardia L, et al. Differential genetic and functional markers of second neoplasias in Hodgkin’s disease patients. Clin Cancer Res. 2009;15:4823–8.

    Article  CAS  PubMed  Google Scholar 

  26. Chang YH, Yu CW, Lai LC, et al. Up-regulation of interleukin-17 expression by human papillomavirus type 16 E6 in nonsmall cell lung cancer. Cancer. 2010;116:4800–9.

    Article  CAS  PubMed  Google Scholar 

  27. Nagao M, Nakajima Y, Kanehiro H, et al. The impact of interferon gamma receptor expression on the mechanism of escape from host immune surveillance in hepatocellular carcinoma. Hepatology. 2000;32:491–500.

    Article  CAS  PubMed  Google Scholar 

  28. Qi ZX, Wang LY, Fan YC, Zhang JJ, Li T, Wang K. Increased peripheral RORalpha and RORgammat mRNA expression is associated with acute-on-chronic hepatitis B liver failure. J Viral Hepat. 2012;19:811–22.

    Article  PubMed  Google Scholar 

  29. Wu W, Shi Y, Li J, Chen F, Chen Z, Zheng M. Tim-3 expression on peripheral T cell subsets correlates with disease progression in hepatitis B infection. Virol J. 2011;8:113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Anderson SJ, Coleclough C. Regulation of CD4 and CD8 expression on mouse T cells. Active removal from the cell surface by two mechanisms. J Immunol. 1993;151:5123–34.

    CAS  PubMed  Google Scholar 

  31. Picker LJ, Singh MK, Zdraveski Z, et al. Direct demonstration of cytokine synthesis heterogeneity among human memory/effector T cells by flow cytometry. Blood. 1995;86:1408–19.

    CAS  PubMed  Google Scholar 

  32. Figueroa-Vega N, Alfonso-Perez M, Benedicto I, et al. Increased circulating pro-inflammatory cytokines and Th17 lymphocytes in Hashimoto’s thyroiditis. J Clin Endocrinol Metab. 2010;95:953–62.

    Article  CAS  PubMed  Google Scholar 

  33. Quigley M, Pereyra F, Nilsson B, et al. Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat Med. 2010;16:1147–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

  35. Rasmussen MH, Sorensen AB, Morris DW, et al. Tumor model-specific proviral insertional mutagenesis of the Fos/Jdp2/Batf locus. Virology. 2005;337:353–64.

    Article  CAS  PubMed  Google Scholar 

  36. Johansen LM, Deppmann CD, Erickson KD, et al. EBNA2 and activated Notch induce expression of BATF. J Virol. 2003;77:6029–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhang X, Zhang H, Ye L. Effects of hepatitis B virus X protein on the development of liver cancer. J Lab Clin Med. 2006;147:58–66.

    Article  CAS  PubMed  Google Scholar 

  38. Lucito R, Schneider RJ. Hepatitis B virus X protein activates transcription factor NF-kappa B without a requirement for protein kinase C. J Virol. 1992;66:983–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Li J, Peet GW, Balzarano D, et al. Novel NEMO/IkappaB kinase and NF-kappa B target genes at the pre-B to immature B cell transition. J Biol Chem. 2001;276:18579–90.

    Article  CAS  PubMed  Google Scholar 

  40. Senga T, Iwamoto T, Humphrey SE, Yokota T, Taparowsky EJ, Hamaguchi M. Stat3-dependent induction of BATF in M1 mouse myeloid leukemia cells. Oncogene. 2002;21:8186–91.

    Article  CAS  PubMed  Google Scholar 

  41. Liao J, Humphrey SE, Poston S, Taparowsky EJ. Batf promotes growth arrest and terminal differentiation of mouse myeloid leukemia cells. Mol Cancer Res. 2011;9:350–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rong G, Zhou Y, Xiong Y, et al. Imbalance between T helper type 17 and T regulatory cells in patients with primary biliary cirrhosis: the serum cytokine profile and peripheral cell population. Clin Exp Immunol. 2009;156:217–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Meng F, Wang J, Ge J, et al. Alteration of interferon-alpha/beta receptors in chronic hepatitis B patients. J Clin Immunol. 2011;31:521–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Koch S, Mousset S, Graser A, et al. IL-6 activated integrated BATF/IRF4 functions in lymphocytes are T-bet-independent and reversed by subcutaneous immunotherapy. Sci Rep. 2013;3:1754.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Li P, Spolski R, Liao W, et al. BATF-JUN is critical for IRF4-mediated transcription in T cells. Nature. 2012;490:543–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Murphy TL, Tussiwand R, Murphy KM. Specificity through cooperation: BATF-IRF interactions control immune-regulatory networks. Nat Rev Immunol. 2013;13:499–509.

    Article  CAS  PubMed  Google Scholar 

  47. Chisari FV, Isogawa M, Wieland SF. Pathogenesis of hepatitis B virus infection. Pathol Biol (Paris). 2010;58:258–66.

    Article  CAS  Google Scholar 

  48. Thimme R, Wieland S, Steiger C, et al. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol. 2003;77:68–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by Grants from Key Project of Chinese Ministry of Science and Technology (2013ZX10002001), Science Foundation of Qilu Hospital of Shandong University (2016QLQN05) and National Natural Science Foundation of China (81171579, 81201287 and 81371832).

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Authors and Affiliations

  1. Department of Hepatology, Qilu Hospital of Shandong University, Jinan, 250012, China

    Li-Yuan Wang, Yu-Chen Fan, Jing Zhao, Xiang-Fen Ji & Kai Wang

  2. Institute of Hepatology, Shandong University, Wenhuaxi Road 107#, Jinan, 250012, China

    Yu-Chen Fan & Kai Wang

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  1. Li-Yuan Wang
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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Wang, LY., Fan, YC., Zhao, J. et al. Increased BATF expression is associated with the severity of liver damage in patients with chronic hepatitis B. Clin Exp Med 18, 263–272 (2018). https://doi.org/10.1007/s10238-017-0480-3

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