Functional characterization of murine interferon regulatory factor 5 (IRF-5) and its role in the innate antiviral response.
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.
Paun
Andrea
A
Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD 21231, USA.
Reinert
Jorgen T
JT
Jiang
Zhaozhao
Z
Medin
Carey
C
Balkhi
Mumtaz Yaseen
MY
Fitzgerald
Katherine A
KA
Pitha
Paula M
PM
D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D017124:Conserved Sequence; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D050835:Interferon Regulatory Factors / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009522:Newcastle disease virus; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016415:Sequence Alignment; D051193:Toll-Like Receptors / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics
D016207:Cytokines; D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse; D051193:Toll-Like Receptors