IFN regulatory factor family members differentially regulate the expression of type III IFN (IFN-lambda) genes.
Virus replication induces the expression of antiviral type I (IFN-alphabeta) and type III (IFN-lambda1-3 or IL-28A/B and IL-29) IFN genes via TLR-dependent and -independent pathways. Although type III IFNs differ genetically from type I IFNs, their similar biological antiviral functions suggest that their expression is regulated in a similar fashion. Structural and functional characterization of the IFN-lambda1 and IFN-lambda3 gene promoters revealed them to be similar to IFN-beta and IFN-alpha genes, respectively. Both of these promoters had functional IFN-stimulated response element and NF-kappaB binding sites. The binding of IFN regulatory factors (IRF) to type III IFN promoter IFN-stimulated response element sites was the most important event regulating the expression of these genes. Ectopic expression of the components of TLR7 (MyD88 plus IRF1/IRF7), TLR3 (Toll/IL-1R domain-containing adapter-inducing factor), or retinoic acid-inducible gene I (RIG-I) signal transduction pathways induced the activation of IFN-lambda1 promoter, whereas the IFN-lambda3 promoter was efficiently activated only by overexpression of MyD88 and IRF7. The ectopic expression of Pin1, a recently identified suppressor for IRF3-dependent antiviral response, decreased the IFN promoter activation induced by any of these three signal transduction pathways, including the MyD88-dependent one. To conclude, the data suggest that the IFN-lambda1 gene is regulated by virus-activated IRF3 and IRF7, thus resembling that of the IFN-beta gene, whereas IFN-lambda2/3 gene expression is mainly controlled by IRF7, thus resembling those of IFN-alpha genes.
Osterlund
Pamela I
PI
Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland. pamela.osterlund@ktl.fi
Pietilä
Taija E
TE
Veckman
Ville
V
Kotenko
Sergei V
SV
Julkunen
Ilkka
I
D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D005786:Gene Expression Regulation / Q000276:immunology*; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D050839:Interferon Regulatory Factor-7 / Q000502:physiology*; D007370:Interferon Type I / Q000096:biosynthesis / Q000235:genetics; D007372:Interferons; D007378:Interleukins / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary / Q000235:genetics; D020218:Response Elements / Q000276:immunology; D012845:Sindbis Virus / Q000502:physiology; D000095022:Interferon Lambda