Soluble IL-6 Receptor And IL-27 Subunit P28 Protein Complex Mediate The Antiviral Response Through The Type Ⅲ IFN Pathway

Innate immune responses constitute the first line of defense against virus infection.The IFNs,including type Ⅰ and type Ⅲ IFN,are activated as a host response to viral infection,and they form an important part of innate antiviral response by interfering directly with the replication of viruses and activating downstream IFN-stimulated genes(ISGs)to elicit subsequent antiviral responses.Type Ⅰ IFNs,primarily IFN-α and IFN-β,are classically defined as crucial cytokines for innate immunity.Type Ⅲ IFNs are a novel antiviral cytokine class comprised of four family members:IFN-λ1,IFN-λ2,IFN-λ3 and IFN-λ4.Type Ⅲ IFNs resemble type Ⅰ IFNs as these cytokines are induced by viral infections,induce ISGs,and result in potent antiviral activity via the JAK-STAT pathway.Despite this view,there are many distinct roles between them.Receptors for type Ⅲ IFNs are distinct from those for type Ⅰ IFNs,and type Ⅲ IFNs are expressed in a cell type-specific manner and primarily act on epithelial cells in vivo.In addition,there are more and more researchers who find out the differences on transcriptional regulation between type Ⅲ IFNs and type Ⅰ IFNs.Although some distinct roles for type Ⅲ IFNs have been reported,how the type Ⅰ and Ⅲ IFNs diverge and complement each other,especially how IFN-λ may be induced differently,has remained poorly defined.Previously,we demonstrated that the soluble IL-6R(sIL-6R)plays an important role in the host antiviral response through induction of type Ⅰ IFN and sIL-6R-mediated antiviral action via the IL-27 subunit p28;however,the mechanism that underlies sIL-6R and p28 antiviral action and whether type Ⅲ IFN is involved remain unknown.In this study,we constructed a sIL-6R and p28 fusion protein(sIL-6R/p28 FP)and demonstrated that the fusion protein has stronger antiviral activity than sIL-6R alone.In addition,sIL-6R/p28 FP associated with mitochondrial antiviral signaling protein(MAVS)and TNFR-associated factor 6(TRAF6),and the antiviral activity mediated by sIL-6R/p28 FP was dependent on mitochondrial antiviral signaling protein.Furthermore,significantly reduced binding of p50/p65 and IFN regulatory factor 3 to the IFN-λ1 promoter was observed in sIL-6R knockout cells compared with the control cells.We revealed a novel heterodimer of c-Fos and ATF1 was identified as a crucial transcriptional activator of IFN-λ1.The sIL-6R/p28 FP upregulated IFN-λ1 expression by increasing the binding abilities of c-Fos and ATF1 to the IFN-λ1promoter via the p38 MAPK signaling pathway.In conclusion,our research based on previous study of sIL-6R antiviral action and further reveals the mechanisms underlies the antiviral responses,especially reveals the important role of sIL-6R/p28 FP in mediating virus-induced type Ⅲ IFN production.