151: Interferon lambda 4 (IFN-λ4) induces a pro-inflammatory state in human hepatic cells which can be blocked by a monoclonal antibody

Abstract

Interferon lambda 4 (IFN-λ4) is a novel human type-III interferon. An exonic genetic variant (rs368234815-ΔG), which creates the IFN-λ4 protein, is the strongest host factor predicting clearance of hepatitis C virus (HCV) infection. Individuals who carry the ΔG allele and thus can generate IFN-λ4, are less likely to clear HCV compared to individuals who do not carry this allele and are unable to generate IFN-λ4. We show that IFN-λ4 can be detected at a low level with a MesoScale ELISA assay in culture media of human hepatic cells (HepG2 and fresh primary human hepatocytes) transiently transfected with IFNL4-expressing construct. The secreted IFN-λ4 protein is able to induce strong expression of a panel of interferon stimulated genes (ISGs) in a transwell assay and this effect could be blocked by a monoclonal antibody against IFN-λ4 (α-IFN-λ4). Specifically, in primary hepatocytes secreted IFN-λ4 induced strong activation of the pro-inflammatory chemokine IP-10 (encoded by CXCL10) both on mRNA and protein level and this induction was blocked by the α-IFN-λ4 antibody. Increased expression of IP-10 is associated with hepatoinflammation and reduced response to HCV treatment. The α-IFN-λ4 antibody did not block the signalling of other interferons (IFN-α, IFN-β, IFN-γ, and IFN-λ3), suggesting a possible use of this antibody for targeted blocking of IFN-λ4 signalling. In conclusion, we propose a pathogenic mechanism of IFN-λ4 as a moderately secreted interferon stimulating ISGs and inducing a pro-inflammatory state in human hepatic cells; we also suggest a tool of blocking this induction with a monoclonal antibody.