Skip to main content
Top
Published in: Journal of Clinical Immunology 7/2013

Open Access 01-10-2013 | Original Research

Expression Pattern of Serum Cytokines in Hepatitis B Virus Infected Patients with Persistently Normal Alanine Aminotransferase Levels

Authors: Dengming He, Maoshi Li, Shimin Guo, Peng Zhu, Hongfei Huang, Guohua Yan, Quanxin Wu, Shiqi Tao, Zhaoxia Tan, Yuming Wang

Published in: Journal of Clinical Immunology | Issue 7/2013

Login to get access

Abstract

Purpose

About 60–80 % of chronic hepatitis B virus (HBV) carriers are characterized with persistently normal alanine transaminase (ALT). Differences of cytokine expression are associated with the prognosis of HBV infection. We investigated the expression pattern of 30 cytokines associated with anti-HBV immunity in patients with normal ALT.

Methods

Four patient groups (immune tolerance, inactive hepatitis B surface antigen carriers, resolved hepatitis B, and control; 10 subjects per group) were assigned. Thirty cytokines, including IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-7, IL-9, IL-10, IL-12p40, IL-12p70, IL-15, IL-17A, IL-17C, IL-21, IL-22, IL-23p19, IL-28A, IL-29, CCL5, CCL16, CCL20, CCL22, CXCL9, CXCL10, CXCL11, TNFRSF8, TNFRSF18, IL-6R, gp130, and TGF-β1, were measured using a human cytokine antibody array. Signal intensities were obtained by laser scanner. Protein-protein interactions were analyzed by STRING (Search Tool for the Retrieval of Interacting Genes/Proteins).

Results

Significant differences of signal intensities were observed for IL-2, IL-4, IL-6, IL-7, IL-9, IL-10, IL-12p40, IL-12p70, IL-15, IL-21, IL-23p19, IL-28A, and IL-29. The lowest intensity was in controls. Among three HBV infection groups, significant differences were observed in IL-2, IL-4, IL-12p70, IL-15, IL-21, IL-23p19, and IL-29. The highest intensity was in the inactive group. All cytokines with significant differences were involved JAK-STAT signaling that up-regulate FOXP3, SOCS3 and MX1.

Conclusion

Differential expression of cytokines in JAK-STAT signaling is an important factor associated with prognosis of HBV infection. The elevation of γC cytokines, IL-12p70, IL-23p19, and IL-29 may promote spontaneous HBeAg seroconversion and HBV clearance.
Appendix
Available only for authorised users
Literature
2.
go back to reference European Association For The Study Of The L. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol. 2012;57(1):167–85. European Association For The Study Of The L. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol. 2012;57(1):167–85.
3.
go back to reference Ganem D, Prince AM. Hepatitis B virus infection–natural history and clinical consequences. N Engl J Med. 2004;350(11):1118–29.PubMedCrossRef Ganem D, Prince AM. Hepatitis B virus infection–natural history and clinical consequences. N Engl J Med. 2004;350(11):1118–29.PubMedCrossRef
4.
go back to reference Rizzetto M, Ciancio A. Chronic HBV-related liver disease. Mol Asp Med. 2008;29(1–2):72–84.CrossRef Rizzetto M, Ciancio A. Chronic HBV-related liver disease. Mol Asp Med. 2008;29(1–2):72–84.CrossRef
5.
go back to reference Yuen MF, Wong DK, Sablon E, Tse E, Ng IO, Yuan HJ, et al. HBsAg seroclearance in chronic hepatitis B in the Chinese: virological. Hepatology. 2004;39(6):1694–701.PubMedCrossRef Yuen MF, Wong DK, Sablon E, Tse E, Ng IO, Yuan HJ, et al. HBsAg seroclearance in chronic hepatitis B in the Chinese: virological. Hepatology. 2004;39(6):1694–701.PubMedCrossRef
6.
go back to reference Fattovich G, Giustina G, Sanchez-Tapias J, Quero C, Mas A, Olivotto PG, et al. Delayed clearance of serum HBsAg in compensated cirrhosis B: relation to. Am J Gastroenterol. 1998;93(6):896–900.PubMedCrossRef Fattovich G, Giustina G, Sanchez-Tapias J, Quero C, Mas A, Olivotto PG, et al. Delayed clearance of serum HBsAg in compensated cirrhosis B: relation to. Am J Gastroenterol. 1998;93(6):896–900.PubMedCrossRef
7.
go back to reference Chen Y-C, Sheen IS, C-m C, Liaw Y-F. Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection. Gastroenterology. 2002;123(4):1084–9.PubMedCrossRef Chen Y-C, Sheen IS, C-m C, Liaw Y-F. Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection. Gastroenterology. 2002;123(4):1084–9.PubMedCrossRef
8.
go back to reference Arai M, Togo S, Kanda T, Fujiwara K, Imazeki F, Yokosuka O. Quantification of hepatitis B surface antigen can help predict spontaneous. Eur J Gastroenterol Hepatol. 2012;24(4):414–8.PubMed Arai M, Togo S, Kanda T, Fujiwara K, Imazeki F, Yokosuka O. Quantification of hepatitis B surface antigen can help predict spontaneous. Eur J Gastroenterol Hepatol. 2012;24(4):414–8.PubMed
9.
go back to reference Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol. 2005;5(3). Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol. 2005;5(3).
10.
go back to reference Vinader V, Afarinkia K. A beginner’s guide to chemokines. Futur Med Chem. 2012;4(7):845–52.CrossRef Vinader V, Afarinkia K. A beginner’s guide to chemokines. Futur Med Chem. 2012;4(7):845–52.CrossRef
11.
go back to reference Garabedian L, Struyf S, Opdenakker G, Sozzani S, Van Damme J, Laureys G. Langerhans cell histiocytosis: a cytokine/chemokine-mediated disorder? Eur Cytokine Netw. 2011;22(3):148–53.PubMed Garabedian L, Struyf S, Opdenakker G, Sozzani S, Van Damme J, Laureys G. Langerhans cell histiocytosis: a cytokine/chemokine-mediated disorder? Eur Cytokine Netw. 2011;22(3):148–53.PubMed
12.
go back to reference Tacke F, Luedde T, Trautwein C. Inflammatory pathways in liver homeostasis and liver injury. Clin Rev Allergy Immunol. 2009;36(1):4–12.PubMedCrossRef Tacke F, Luedde T, Trautwein C. Inflammatory pathways in liver homeostasis and liver injury. Clin Rev Allergy Immunol. 2009;36(1):4–12.PubMedCrossRef
14.
go back to reference Kowalewska PM, Patrick AL, Fox-Robichaud AE. Innate immunity of the liver microcirculation. Cell Tissue Res. 2011;343(1):85–96.PubMedCrossRef Kowalewska PM, Patrick AL, Fox-Robichaud AE. Innate immunity of the liver microcirculation. Cell Tissue Res. 2011;343(1):85–96.PubMedCrossRef
15.
go back to reference Jensen LJ, Kuhn M, Stark M, Chaffron S, Creevey C, Muller J, et al. STRING 8—a global view on proteins and their functional interactions in 630. Nucleic Acids Res. 2009;37(Database issue):D412–6.PubMedCrossRef Jensen LJ, Kuhn M, Stark M, Chaffron S, Creevey C, Muller J, et al. STRING 8—a global view on proteins and their functional interactions in 630. Nucleic Acids Res. 2009;37(Database issue):D412–6.PubMedCrossRef
16.
17.
go back to reference Maini MK, Boni C, Lee CK, Larrubia JR, Reignat S, Ogg GS, et al. The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med. 2000;191(8):1269–80.PubMedCrossRef Maini MK, Boni C, Lee CK, Larrubia JR, Reignat S, Ogg GS, et al. The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med. 2000;191(8):1269–80.PubMedCrossRef
18.
go back to reference Overwijk WW, Schluns KS. Functions of gammaC cytokines in immune homeostasis: current and potential. Clin Immunol. 2009;132(2):153–65.PubMedCrossRef Overwijk WW, Schluns KS. Functions of gammaC cytokines in immune homeostasis: current and potential. Clin Immunol. 2009;132(2):153–65.PubMedCrossRef
19.
go back to reference Chen YT, Kung JT. IL-4 inducibility in NKT cells, naive CD4+ T cells and TCR-gamma delta T cells. J Biomed Sci. 2007;14(4):533–8.PubMedCrossRef Chen YT, Kung JT. IL-4 inducibility in NKT cells, naive CD4+ T cells and TCR-gamma delta T cells. J Biomed Sci. 2007;14(4):533–8.PubMedCrossRef
20.
go back to reference Hunig T, Luhder F, Elflein K, Gogishvili T, Frohlich M, Guler R, et al. CD28 and IL-4: two heavyweights controlling the balance between immunity and. Med Microbiol Immunol. 2010;199(3):239–46.PubMedCrossRef Hunig T, Luhder F, Elflein K, Gogishvili T, Frohlich M, Guler R, et al. CD28 and IL-4: two heavyweights controlling the balance between immunity and. Med Microbiol Immunol. 2010;199(3):239–46.PubMedCrossRef
21.
go back to reference Gilmour J, Lavender P. Control of IL-4 expression in T helper 1 and 2 cells. Immunology. 2008;124(4):437–44.PubMedCrossRef Gilmour J, Lavender P. Control of IL-4 expression in T helper 1 and 2 cells. Immunology. 2008;124(4):437–44.PubMedCrossRef
22.
go back to reference Villinger F, Miller R, Mori K, Mayne AE, Bostik P, Sundstrom JB, et al. IL-15 is superior to IL-2 in the generation of long-lived antigen specific memory. Vaccine. 2004;22(25–26):3510–21.PubMedCrossRef Villinger F, Miller R, Mori K, Mayne AE, Bostik P, Sundstrom JB, et al. IL-15 is superior to IL-2 in the generation of long-lived antigen specific memory. Vaccine. 2004;22(25–26):3510–21.PubMedCrossRef
23.
go back to reference Yin W, Xu L, Sun R, Wei H, Tian Z. Interleukin-15 suppresses hepatitis B virus replication via IFN-beta production. Liver Int. 2012;32(8):1306–14.PubMedCrossRef Yin W, Xu L, Sun R, Wei H, Tian Z. Interleukin-15 suppresses hepatitis B virus replication via IFN-beta production. Liver Int. 2012;32(8):1306–14.PubMedCrossRef
24.
go back to reference Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation. Nature. 2000;408(6808):57–63.PubMedCrossRef Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation. Nature. 2000;408(6808):57–63.PubMedCrossRef
25.
go back to reference Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, Sher A, et al. A critical role for IL-21 in regulating immunoglobulin production. Science. 2002;298(5598):1630–4.PubMedCrossRef Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, Sher A, et al. A critical role for IL-21 in regulating immunoglobulin production. Science. 2002;298(5598):1630–4.PubMedCrossRef
26.
go back to reference Ma S-W, Huang X, Li Y-Y, Tang L-B, Sun X-F, Jiang X-T, et al. High serum IL-21 levels after 12 weeks of antiviral therapy predict HBeAg seroconversion in chronic hepatitis B. J Hepatol. 2012;56(4). Ma S-W, Huang X, Li Y-Y, Tang L-B, Sun X-F, Jiang X-T, et al. High serum IL-21 levels after 12 weeks of antiviral therapy predict HBeAg seroconversion in chronic hepatitis B. J Hepatol. 2012;56(4).
27.
go back to reference Mujib S, Jones RB, Lo C, Aidarus N, Clayton K, Sakhdari A, et al. Antigen-independent induction of Tim-3 expression on human T cells by the common. J Immunol. 2012;188(8):3745–56.PubMedCrossRef Mujib S, Jones RB, Lo C, Aidarus N, Clayton K, Sakhdari A, et al. Antigen-independent induction of Tim-3 expression on human T cells by the common. J Immunol. 2012;188(8):3745–56.PubMedCrossRef
28.
go back to reference Novelli F, Casanova JL. The role of IL-12, IL-23 and IFN-gamma in immunity to viruses. Cytokine Growth Factor Rev. 2004;15(5):367–77.PubMedCrossRef Novelli F, Casanova JL. The role of IL-12, IL-23 and IFN-gamma in immunity to viruses. Cytokine Growth Factor Rev. 2004;15(5):367–77.PubMedCrossRef
29.
go back to reference Croxford AL, Mair F, Becher B. IL-23: one cytokine in control of autoimmunity. Eur J Immunol. 2012;42(9):2263–73.PubMedCrossRef Croxford AL, Mair F, Becher B. IL-23: one cytokine in control of autoimmunity. Eur J Immunol. 2012;42(9):2263–73.PubMedCrossRef
30.
go back to reference Xia L, Tian D, Huang W, Zhu H, Wang J, Zhang Y, et al. Upregulation of IL-23 expression in patients with chronic hepatitis B is mediated. J Immunol. 2012;188(2):753–64.PubMedCrossRef Xia L, Tian D, Huang W, Zhu H, Wang J, Zhang Y, et al. Upregulation of IL-23 expression in patients with chronic hepatitis B is mediated. J Immunol. 2012;188(2):753–64.PubMedCrossRef
31.
go back to reference Kao JT, Lai HC, Tsai SM, Lin PC, Chuang PH, Yu CJ, et al. Rather than interleukin-27, interleukin-6 expresses positive correlation with. Liver Int. 2012;32(6):928–36.PubMedCrossRef Kao JT, Lai HC, Tsai SM, Lin PC, Chuang PH, Yu CJ, et al. Rather than interleukin-27, interleukin-6 expresses positive correlation with. Liver Int. 2012;32(6):928–36.PubMedCrossRef
32.
go back to reference Hosel M, Quasdorff M, Wiegmann K, Webb D, Zedler U, Broxtermann M, et al. Not interferon, but interleukin-6 controls early gene expression in hepatitis B. Hepatology. 2009;50(6):1773–82.PubMedCrossRef Hosel M, Quasdorff M, Wiegmann K, Webb D, Zedler U, Broxtermann M, et al. Not interferon, but interleukin-6 controls early gene expression in hepatitis B. Hepatology. 2009;50(6):1773–82.PubMedCrossRef
33.
go back to reference Uze G, Monneron D. IL-28 and IL-29: newcomers to the interferon family. Biochimie. 2007;89(6–7):729–34.PubMedCrossRef Uze G, Monneron D. IL-28 and IL-29: newcomers to the interferon family. Biochimie. 2007;89(6–7):729–34.PubMedCrossRef
34.
go back to reference Witte K, Witte E, Sabat R, Wolk K. IL-28A, IL-28B, and IL-29: promising cytokines with type I interferon-like. Cytokine Growth Factor Rev. 2010;21(4):237–51.PubMedCrossRef Witte K, Witte E, Sabat R, Wolk K. IL-28A, IL-28B, and IL-29: promising cytokines with type I interferon-like. Cytokine Growth Factor Rev. 2010;21(4):237–51.PubMedCrossRef
35.
go back to reference Gordien E, Rosmorduc O, Peltekian C, Garreau F, Brechot C, Kremsdorf D. Inhibition of hepatitis B virus replication by the interferon-inducible MxA. J Virol. 2001;75(6):2684–91.PubMedCrossRef Gordien E, Rosmorduc O, Peltekian C, Garreau F, Brechot C, Kremsdorf D. Inhibition of hepatitis B virus replication by the interferon-inducible MxA. J Virol. 2001;75(6):2684–91.PubMedCrossRef
36.
go back to reference Haller O, Staeheli P, Kochs G. Interferon-induced Mx proteins in antiviral host defense. Biochimie. 2007;89(6–7):812–8.PubMedCrossRef Haller O, Staeheli P, Kochs G. Interferon-induced Mx proteins in antiviral host defense. Biochimie. 2007;89(6–7):812–8.PubMedCrossRef
37.
go back to reference Kong XF, Zhang XX, Gong QM, Gao J, Zhang SY, Wang L, et al. MxA induction may predict sustained virologic responses of chronic hepatitis B patients with IFN-alpha treatment. J Interferon Cytokine Res. 2007;27(9):809–18.PubMedCrossRef Kong XF, Zhang XX, Gong QM, Gao J, Zhang SY, Wang L, et al. MxA induction may predict sustained virologic responses of chronic hepatitis B patients with IFN-alpha treatment. J Interferon Cytokine Res. 2007;27(9):809–18.PubMedCrossRef
38.
go back to reference Robek MD, Boyd BS, Chisari FV. Lambda interferon inhibits hepatitis B and C virus replication. J Virol. 2005;79(6):3851–4.PubMedCrossRef Robek MD, Boyd BS, Chisari FV. Lambda interferon inhibits hepatitis B and C virus replication. J Virol. 2005;79(6):3851–4.PubMedCrossRef
39.
go back to reference Muir AJ, Shiffinan ML, Zaman A, Yoffe B, de la Torre A, Flamm S, et al. Phase 1b study of Pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection. Hepatology. 2010;52(3):822–32.PubMedCrossRef Muir AJ, Shiffinan ML, Zaman A, Yoffe B, de la Torre A, Flamm S, et al. Phase 1b study of Pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection. Hepatology. 2010;52(3):822–32.PubMedCrossRef
40.
go back to reference Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, Del Vecchio E, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137(1):1–9.PubMedCrossRef Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, Del Vecchio E, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137(1):1–9.PubMedCrossRef
Metadata
Title
Expression Pattern of Serum Cytokines in Hepatitis B Virus Infected Patients with Persistently Normal Alanine Aminotransferase Levels
Authors
Dengming He
Maoshi Li
Shimin Guo
Peng Zhu
Hongfei Huang
Guohua Yan
Quanxin Wu
Shiqi Tao
Zhaoxia Tan
Yuming Wang
Publication date
01-10-2013
Publisher
Springer US
Published in
Journal of Clinical Immunology / Issue 7/2013
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-013-9931-0

Other articles of this Issue 7/2013

Journal of Clinical Immunology 7/2013 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.