Expression of type III lambda interferon genes is showing similar two-wave regulation with type I alpha/beta interferon genes (B50)

Abstract

Abstract In virus infection the replication of viral genome triggers the expression of antiviral genes, like type I interferons (IFN-alpha/beta), by transcription factors activated through both TLR-dependent and independent pathways. Recently, another class of antiviral type III interferons (IFN-lambda1-3) was identified. Here is presented a detailed characterization of the IFN-lambda1 and IFN-lambda3 gene promoters and functional characterization of virus-specific activation of transcription factors regulating these promoters. Both of these promoters have a functional interferon-stimulated response element (ISRE) and NF-kappaB binding site, although the interferon regulatory factors (IRFs)-binding ISRE was the most crucial regulatory element on these promoters. Ectopic expression of the components of the three virus-induced signaling pathways (MyD88+IRF7, Trif and RIG-I) induced the activation of IFN-lambda1 promoter, whereas the IFN-lambda3 promoter was activated to higher extent only by IRF7 alone or in combination with MyD88. Recently documented IRF3 suppressor Pin1 down-regulated all the three signaling cascades induced IFN promoter activation, but not the NF-kappaB mediated transcription. These results suggest that IFN-lambda1 gene is regulated by both IRF3 and IRF7 like IFN-beta gene, whereas IFN-lambda2/3 genes are induced mainly after IRF7-mediated positive feedback.