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

Abstract

IL-27, a member of the IL-12 family, plays a critical role in the control of innate and adaptive immune responses. IFN-λ1, a member of the type III IFN family, shows antiviral abilities. In this study, we investigated the effects of IL-27 and IFN-λ1 on the replication of hepatitis B virus (HBV), a major pathogen associated with a high risk for cirrhosis, liver failure, and hepatocellular carcinoma. We revealed that HBV infection activates IL-27 expression and IFN-λ1 production and demonstrated that viral-activated IL-27 and IFN-λ1 are coordinated to inhibit HBV replication. Initially, HBV infection upregulates IL-27 expression, which, in turn, stimulates IFN-λ1 production through regulating ERK1/2 signaling and by enhancing NF-κB nuclear translocation to bind to the IFN-λ1 promoter. Moreover, IL-27–activated IFN-λ1 upregulates IFN-λ1 receptor (IL-28R1 and IL-10Rβ) activity, resulting in the activation of the STAT1/2 pathway, which, in turn, induces the expression of IFN-stimulated genes, including IFN-inducible dsRNA-activated protein kinase, oligoadenylate synthetase 1, and IFN-induced GTP-binding protein 1 and, finally, inhibits HBV protein expression and viral capsid–associated DNA replication. More interestingly, we also revealed that type I IFN (IFN-α) is also involved in the downregulation of HBV replication mediated by IL-27. Thus, we identified a previously unknown mechanism by which IL-27 and IFN-λ1 are coordinated to regulate virus replication through type I IFN.

The Immunobiology of Interleukin-27

“…Consistent with this observation, the ability of IL-27 to induce type I IFNs can inhibit the replication of HIV in monocytes (161), a process that involves the ability of IL-27 to promote monocyte differentiation into macrophages, which are resistant to HIV (162). IL-27 has also been shown to engage the antiviral responses of macrophages to hepatitis and influenza (163,164), and this may occur at the level of microRNAs associated with antiviral activities (165). In contrast to these activities, in human macrophages, IL-27 can downregulate the receptors for IL-1 and TNF-α (166) and promote the growth of Mycobacterium tuberculosis (16).…”

Interleukin-27 and IFNγ regulate the expression of CXCL9, CXCL10, and CXCL11 in hepatitis

“…IL-27 dimeric receptor is expressed by CD4 + T lymphocytes, NK cells, and hepatocytes [5,7,8,25]. IL-27 was previously reported to be associated in liver disease including hepatocellular carcinoma [43], hepatitis B virus (HBV) infection [24,26,44], in disseminated neuroblastoma metastasis in the liver [45,46], in Leishmania donovani infection [16] and in T cellmediated hepatitis [22,23,47,48]. The present study aimed to investigate the role of IL-27 during liver inflammation and its effects on orchestration of CXCR3 ligands (CXCL9, CXCL10, and CXCL11 chemokines) in hepatic cells both in vitro and in vivo studies.…”

“…The dendritic cell-derived IL-27p28 has been shown to regulate IFNγ production by CD4 + T cells, and IL-27p28 deficiency in mice led to more severe liver injury [24]. IL-27 induced STAT1-dependent response in hepatic tissue (hepatoma cell line and in hepatocytes) by regulating IFNγ-related gene expression [25].…”

Hepatitis B Virus e Antigen Activates the Suppressor of Cytokine Signaling 2 to Repress Interferon Action

“…Type III IFNs, including IFN-λ1, IFN-λ2, and IFN-λ3, bind to a novel receptor composing cytokine receptor family 2 member 12 (CRF2-12 or IFN-λR1) and cytokine receptor family 2 member 4 (CRF2-4 or IL-10Rβ) 7 . Although type I and type III IFNs recognize different receptors, they share many common biological activities 8, 9 . After binding to receptors, IFNs activate JAK/STAT pathway 10 .…”