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) Genes1
* Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland; and
Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry, New Jersey Medical School, Newark, NJ 07103
Virus replication induces the expression of antiviral type I (IFN-
) and type III (IFN-
1–3 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-1 and IFN-3 gene promoters revealed them to be similar to IFN- and IFN- genes, respectively. Both of these promoters had functional IFN-stimulated response element and NF-
B 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-1 promoter, whereas the IFN-3 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-1 gene is regulated by virus-activated IRF3 and IRF7, thus resembling that of the IFN- gene, whereas IFN-2/3 gene expression is mainly controlled by IRF7, thus resembling those of IFN- genes.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported in part by the Medical Research Council of the Academy of Finland and the U.S. Public Health Services Grant R01 AI057468 from the National Institute of Allergy and Infectious Diseases.
2 Address correspondence and reprint requests to Dr. Pamela Österlund, Department of Viral Diseases and Immunology, National Public Health Institute, Mannerheimintie 166, Helsinki, Finland. E-mail address: pamela.osterlund{at}ktl.fi
3 Abbreviations used in this paper: IRF, IFN regulatory factor; DC, dendritic cell; luc, luciferase; TRIF, Toll/IL-1R domain-containing adapter-inducing IFN-; IKK
, IB kinase ; TBK1, TANK-binding kinase 1; RIG-I, retinoic acid-inducible gene I; moDC, monocyte-derived DC; SV, Sendai virus; MOI, multiplicity of infec- tion; ISRE, IFN-stimulated response element; PRDI, positive-regulatory domain I; HEK239, human embryonic kidney 239.
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