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

Li, Xuefen; Zhu, Qiaoyun; Ye, Bo; Zhu, Chi; Dong, Yuejiao; Ni, Qin

doi:10.1002/jcla.24860

Cited by 4 publications

(2 citation statements)

References 42 publications

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“…cGAMP induces IL-35 expression by B cells through an IRF3-dependent pathway that is independent of type I interferon 39 . Additionally, IL-35 expression is upregulated via JNK/c-Jun signaling mediated by HBx 40 . This pathway leads to the transactivation of the IL-35 subunits Ebi3 and p35 promoter, thereby promoting IL-35 production.…”

Section: Discussionmentioning

confidence: 99%

Adaptive plasticity of natural interleukin-35-induced regulatory T cells (Tr35) that are required for T-cell immune regulation

Wei,

Zhang,

Cui

et al. 2024

Theranostics

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Background: IL-35 potently inhibits immune responses both in vivo and in vitro . However, the specific characteristics of IL-35-producing cells, including their developmental origin, cellular phenotype, and function, are unknown. Methods: By using a novel IL-35 reporter mouse (Ebi3-Dre-Thy1.1) and double transgenic fate-mapping reporter mice (35EbiT-Rosa26-rox-tdTomato reporter mice or Foxp3 fate-mapping system), we tracked and analyzed the differentiation and developmental trajectories of Tr35 cells in vivo . And then we investigated the therapeutic effects of OVA-specific Tr35 cells in an OVA-induced allergic airway disease model. Results: We identified a subset of cells, denoted Tr35 cells, that secrete IL-35 but do not express Foxp3. These cells have high expression of molecules associated with T-cell activation and can inhibit T-cell proliferation in vitro . Our analyses showed that Tr35 cells are a distinct subpopulation of cells that are independent of Tr1 cells. Tr35 cells exhibit a unique gene expression profile and tissue distribution. The presence of Thy1.1 (Ebi3) expression in Tr35 cells indicates their active secretion of IL-35. However, the proportion of ex-Tr35 cells (Thy1.1 - ) is significantly higher compared to Tr35 cells (Thy1.1 + ). This suggests that Tr35 cells possess the ability to regulate IL-35 expression rapidly in vivo . Tr35 cells downregulated the expression of the inflammatory cytokines IL-4, IFN-γ and IL-17A. However, once Tr35 cells lost IL-35 expression and became exTr35 cells, the expression of inflammatory cytokines was upregulated. Importantly, our findings indicate that Tr35 cells have therapeutic potential. In an OVA-induced allergic airway disease mouse model, Tr35 cell reinfusion significantly reduced airway hyperresponsiveness and histopathological airway and lung inflammation. Conclusions: We have identified a subset of Tregs, Tr35 cells, that are distinct from Tr1 cells. Tr35 cells can dynamically regulate the secretion of inflammatory cytokines by controlling IL-35 expression to regulate inflammatory immune responses.

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Section: Discussionmentioning

confidence: 99%

Adaptive plasticity of natural interleukin-35-induced regulatory T cells (Tr35) that are required for T-cell immune regulation

Wei,

Zhang,

Cui

et al. 2024

Theranostics

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“…Tao et al showed, using the HepG2-NTCP HBV infection cell model, that IL-35 could promote HBV replication; IL-35 treatment led to higher levels of HBV DNA, even though no differences in serum transaminases were noted between the treated group and controls [82]. Likewise, patients with CHB seem to have higher serum levels of IL-35 when compared with controls, with IL-35 being positively correlated with HBV DNA levels [82][83][84][85][86][87][88], while it also seems to suppress the proliferation of HBV antigen-specific CTLs and interferon (IFN)-γ production both in vitro and ex vivo [89,90]. Interestingly enough, in all of these studies, liver inflammation was largely dampened, accessed either by serum transaminases or liver biopsies, highlighting the anti-inflammatory effect of IL-35.…”

Section: Interleukin 35mentioning

confidence: 99%

The Role of Interleukins in HBV Infection: A Narrative Review

Dimitriadis,

Katelani,

Pappa

et al. 2023

JPM

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Hepatitis B virus (HBV) infection is a worldwide medical issue with significant morbidity and mortality, as it is the main cause of chronic liver disease and hepatocellular carcinoma (HCC). Both innate and adaptive immune responses play a key role in HBV replication and suppression. Recently, the pathophysiological function of interleukins (IL) in the natural course of HBV has gained much attention as a result of the broad use of anti-interleukin agents for a variety of autoimmune diseases and the accompanying risk of HBV reactivation. We present a narrative review regarding the role of IL in HBV infection. Collectively, the pro-inflammatory ILs, namely IL-1, IL-5, IL-6, IL-12 and IL-21, seem to play a critical role in the suppression of HBV replication. In contrast, the anti-inflammatory cytokines IL-10, IL-23 and IL-35 probably act as HBV replication enhancers, while IL-17 has been correlated with HBV-related liver injury. Interestingly enough, IL-2, IL-4 and IL-12 have been tried as therapeutic options against HBV infection with contradictory results. Lastly, the role of IL-22 remains largely ill defined, although preliminary data suggest that it may play a significant role in HBV replication, proliferation and subsequent liver damage.

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

Zhu

et al. 2023

Clinical Laboratory Analysis

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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.

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

Cited by 4 publications

References 42 publications

Adaptive plasticity of natural interleukin-35-induced regulatory T cells (Tr35) that are required for T-cell immune regulation

Adaptive plasticity of natural interleukin-35-induced regulatory T cells (Tr35) that are required for T-cell immune regulation

The Role of Interleukins in HBV Infection: A Narrative Review

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

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