Functional characterization of murine interferon regulatory factor 5 (IRF-5) and its role in the innate antiviral response
Department of Medicine, Division of Infectious Diseases and Immunology
Alternative Splicing; Amino Acid Sequence; Animals; Cell Line; Conserved Sequence; Cytokines; Dimerization; Humans; Interferon Regulatory Factors; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Newcastle Disease; Promoter Regions, Genetic; Protein Binding; Sequence Alignment; Toll-Like Receptors; Transcription, Genetic
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 alpha (TNFalpha) in Newcastle disease virus-infected Irf5(-)(/)(-) mice. IRF-5 is critical for TLR3-, TLR4-, and TLR9-dependent induction of TNFalpha 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 TNFalpha 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.
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Citation: J Biol Chem. 2008 May 23;283(21):14295-308. Epub 2008 Mar 10. Link to article on publisher's site
Paun, Andrea; Reinert, Jorgen T.; Jiang, Zhaozhao; Medin, Carey L.; Balkhi, Mumtaz Yaseen; Fitzgerald, Katherine A.; and Pitha, Paula M., "Functional characterization of murine interferon regulatory factor 5 (IRF-5) and its role in the innate antiviral response" (2008). Infectious Diseases and Immunology Publications and Presentations. 71.