IL-27,a Cytokine, And IFN-λ1,a Type ⅢIFN, Are Coordinated To Regulate Virus Replication Through Type ⅠIFN

Hepatitis B Virus, a member of the Hepadnaviridae family, is a small DNA virus with a partially double-stranded DNA genome. HBV infection is a global health problem. The WHO estimates that2billion people have been infected with HBV, and more than350million have chronic infection. HBV causes transient and chronic infections of liver, and even more worse, a high risk for liver cirrhosis and hepatocellular carcinoma.Cytokines play a critical role in controlling the innate and adaptive immune responses. IL-27, a member of the IL-12family, is a heterodimeric cytokine composed of EBV-induced protein3(EBI3) and IL-27p28protein. The signal transduction receptor complex for IL-27is composed of the cytokine receptor IL-27Rα (WSX-1or alternatively T cell cytokine receptor [TCCR]) and the gp130protein. IFN-λ1belongs to the type Ⅲ IFN family. Although IFN-λ1binds to distinct receptors, IL-28R1and IL-10Rβ, it activates signal transduction pathways by a manner similar to that activated by type I IFN through inducing tyrosine phosphorylation of STAT protein. IFN-λ also shows antiviral abilities.In this study, we investigated the effects of IL-27and IFN-λ1on the replication of hepatitis B virus (HBV). We revealed that HBV infection activates IL-27expression and IFN-λ1production and demonstrated that viral-activated IL-27and IFN-X1are coordinated to inhibit HBV replication. Initially, HBV infection upregulates IL-27expression, which, in turn, stimulates IFN-γ1production through regulating ERK1/2signaling and by enhancing NF-κB nuclear translocation to bind to the IFN-X1promoter. Moreover, IL-27activated IFN-X1upregulates IFN-γ1receptor (IL-28R1and IL-10Rβ) activity, resulting in the activation of the STAT1/2pathway, which, in turn induces the expression of IFN-stimulated genes, including IFN-inducible PKR, OAS1and Mxl and, finally, inhibits HBV protein expression and viral capsid-associated DNA replication. More interestingly, we also revealed that type I IFN (IFN-a) is also involved in the downregulation of HBV replication mediated by IL-27. Thus, we identified a previously unkown mechanism by which IL-27and IFN-γ1are coordinated to regulated virus replication through type I IFN.