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      JNK/c‐Jun pathway activation is essential for HBx‐induced IL‐35 elevation to promote persistent HBV infection

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          Abstract

          Background

          Immunoregulation plays pivotal roles during chronic hepatitis B virus (HBV) infection. Studies have shown that Interleukin (IL)‐35 is an important molecule associated with inadequate immune response against HBV. However, the mechanisms involved in the up‐regulation of IL‐35 expression during persistent HBV infection remain unknown.

          Methods

          In this study, we constructed a plasmid expressing the HBV X protein (pCMV‐HBx) to evaluate the relationship between HBx and IL‐35. Activation of the JNK/c‐Jun pathway was analyzed and chromatin immunoprecipitation followed by sequencing and luciferase reporter assays were performed to determine whether c‐Jun could regulate IL‐35 transcription.

          Results

          HBx can significantly activate IL‐35 promoter in both LO2 and HepG2 cells compared to the control plasmid (pCMV‐Tag2) using the dual‐luciferase assay. Whereas other viral proteins, such as S, preS1, the core protein, had no significant effect on IL‐35 expression. Similarly, WB and qRT‐PCR also showed that HBx can significantly promote IL‐35 expression at protein and mRNA levels in the aforementioned cells. The relevant pathway mechanism showed that the expression of JNK and c‐Jun genes was significantly higher in transfected cells carrying pCMV‐HBx than in the pCMV‐Tag2‐transfected and ‐untransfected cells. WB analysis revealed that phosphorylated JNK and c‐Jun were overexpressed after HBx action. Conversely, the addition of the JNK/c‐Jun signaling pathway inhibitor could significantly suppress HBx‐induced IL‐35 expression in a dose‐dependent manner.

          Conclusions

          A novel molecular mechanism of HBV‐induced IL‐35 expression was revealed, which involves JNK/c‐Jun signaling in up‐regulating IL‐35 expression via HBx, resulting in transactivation of the IL‐35 subunit EBI3 and p35 promoter.

          Abstract

          In this study, we investigated the related molecular mechanisms of IL‐35 up‐regulation induced by hepatitis B virus (HBV)‐related proteins, especially HBV X protein (HBx). Previous studies have shown that IL‐35 exhibits a strong inhibitory effect on HBV‐specific CD8 + T lymphocytes, which triggers persistent viral infection and HBV‐related liver diseases. Our results clarify the molecular mechanism involved in the up‐regulation of IL‐35 via HBx/JNK/c‐Jun pathway, which may contribute to developing treatment strategies for HBV infection‐induced liver diseases.

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          Most cited references41

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          The inhibitory cytokine IL-35 contributes to regulatory T-cell function.

          Lauren W. Collison, Creg J Workman, Timothy T Kuo … (2007)
          Regulatory T (T(reg)) cells are a critical sub-population of CD4+ T cells that are essential for maintaining self tolerance and preventing autoimmunity, for limiting chronic inflammatory diseases, such as asthma and inflammatory bowel disease, and for regulating homeostatic lymphocyte expansion. However, they also suppress natural immune responses to parasites and viruses as well as anti-tumour immunity induced by therapeutic vaccines. Although the manipulation of T(reg) function is an important goal of immunotherapy, the molecules that mediate their suppressive activity remain largely unknown. Here we demonstrate that Epstein-Barr-virus-induced gene 3 (Ebi3, which encodes IL-27beta) and interleukin-12 alpha (Il12a, which encodes IL-12alpha/p35) are highly expressed by mouse Foxp3+ (forkhead box P3) T(reg) cells but not by resting or activated effector CD4+ T (T(eff)) cells, and that an Ebi3-IL-12alpha heterodimer is constitutively secreted by T(reg) but not T(eff) cells. Both Ebi3 and Il12a messenger RNA are markedly upregulated in T(reg) cells co-cultured with T(eff) cells, thereby boosting Ebi3 and IL-12alpha production in trans. T(reg)-cell restriction of this cytokine occurs because Ebi3 is a downstream target of Foxp3, a transcription factor that is required for T(reg)-cell development and function. Ebi3-/- and Il12a-/- T(reg) cells have significantly reduced regulatory activity in vitro and fail to control homeostatic proliferation and to cure inflammatory bowel disease in vivo. Because these phenotypic characteristics are distinct from those of other IL-12 family members, this novel Ebi3-IL-12alpha heterodimeric cytokine has been designated interleukin-35 (IL-35). Ectopic expression of IL-35 confers regulatory activity on naive T cells, whereas recombinant IL-35 suppresses T-cell proliferation. Taken together, these data identify IL-35 as a novel inhibitory cytokine that may be specifically produced by T(reg) cells and is required for maximal suppressive activity.
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            Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study

            Joël Mossong, Homie Razavi, Stefan Zeuzem … (2018)
            The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate viral hepatitis by 2030. Although no virological cure exists for hepatitis B virus (HBV) infection, existing therapies to control viral replication and prophylaxis to minimise mother-to-child transmission make elimination of HBV feasible. We aimed to estimate the national, regional, and global prevalence of HBsAg in the general population and in the population aged 5 years in 2016, as well as coverage of prophylaxis, diagnosis, and treatment.
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              IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases.

              Ping Shen, Toralf Roch, Vicky Lampropoulou … (2014)
              B lymphocytes have critical roles as positive and negative regulators of immunity. Their inhibitory function has been associated primarily with interleukin 10 (IL-10) because B-cell-derived IL-10 can protect against autoimmune disease and increase susceptibility to pathogens. Here we identify IL-35-producing B cells as key players in the negative regulation of immunity. Mice in which only B cells did not express IL-35 lost their ability to recover from the T-cell-mediated demyelinating autoimmune disease experimental autoimmune encephalomyelitis (EAE). In contrast, these mice displayed a markedly improved resistance to infection with the intracellular bacterial pathogen Salmonella enterica serovar Typhimurium as shown by their superior containment of the bacterial growth and their prolonged survival after primary infection, and upon secondary challenge, compared to control mice. The increased immunity found in mice lacking IL-35 production by B cells was associated with a higher activation of macrophages and inflammatory T cells, as well as an increased function of B cells as antigen-presenting cells (APCs). During Salmonella infection, IL-35- and IL-10-producing B cells corresponded to two largely distinct sets of surface-IgM(+)CD138(hi)TACI(+)CXCR4(+)CD1d(int)Tim1(int) plasma cells expressing the transcription factor Blimp1 (also known as Prdm1). During EAE, CD138(+) plasma cells were also the main source of B-cell-derived IL-35 and IL-10. Collectively, our data show the importance of IL-35-producing B cells in regulation of immunity and highlight IL-35 production by B cells as a potential therapeutic target for autoimmune and infectious diseases. This study reveals the central role of activated B cells, particularly plasma cells, and their production of cytokines in the regulation of immune responses in health and disease.
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                Author and article information

                Contributors
                Xuefen Li:
                ORCID: https://orcid.org/0000-0002-2989-3477
                zylxf@zju.edu.cn
                Journal
                Journal ID (nlm-ta): J Clin Lab Anal
                Journal ID (iso-abbrev): J Clin Lab Anal
                Journal ID (doi): 10.1002/(ISSN)1098-2825
                Journal ID (publisher-id): JCLA
                Title: Journal of Clinical Laboratory Analysis
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 0887-8013
                ISSN (Electronic): 1098-2825
                Publication date (Electronic): 14 March 2023
                Publication date Collection: March 2023
                Volume: 37
                Issue: 5 ( doiID: 10.1002/jcla.v37.5 )
                Electronic Location Identifier: e24860
                Affiliations
                [ 1 ] Department of Laboratory Medicine, Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou China
                [ 2 ] Central Laboratory, Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou China
                [ 3 ] Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou China
                Author notes
                [*] [* ] Correspondence

                Xuefen Li, Department of Laboratory Medicine, Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China.

                Email: zylxf@ 123456zju.edu.cn

                Author information
                https://orcid.org/0000-0002-2989-3477
                Article
                Publisher ID: JCLA24860 Other ID: JCLA-22-2863.R1
                DOI: 10.1002/jcla.24860
                PMC ID: 10098067
                PubMed ID: 36916737
                SO-VID: 18bbc29c-b132-4728-bd85-b0ec06ae89bf
                Copyright © © 2023 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date revision received : 16 February 2023
                Date received : 18 October 2022
                Date accepted : 02 March 2023
                Page count
                Figures: 6, Tables: 0, Pages: 9, Words: 5203
                Funding
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Award ID: 82072357
                Funded by: Natural Science Foundation of Zhejiang Province , doi 10.13039/501100004731;
                Award ID: LQ20H200002
                Categories
                Subject: Research Article
                Subject: Research Articles
                Custom metadata
                source-schema-version-number 2.0
                cover-date March 2023
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.7 mode:remove_FC converted:13.04.2023

                ScienceOpen disciplines: Clinical chemistry
                Keywords: hbv x protein,hepatitis b virus (hbv),immune regulation,interleukin‐35,pathway activity
                Data availability:
                ScienceOpen disciplines: Clinical chemistry
                Keywords: hbv x protein, hepatitis b virus (hbv), immune regulation, interleukin‐35, pathway activity

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