A study by Australia’s Westmead Institute has revealed an unexpected role for zinc in liver disease. Researchers at the institute’s Storr Liver Center showed that zinc is a strong and specific inhibitor of the pro-inflammatory cytokine interferon lambda 3 (IFN-λ3), which has been linked to accelerated progression of liver cirrhosis in acute and chronic viral infection, such as influenza and hepatitis C.
Their study, “Zinc is a potent and specific inhibitor of IFN-λ3 signalling,” appeared in Nature Communications.
Until recently, interferon lambdas (IFN-λs, type III interferons) such as IFN-λ3 were described as antiviral and pro-inflammatory cytokines (or proteins that activate the immune system). Although IFN-λs are important in response to acute infection, experimental evidence has shown that IFN-λs may induce chronic inflammation and tissue damage such as liver cirrhosis.
Several genome-wide association studies have shown that patients with the single-nucleotide mutations rs12979860 and rs8099917 within the interferon lambda (IFNL) gene are more likely to clear hepatitis C virus (HCV) infection, as well as reduce inflammation and fibrosis progression in viral and non-viral liver disease. However, the exact mechanisms how IFN-λ polymorphisms promote HCV clearance remain unclear.
Associate professor Golo Ahlenstiel and his team had previously found that multiple members of the MT1 metallothionein gene family are highly expressed in the liver of individuals with the favorable IFNL rs8099917 TT responder genotype to hepatitis C virus infections. More recently, the team discovered a link between the rs12979860 CC mutation and increased metallothionein expression in the liver through higher serum zinc levels.
Zinc inhibits the binding of IFN-λ3 to the interferon lambda receptor, which decreases antiviral activity and increases viral replication in vitro. Importantly, HCV patients with high zinc levels have low levels of antiviral and inflammatory proteins and high viral loads in liver cells, confirming the inhibitory role of zinc in vivo.
“Our data suggests that serum zinc levels in patients with chronic hepatitis C are genetically predetermined by the IFN-λ3 polymorphism,” Dr. Scott Read, the study’s first author, said in a press release. “The data highlights the potential for zinc to be used as a simple and effective treatment against acute and chronic inflammation in the liver.”
Ahlenstiel and his group are now studying the potential application of zinc as a simple and effective treatment to modulate IFN-λ3-mediated immune activation in human chronic disease.