Research advances in cytokines in the treatment of chronic hepatitis B

Zixiang GAO; Zhongliang SHEN; Jing LIU; Youhua XIE

doi:10.3969/j.issn.1001-5256.2022.08.002

Volume 38 Issue 8

Aug. 2022

Turn off MathJax

Article Contents

Article Navigation > Journal of Clinical Hepatology > 2022 > 38(8): 1710-1715

PDF( 1905 KB)

Research advances in cytokines in the treatment of chronic hepatitis B

DOI: 10.3969/j.issn.1001-5256.2022.08.002

Zixiang GAO¹,
Zhongliang SHEN^{1, 2},
Jing LIU^{1, 3},
Youhua XIE^{1, 4
,
,
,}

1.
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS) and Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
2.
Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China
3.
Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
4.
Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China

Research funding:

National Natural Science Foundation of China (81971921)

More Information

Corresponding author: XIE Youhua, yhxie@fudan.edu.cn(ORCID: 0000-0002-2416-7708)
Received Date: 2022-05-20
Accepted Date: 2022-07-06
Published Date: 2022-08-20

Abstract

Abstract

At present, there are still about 250 million people with chronic hepatitis B virus (HBV) infection around the world, which seriously threatens human life and health. Chronic hepatitis B (CHB) can develop into liver diseases such as liver fibrosis, liver cirrhosis, and hepatocellular carcinoma; however, there is still a limited number of antiviral drugs and an extremely low cure rate in clinical practice, and thus it is urgent to develop new antiviral drugs. HBV has strong hepatotropism and only infects a few primates such as humans and chimpanzees under natural conditions. Whether immune response (innate immunity and adaptive immunity) can effectively recognize and eliminate or inhibit HBV is an important factor leading to different outcomes after virus infection, and cytokines play an important immunoregulatory role in this process. This article summarizes and discusses the research advances in some key cytokines in CHB infection and treatment.
- Hepatitis B Virus,
- Cytokines,
- Hepatitis B, Chronic,
- Therapeutics

FullText(HTML)

References(45)

References

[1]	TIAN ZJ, SHEN Y, LI XR, et al. Increased interleukin-32, interleukin-1, and interferon-γ levels in serum from hepatitis B patients and in HBV-stimulated peripheral blood mononuclear cells from healthy volunteers[J]. J Infect Public Health, 2019, 12(1): 7-12. DOI: 10.1016/j.jiph.2018.06.006.
[2]	LEI Q, LI T, KONG L, et al. HBV-Pol is crucial for HBV-mediated inhibition of inflammasome activation and IL-1β production[J]. Liver Int, 2019, 39(12): 2273-2284. DOI: 10.1111/liv.14214.
[3]	WANG Y, CUI L, YANG G, et al. Hepatitis B e antigen inhibits NF-κB activity by interrupting K63-linked ubiquitination of NEMO[J]. J Virol, 2019, 93(2): e00667-18. DOI: 10.1128/JVI.00667-18.
[4]	DELPHIN M, FAURE-DUPUY S, ISORCE N, et al. Inhibitory effect of IL-1β on HBV and HDV replication and HBs antigen-dependent modulation of its secretion by macrophages[J]. Viruses, 2021, 14(1): 65. DOI: 10.3390/v14010065.
[5]	KIMURA K, KAKIMI K, WIELAND S, et al. Interleukin-18 inhibits hepatitis B virus replication in the livers of transgenic mice[J]. J Virol, 2002, 76(21): 10702-10707. DOI: 10.1128/jvi.76.21.10702-10707.2002.
[6]	ZHU M, ZHANG X. Effect of IL-18 on intrauterine infection of HBV in mice on cell molecular level[J]. Saudi J Biol Sci, 2020, 27(6): 1685-1690. DOI: 10.1016/j.sjbs.2020.04.028.
[7]	NAKANISHI K. Unique action of interleukin-18 on T cells and other immune cells[J]. Front Immunol, 2018, 9: 763. DOI: 10.3389/fimmu.2018.00763.
[8]	ZHAO PW, SHI X, LI C, et al. IL-33 enhances humoral immunity against chronic HBV infection through activating CD4(+)CXCR5(+) TFH cells[J]. J Interferon Cytokine Res, 2015, 35(6): 454-463. DOI: 10.1089/jir.2013.0122.
[9]	SHEN Z, YANG H, YANG S, et al. Hepatitis B virus persistence in mice reveals IL-21 and IL-33 as regulators of viral clearance[J]. Nat Commun, 2017, 8(1): 2119. DOI: 10.1038/s41467-017-02304-7.
[10]	GAO X, CHI X, WANG X, et al. IL-33 Inhibits hepatitis B virus through its receptor ST2 in hydrodynamic HBV mouse model[J]. Mediators Inflamm, 2020, 2020: 1403163. DOI: 10.1155/2020/1403163.
[11]	GONG Y, TINGXI Z, QING L, et al. Elevated production of IL-36α in chronic hepatitis B virus-infected patients correlates with viral load[J]. Microb Pathog, 2017, 113: 412-415. DOI: 10.1016/j.micpath.2017.11.023.
[12]	LI C, JI H, CAI Y, et al. Serum interleukin-37 concentrations and HBeAg seroconversion in chronic HBV patients during telbivudine treatment[J]. J Interferon Cytokine Res, 2013, 33(10): 612-618. DOI: 10.1089/jir.2013.0001.
[13]	DONG Y, LI X, ZHANG L, et al. CD4⁺ T cell exhaustion revealed by high PD-1 and LAG-3 expression and the loss of helper T cell function in chronic hepatitis B[J]. BMC Immunol, 2019, 20(1): 27. DOI: 10.1186/s12865-019-0309-9.
[14]	WANG D, FU B, SHEN X, et al. Restoration of HBV-specific CD8⁺ T-cell responses by sequential low-dose IL-2 treatment in non-responder patients after IFN-α therapy[J]. Signal Transduct Target Ther, 2021, 6(1): 376. DOI: 10.1038/s41392-021-00776-0.
[15]	TOMOVA R, ANTONOV K, IVANOVA A, et al. Low-dose IL-2 therapy reduces HCV RNA and HBV DNA: case report[J]. Anticancer Res, 2009, 29(12): 5241-5244.
[16]	JIANG Y, MA Z, XIN G, et al. Th1 and Th2 immune response in chronic hepatitis B patients during a long-term treatment with adefovir dipivoxil[J]. Mediators Inflamm, 2010, 2010: 143026. DOI: 10.1155/2010/143026.
[17]	YAO Y, LI J, LU Z, et al. Proteomic analysis of the interleukin-4(IL-4) response in hepatitis B virus-positive human hepatocelluar carcinoma cell line HepG2.2.15[J]. Electrophoresis, 2011, 32(15): 2004-2012. DOI: 10.1002/elps.201100147.
[18]	LU Y, WU Z, PENG Q, et al. Role of IL-4 gene polymorphisms in HBV-related hepatocellular carcinoma in a Chinese population[J]. PLoS One, 2014, 9(10): e110061. DOI: 10.1371/journal.pone.0110061.
[19]	YIN W, XU L, SUN R, et al. Interleukin-15 suppresses hepatitis B virus replication via IFN-β production in a C57BL/6 mouse model[J]. Liver Int, 2012, 32(8): 1306-1314. DOI: 10.1111/j.1478-3231.2012.02773.x.
[20]	DI SCALA M, OTANO I, GIL-FARIÑA I, et al. Complementary effects of interleukin-15 and alpha interferon induce immunity in hepatitis B virus transgenic mice[J]. J Virol, 2016, 90(19): 8563-8574. DOI: 10.1128/JVI.01030-16.
[21]	SHEN Z, WU J, GAO Z, et al. Characterization of IL-21-expressing recombinant hepatitis B virus (HBV) as a therapeutic agent targeting persisting HBV infection[J]. Theranostics, 2020, 10(12): 5600-5612. DOI: 10.7150/thno.44715.
[22]	TANG L, CHEN C, GAO X, et al. Interleukin 21 reinvigorates the antiviral activity of hepatitis B virus (HBV)-specific CD8⁺ T cells in chronic HBV infection[J]. J Infect Dis, 2019, 219(5): 750-759. DOI: 10.1093/infdis/jiy576.
[23]	PUBLICOVER J, GOODSELL A, NISHIMURA S, et al. IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B[J]. J Clin Invest, 2011, 121(3): 1154-1162. DOI: 10.1172/JCI44198.
[24]	LIU B, GAO W, ZHANG L, et al. Th17/Treg imbalance and increased interleukin-21 are associated with liver injury in patients with chronic severe hepatitis B[J]. Int Immunopharmacol, 2017, 46: 48-55. DOI: 10.1016/j.intimp.2017.02.019.
[25]	ZHOU X, YANG F, YANG Y, et al. HBV facilitated hepatocellular carcinoma cells proliferation by up-regulating angiogenin expression through IL-6[J]. Cell Physiol Biochem, 2018, 46(2): 461-470. DOI: 10.1159/000488614.
[26]	PALUMBO GA, SCISCIANI C, PEDICONI N, et al. IL6 inhibits HBV transcription by targeting the epigenetic control of the nuclear cccDNA minichromosome[J]. PLoS One, 2015, 10(11): e0142599. DOI: 10.1371/journal.pone.0142599.
[27]	DADMANESH M, GHORBAN K, HASSANSHAHI G, et al. Current information concerning association of IL-12 and hepatitis B infection[J]. Clin Lab, 2014, 60(2): 185-191. DOI: 10.7754/clin.lab.2013.130201.
[28]	HE D, YAN G, WANG Y. Serum levels of interleukin-12 in various clinical states with hepatitis B virus infection[J]. Cell Immunol, 2012, 272(2): 162-165. DOI: 10.1016/j.cellimm.2011.10.016.
[29]	ZENG Z, KONG X, LI F, et al. IL-12-based vaccination therapy reverses liver-induced systemic tolerance in a mouse model of hepatitis B virus carrier[J]. J Immunol, 2013, 191(8): 4184-4193. DOI: 10.4049/jimmunol.1203449.
[30]	SCHURICH A, PALLETT LJ, LUBOWIECKI M, et al. The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells[J]. PLoS Pathog, 2013, 9(3): e1003208. DOI: 10.1371/journal.ppat.1003208.
[31]	CAO Y, ZHANG R, ZHANG W, et al. IL-27, a cytokine, and IFN-λ1, a type Ⅲ IFN, are coordinated to regulate virus replication through type Ⅰ IFN[J]. J Immunol, 2014, 192(2): 691-703. DOI: 10.4049/jimmunol.1300252.
[32]	TAN G, XIAO Q, SONG H, et al. Type Ⅰ IFN augments IL-27-dependent TRIM25 expression to inhibit HBV replication[J]. Cell Mol Immunol, 2018, 15(3): 272-281. DOI: 10.1038/cmi.2016.67.
[33]	KHANAM A, AYITHAN N, TANG L, et al. IL-21-deficient T follicular helper cells support B Cell responses through IL-27 in patients with chronic hepatitis B[J]. Front Immunol, 2020, 11: 599648. DOI: 10.3389/fimmu.2020.599648.
[34]	EJRNAES M, FILIPPI CM, MARTINIC MM, et al. Resolution of a chronic viral infection after interleukin-10 receptor blockade[J]. J Exp Med, 2006, 203(11): 2461-2472. DOI: 10.1084/jem.20061462.
[35]	PAQUISSI FC. Immunity and fibrogenesis: the role of Th17/IL-17 axis in HBV and HCV-induced chronic hepatitis and progression to cirrhosis[J]. Front Immunol, 2017, 8: 1195. DOI: 10.3389/fimmu.2017.01195.
[36]	WANG B, ZHAO XP, FAN YC, et al. 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[J]. Antiviral Res, 2013, 97(3): 285-292. DOI: 10.1016/j.antiviral.2012.12.018.
[37]	WANG X, DONG A, XIAO J, et al. Overcoming HBV immune tolerance to eliminate HBsAg-positive hepatocytes via pre-administration of GM-CSF as a novel adjuvant for a hepatitis B vaccine in HBV transgenic mice[J]. Cell Mol Immunol, 2016, 13(6): 850-861. DOI: 10.1038/cmi.2015.64.
[38]	LUCIFORA J, XIA Y, REISINGER F, et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA[J]. Science, 2014, 343(6176): 1221-1228. DOI: 10.1126/science.1243462.
[39]	CHEN J, LI Y, LAI F, et al. Functional comparison of interferon-α subtypes reveals potent hepatitis B virus suppression by a concerted action of interferon-α and interferon-γ signaling[J]. Hepatology, 2021, 73(2): 486-502. DOI: 10.1002/hep.31282.
[40]	WANG H, LUO H, WAN X, et al. TNF-α/IFN-γ profile of HBV-specific CD4 T cells is associated with liver damage and viral clearance in chronic HBV infection[J]. J Hepatol, 2020, 72(1): 45-56. DOI: 10.1016/j.jhep.2019.08.024.
[41]	XU F, SONG H, XIAO Q, et al. Type Ⅲ interferon-induced CBFβ inhibits HBV replication by hijacking HBx[J]. Cell Mol Immunol, 2019, 16(4): 357-366. DOI: 10.1038/s41423-018-0006-2.
[42]	QIAO Y, HAN X, GUAN G, et al. TGF-β triggers HBV cccDNA degradation through AID-dependent deamination[J]. FEBS Lett, 2016, 590(3): 419-427. DOI: 10.1002/1873-3468.12058.
[43]	YOSHIO S, MANO Y, DOIH, et al. Cytokine and chemokine signatures associated with hepatitis B surface antigen loss in hepatitis B patients[J]. JCI Insight, 2018, 3(20): e122268. DOI: 10.1172/jci.insight.122268.
[44]	LI Y, TANG L, GUO L, et al. CXCL13-mediated recruitment of intrahepatic CXCR5⁺CD8⁺ T cells favors viral control in chronic HBV infection[J]. J Hepatol, 2020, 72(3): 420-430. DOI: 10.1016/j.jhep.2019.09.031.
[45]	YAN Y, ZHAO W, LIU W, et al. CCL19 enhances CD8⁺ T-cell responses and accelerates HBV clearance[J]. J Gastroenterol, 2021, 56(8): 769-785. DOI: 10.1007/s00535-021-01799-8.

Relative Articles

Supplements(0)

Cited By

Proportional views

Proportional views

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142

Get Citation

PDF

XML

Article Metrics

Article views (681) PDF downloads(144)

Research advances in cytokines in the treatment of chronic hepatitis B

DOI: 10.3969/j.issn.1001-5256.2022.08.002

Abstract

References

Proportional views

Catalog

通讯作者: 陈斌, bchen63@163.com

Article Metrics

Proportional views

Related

Research advances in cytokines in the treatment of chronic hepatitis B

DOI: 10.3969/j.issn.1001-5256.2022.08.002

Abstract

References

Proportional views

Catalog

通讯作者: 陈斌, bchen63@163.com

Article Metrics

Proportional views

Related

About Journal

Submission Guideline

Journal Online

Hepatobiliary College

Guidelines

Export File

Citation

Format

Content