Abstract
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.
Highlights
Lambda interferons (IFNL, IFN-l) are pro-inflammatory cytokines important in acute and chronic viral infection
We have recently shown the IFNL rs12979860 single-nucleotide polymorphisms (SNPs) is a strong predictor of hepatic inflammation and progressive end-organ damage in viral (that is, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection) and nonviral chronic liver diseases[23]
To better understand the regulation of the metallothioneins in the liver, we examined metallothionein induction in response to three diverse stimuli: viral infection with influenza virus (H1N1), herpes simplex virus 1 (HSV-1), HBV, or HCV, cytokine treatment (IFN-a, IFN-l3 and IL-6) and metal exposure
Summary
Lambda interferons (IFNL, IFN-l) are pro-inflammatory cytokines important in acute and chronic viral infection. Individuals possessing the favourable IFN-l ‘responder’ genotype (rs12979860 CC, rs368234815 TT and rs8099917 TT) maintain lower basal ISG expression in the liver, possibly due to lack of a functional IFNl4, and as a result are more responsive to IFN-a treatment[19,20] Another SNP within the IFN-l4 protein coding region that converts a proline to a serine residue (rs117648444) was found to further improve rapid virological response[21]. We have recently shown the IFNL rs12979860 SNP is a strong predictor of hepatic inflammation and progressive end-organ damage in viral (that is, hepatitis B virus (HBV) and HCV infection) and nonviral chronic liver diseases (non-alcoholic steatohepatitis)[23]. This type of immune dysfunction has been well characterized in HIV patients, where chronic IFN-a production contributes to numerous HIV-related co-morbidities[24]
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