Functional Characterization of Murine Interferon Regulatory Factor 5 (IRF-5) and Its Role in the Innate Antiviral Response

• Published in: The Journal of biological chemistry Vol. 283; no. 21; pp. 14295 - 14308
• Main Authors: Paun, Andrea, Reinert, Jorgen T., Jiang, Zhaozhao, Medin, Carey, Balkhi, Mumtaz Yaseen, Fitzgerald, Katherine A., Pitha, Paula M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.05.2008; American Society for Biochemistry and Molecular Biology
• Subjects: Alternative Splicing - genetics; Amino Acid Sequence; Animals; Cell Line; Conserved Sequence; Cytokines - genetics; Cytokines - metabolism; Dimerization; Humans; Interferon Regulatory Factors - chemistry; Interferon Regulatory Factors - deficiency; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Newcastle disease virus; Promoter Regions, Genetic - genetics; Protein Binding; Sequence Alignment; Toll-Like Receptors - metabolism; Transcription, Genetic - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M800501200

Although the role of human IRF-5 in antiviral and inflammatory responses in vitro has been well characterized, much remains to be elucidated about murine IRF-5. Murine IRF-5, unlike the heavily spliced human gene, is primarily expressed as a full-length transcript, with only a single splice variant that was detected in very low levels in the bone marrow of C57BL/6J mice. This bone marrow variant contains a 288-nucleotide deletion from exons 4–6 and exhibits impaired transcriptional activity. The murine IRF-5 can be activated by both TBK1 and MyD88 to form homodimers and bind to and activate transcription of type I interferon and inflammatory cytokine genes. The importance of IRF-5 in the antiviral and inflammatory response in vivo is highlighted by marked reductions in serum levels of type I interferon and tumor necrosis factor α (TNFα) in Newcastle disease virus-infected Irf5–/– mice. IRF-5 is critical for TLR3-, TLR4-, and TLR9-dependent induction of TNFα in CD11c+ dendritic cells. In contrast, TLR9, but not TLR3/4-mediated induction of type I IFN transcription, is dependent on IRF-5 in these cells. In addition, IRF-5 regulates TNFα but not type I interferon gene transcription in Newcastle disease virus-infected peritoneal macrophages. Altogether, these data reveal the cell type-specific importance of IRF-5 in MyD88-mediated antiviral pathways and the widespread role of IRF-5 in the regulation of inflammatory cytokines.