Data from: Zinc is a potent and specific inhibitor of IFN-λ3 signalling

Lambda interferons (IFNL, IFN-λ) are pro-inflammatory cytokines important in acute and chronic viral infection. Single-nucleotide polymorphisms rs12979860 and rs8099917 within the IFNL gene locus predict hepatitis C virus (HCV) clearance, as well as inflammation and fibrosis progression in viral and non-viral liver disease. The underlying mechanism, however, is not defined. Here we show that the rs12979860 CC genotype correlates with increased hepatic metallothionein expression through increased systemic zinc levels. Zinc interferes with IFN-λ3 binding to IFNL receptor 1 (IFNLR1), resulting in decreased antiviral activity and increased viral replication (HCV, influenza) in vitro. HCV patients with high zinc levels have low hepatocyte antiviral and inflammatory gene expression and high viral loads, confirming the inhibitory role of zinc in vivo. We provide the first evidence that zinc can act as a potent and specific inhibitor of IFN-λ3 signalling and highlight its potential as a target of therapeutic intervention for IFN-λ3-mediated chronic disease.Lambda干扰素（Lambda interferons, IFNL, IFN-λ）是一类在急慢性病毒感染中发挥关键作用的促炎细胞因子。定位于IFNL基因座的单核苷酸多态性rs12979860与rs8099917，可有效预测丙型肝炎病毒（HCV）的清除效果，同时还能预判病毒性与非病毒性肝病患者的炎症反应及纤维化进展进程。然而，其背后的潜在分子机制迄今尚未阐明。本研究证实，rs12979860 CC基因型可通过提升全身锌水平，上调肝脏金属硫蛋白的表达。锌会干扰IFN-λ3与IFNL受体1（IFNLR1）的结合，进而在体外实验中削弱抗病毒活性并促进病毒复制（涵盖HCV、流感病毒）。锌水平较高的HCV患者，其肝细胞的抗病毒与炎症基因表达水平更低、病毒载量更高，这一临床证据验证了锌在体内的抑制作用。本研究首次揭示锌可作为IFN-λ3信号通路的强效特异性抑制剂，并指出其有望成为干预IFN-λ3介导慢性疾病的治疗靶点。