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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Exosomal Interferon‐Induced Transmembrane Protein 2 Transmitted to Dendritic Cells Inhibits Interferon Alpha Pathway Activation and Blocks Anti–Hepatitis B Virus Efficacy of Exogenous Interferon Alpha
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Exosomal Interferon‐Induced Transmembrane Protein 2 Transmitted to Dendritic Cells Inhibits Interferon Alpha Pathway Activation and Blocks Anti–Hepatitis B Virus Efficacy of Exogenous Interferon Alpha

机译：传递到树突细胞的外泌体干扰素诱导的跨膜蛋白2抑制干扰素α途径激活并阻断外源干扰素α的抗乙型肝炎病毒疗效

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摘要

The negative regulators in the interferon (IFN) signaling pathway inhibit intrahepatic immune response, resulting in suboptimal therapeutic response to IFNα treatment in chronic hepatitis B (CHB) patients. Identifying the key negative factors and elucidating the regulating mechanism are essential for improving anti‐HBV (hepatitis B virus) efficacy of IFNα. From the Gene Expression Omnibus (GEO) database, we downloaded and analyzed gene expression profiles of CHB patients with different responses to IFNα (GSE54747), and found that innate immune status was associated with the IFNα‐based therapeutic response in CHB patients. Through PCR array, we found higher baseline level of IFN‐induced transmembrane protein 2 (IFITM2) mRNA and lower baseline level of IFNα mRNA in peripheral blood mononuclear cells (PBMCs) of CHB patients with suboptimal response to IFNα treatment. Increased IFITM2 protein was also found in the serum of IFNα nonresponsive patients. With further experiments, we found that overexpressing IFITM2 in Huh7 cells suppressed endogenous IFNα synthesis by inhibiting phosphorylation of extracellular signal–regulated kinase (ERK), TANK‐binding kinase 1 (TBK1), and interferon regulatory factor 3 (IRF3); knocking out IFITM2 enhanced activation of the endogenous IFNα synthesis pathway, exhibiting better inhibition on HBV replication. We also found that IFITM2 protein was shuttled by exosomes to dendritic cells (DCs), the main source of endogenous IFNα. Exosome‐mediated transport of IFITM2 inhibited synthesis of endogenous IFNα in DCs whereas the inhibitory effect was abolished when IFITM2 was knocked out. Furthermore, we demonstrated that both palmitoylation inhibitor and mutation on 70/71 sites of IFITM2 protein influenced its incorporation into exosomes. Mutated IFITM2 protein increased the effect of IFNα against HBV. Conclusion: Exosome‐mediated transport of IFITM2 to DCs inhibits IFNα pathway activation and blocks anti‐HBV efficacy of exogenous IFNα. The findings provide an explanation to the suboptimal response of CHB patients to IFNα treatment.
机译：干扰素（IFN）信号通路中的负调节剂抑制肝内免疫应答，导致慢性乙型肝炎（CHB）患者IFNα治疗的次优疗法反应。鉴定关键的负因子并阐明调节机制对于改善IFNα的抗HBV（乙型肝炎病毒）疗效至关重要。从基因表达综合征（Geo）数据库，我们下载并分析了对IFNα（GSE54747）的不同反应的CHB患者的基因表达谱，发现先天免疫状态与CHB患者的IFNα的治疗反应相关。通过PCR阵列，我们发现IFN诱导的跨膜蛋白2（IFITM2）mRNA的较高基线水平和较低的CHB血液单核细胞（PBMC）的IFNαmRNA的基线水平，对IFNα治疗的次优响应。在IFNα非反应患者的血清中也发现了IFITM2蛋白质的增加。通过进一步的实验，我们发现通过抑制细胞外信号调节激酶（ERK），罐结合激酶1（TBK1）和干扰素调节因子3（IRF3）抑制uHH7细胞中的过表达IFNα合成。敲除IFITM2增强的内源性IFNα合成途径的激活，在HBV复制上表现出更好的抑制作用。我们还发现，IFITM2蛋白被外泌体穿梭于树突细胞（DCS），内源性IFNα的主要来源。外出介导的IFITM2的迁移抑制DC中内源性IFNα的合成，而当IFITM2被敲出时，抑制效果被废除。此外，我们证明，IFITM2蛋白的70/71位点上的棕榈酰抑制剂和突变会影响其掺入外泌体。突变的iFitm2蛋白增加了IFNα对HBV的影响。结论：外出介导的IFITM2至DCs的迁移抑制IFNα途径激活并阻断外源IFNα的抗HBV疗效。结果为CHB患者对IFNα治疗的次优响应提供了解释。

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  • 作者

    Shi Ying; Du Lingyao; Lv Duoduo; Li Hong; Shang Jin; Lu Jiajie; Zhou Lingyun; Bai Lang; Tang Hong;

  • 作者单位

    Division of Infectious Diseases State Key Laboratory of Biotherapy and Center of Infectious;

    Division of Infectious Diseases State Key Laboratory of Biotherapy and Center of Infectious;

    Center of Infectious DiseasesWest China Hospital of Sichuan UniversityChengdu China;

    Center of Infectious DiseasesWest China Hospital of Sichuan UniversityChengdu China;

    Center of Infectious DiseasesWest China Hospital of Sichuan UniversityChengdu China;

    Center of Infectious DiseasesWest China Hospital of Sichuan UniversityChengdu China;

    Center of Infectious DiseasesWest China Hospital of Sichuan UniversityChengdu China;

    Center of Infectious DiseasesWest China Hospital of Sichuan UniversityChengdu China;

    Division of Infectious Diseases State Key Laboratory of Biotherapy and Center of Infectious;

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  • 正文语种 eng
  • 中图分类 消化系及腹部疾病;
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