Inhibition of SATB1 expression in regulatory T cells contributes to hepatitis B virus-related chronic liver inflammation

Li,Xue-Fen; Tian,Li; Wang,Yi-Yin; Kong,Hai-Shen; Dong,Yue-Jiao; Zhu,Qiao-Yun; Ni,Qin; Chen,Yu

doi:10.3892/mmr.2014.2752

Inhibition of SATB1 expression in regulatory T cells contributes to hepatitis B virus-related chronic liver inflammation

Authors:
- Xue-Fen Li
- Li Tian
- Yi-Yin Wang
- Hai-Shen Kong
- Yue-Jiao Dong
- Qiao-Yun Zhu
- Qin Ni
- Yu Chen
View Affiliations

Affiliations: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China, Department of Laboratory Medicine, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
Published online on: October 23, 2014 https://doi.org/10.3892/mmr.2014.2752
Pages: 231-236

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Regulatory T cells (Tregs) contribute to the pathogenesis of chronic hepatitis B (CHB). Special AT-rich sequence-binding protein 1 (SATB1) may be a key component of this process. In the present study, Tregs and conventional T cells (Tconvs) were isolated by magnetic cell sorting of peripheral blood from CHB patients (n=57), individuals with resolved hepatitis B virus (HBV) infections (n=15), and healthy controls (n=29). SATB1 expression was studied by reverse transcription‑quantitative PCR, flow cytometry and immunofluorescence microscopy, and the correlation of SATB1 expression to the expression of liver inflammation serum markers and the HBV DNA load was assessed. CHB patients showed significantly reduced SATB1 expression in Tregs than healthy controls and individuals with resolved HBV infections. Moreover, SATB1 expression in Tregs was significantly lower than in Tconvs of patients with chronic HBV infection. Serum HBV DNA and liver inflammation markers were inversely correlated to the SATB1 mRNA level in Tregs. Antiviral treatment was accompanied by increased expression of the SATB1 gene in Tregs. Thus, Tregs from CHB patients have reduced levels of SATB1, which is resolved with antiviral therapy. Inhibition of SATB1 expression may impair the hepatic inflammatory response and contribute to HBV persistence.

View Figures

View References

1	Lee WM: Hepatitis B virus infection. N Engl J Med. 337:1733–1745. 1997. View Article : Google Scholar : PubMed/NCBI
2	Dienstag JL: Hepatitis B virus infection. N Engl J Med. 359:1486–1500. 2008. View Article : Google Scholar : PubMed/NCBI
3	Maini MK, Boni C, Ogg GS, King AS, Reignat S, Lee CK, Larrubia JR, Webster GJ, McMichael AJ, Ferrari C, Williams R, Vergani D and Bertoletti A: Direct ex vivo analysis of hepatitis B virus-specific CD8⁺T cells associated with the control of infection. Gastroenterology. 117:1386–1396. 1999. View Article : Google Scholar : PubMed/NCBI
4	Wang FS and Zhang Z: Host immunity influences disease progression and antiviral efficacy in humans infected with hepatitis B virus. Expert Rev Gastroenterol Hepatol. 3:499–512. 2009. View Article : Google Scholar : PubMed/NCBI
5	Xu D, Fu J, Jin L, Zhang H, Zhou C, Zou Z, Zhao JM, Zhang B, Shi M, Ding X, Tang Z, Fu YX and Wang FS: Circulating and liver resident CD4⁺CD25⁺ regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B. J Immunol. 177:739–747. 2006.PubMed/NCBI
6	Tadokoro CE, Shakhar G, Shen S, Ding Y, Lino AC, Maraver A, Lafaille JJ and Dustin ML: Regulatory T cells inhibit stable contacts between CD4⁺ T cells and dendritic cells in vivo. J Exp Med. 203:505–511. 2006. View Article : Google Scholar : PubMed/NCBI
7	Stoop JN, van der Molen RG, Baan CC, van der Laan LJ, Kuipers EJ, Kusters JG and Janssen HL: Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology. 41:771–778. 2005. View Article : Google Scholar : PubMed/NCBI
8	Li X, Chen Y, Ma Z, Ye B, Wu W and Li L: Effect of regulatory T cells and adherent cells on the expansion of HBcAg-specific CD8⁺ T cells in patients with chronic hepatitis B virus infection. Cell Immunol. 264:42–46. 2010. View Article : Google Scholar : PubMed/NCBI
9	Beyer M, Thabet Y, Müller RU, Sadlon T, Classen S, Lahl K, Basu S, Zhou X, Bailey-Bucktrout SL, Krebs W, et al: Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation. Nat Immunol. 12:898–907. 2011. View Article : Google Scholar : PubMed/NCBI
10	Burute M, Gottimukkala K and Galande S: Chromatin organizer SATB1 is an important determinant of T-cell differentiation. Immunol Cell Biol. 90:852–859. 2012. View Article : Google Scholar : PubMed/NCBI
11	Nie H, Maika SD, Tucker PW and Gottlieb PD: A role for SATB1, a nuclear matrix association region-binding protein, in the development of CD8SP thymocytes and peripheral T lymphocytes. J Immunol. 174:4745–4752. 2005. View Article : Google Scholar : PubMed/NCBI
12	Yamaguchi H, Tateno M and Yamasaki K: Solution structure and DNA-binding mode of the matrix attachment region-binding domain of the transcription factor SATB1 that regulates the T-cell maturation. J Biol Chem. 281:5319–5327. 2006. View Article : Google Scholar : PubMed/NCBI
13	Chinese Society of Hepatology, Chinese Medical Association; Chinese Society of Infectious Diseases, Chinese Medical Association. Guideline on prevention and treatment of chronic hepatitis B in China (2005). Chin Med J (Engl). 120:2159–2173. 2007.PubMed/NCBI
14	Szodoray P, Papp G, Horvath IF, Barath S, Sipka S, Nakken B and Zeher M: Cells with regulatory function of the innate and adaptive immune system in primary Sjögren’s syndrome. Clin Exp Immunol. 157:343–349. 2009.PubMed/NCBI
15	Franzese O, Kennedy PT, Gehring AJ, Gotto J, Williams R, Maini MK and Bertoletti A: Modulation of the CD8⁺-T-cell response by CD4⁺ CD25⁺ regulatory T cells in patients with hepatitis B virus infection. J Virol. 79:3322–3328. 2005.PubMed/NCBI
16	Sakaguchi S, Yamaguchi T, Nomura T and Ono M: Regulatory T cells and immune tolerance. Cell. 133:775–787. 2008. View Article : Google Scholar : PubMed/NCBI
17	Galande S, Dickinson LA, Mian IS, Sikorska M and Kohwi-Shigematsu T: SATB1 cleavage by caspase 6 disrupts PDZ domain-mediated dimerization, causing detachment from chromatin early in T-cell apoptosis. Mol Cell Biol. 21:5591–5604. 2001. View Article : Google Scholar : PubMed/NCBI
18	Han HJ, Russo J, Kohwi Y and Kohwi-Shigematsu T: SATB1 reprogrammes gene expression to promote breast tumour growth and metastasis. Nature. 452:187–193. 2008. View Article : Google Scholar : PubMed/NCBI
19	Patani N, Jiang W, Mansel R, Newbold R and Mokbel K: The mRNA expression of SATB1 and SATB2 in human breast cancer. Cancer Cell Int. 9:182009. View Article : Google Scholar : PubMed/NCBI
20	Cheng C, Lu X, Wang G, Zheng L, Shu X, Zhu S, Liu K, Wu K and Tong Q: Expression of SATB1 and heparanase in gastric cancer and its relationship to clinicopathologic features. APMIS. 118:855–863. 2010. View Article : Google Scholar : PubMed/NCBI
21	Lu X, Cheng C, Zhu S, Yang Y, Zheng L, Wang G, Shu X, Wu K, Liu K and Tong Q: SATB1 is an independent prognostic marker for gastric cancer in a Chinese population. Oncol Rep. 24:981–987. 2010.PubMed/NCBI
22	Meng WJ, Yan H, Zhou B, Zhang W, Kong XH, Wang R, Zhan L, Li Y, Zhou ZG and Sun XF: Correlation of SATB1 overexpression with the progression of human rectal cancer. Int J Colorectal Dis. 27:143–150. 2012. View Article : Google Scholar : PubMed/NCBI
23	Tu W, Luo M, Wang Z, Yan W, Xia Y, Deng H, He J, Han P and Tian D: Upregulation of SATB1 promotes tumor growth and metastasis in liver cancer. Liver Int. 32:1064–1078. 2012. View Article : Google Scholar
24	Zheng Y, Huang Z, Chen X, Tian Y, Tang J, Zhang Y, Zhang X, Zhou J, Mao Q, Ni B, Wang Q and Wu Y: Effects of telbivudine treatment on the circulating CD4⁺ T-cell subpopulations in chronic hepatitis B patients. Mediators Inflamm. 2012:7898592012. View Article : Google Scholar : PubMed/NCBI