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Functional characterization of murine interferon regulatory factor 5 (IRF-5) and its role in the innate antiviral response

Andrea Paun, The Johns Hopkins University
Jorgen T. Reinert, The Johns Hopkins University
Zhaozhao Jiang, University of Massachusetts Medical School
Carey L. Medin, University of Massachusetts Medical School
Mumtaz Yaseen Balkhi, Johns Hopkins University
Katherine A. Fitzgerald, University of Massachusetts Medical School
Paula M. Pitha, Johns Hopkins University

Abstract

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.

Suggested Citation

Andrea Paun, Jorgen T. Reinert, Zhaozhao Jiang, Carey L. Medin, Mumtaz Yaseen Balkhi, Katherine A. Fitzgerald, and Paula M. Pitha. "Functional characterization of murine interferon regulatory factor 5 (IRF-5) and its role in the innate antiviral response" The Journal of biological chemistry 283.21 (2008).
Available at: http://works.bepress.com/katherine_fitzgerald/96