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

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.

SUBMITTER: Paun A

PROVIDER: S-EPMC2386920 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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

Paun Andrea A Reinert Jorgen T JT Jiang Zhaozhao Z Medin Carey C Balkhi Mumtaz Yaseen MY Fitzgerald Katherine A KA Pitha Paula M PM

The Journal of biological chemistry 20080310 21

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 ...[more]

PMID: 18332133

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Project description:BackgroundInterferon regulatory factors (IRFs), which can be identified based on a unique helix-turn-helix DNA-binding domain (DBD) are a large family of transcription factors involved in host immune response, haemotopoietic differentiation and immunomodulation. Despite the identification of ten IRF family members in mammals, and some recent effort to identify these members in fish, relatively little is known in the composition of these members in other classes of vertebrates, and the evolution and probably the origin of the IRF family have not been investigated in vertebrates.ResultsGenome data mining has been performed to identify any possible IRF family members in human, mouse, dog, chicken, anole lizard, frog, and some teleost fish, mainly zebrafish and stickleback, and also in non-vertebrate deuterostomes including the hemichordate, cephalochordate, urochordate and echinoderm. In vertebrates, all ten IRF family members, i.e. IRF-1 to IRF-10 were identified, with two genes of IRF-4 and IRF-6 identified in fish and frog, respectively, except that in zebrafish exist three IRF-4 genes. Surprisingly, an additional member in the IRF family, IRF-11 was found in teleost fish. A range of two to ten IRF-like genes were detected in the non-vertebrate deuterostomes, and they had little similarity to those IRF family members in vertebrates as revealed in genomic structure and in phylogenetic analysis. However, the ten IRF family members, IRF-1 to IRF-10 showed certain degrees of conservation in terms of genomic structure and gene synteny. In particular, IRF-1, IRF-2, IRF-6, IRF-8 are quite conserved in their genomic structure in all vertebrates, and to a less degree, some IRF family members, such as IRF-5 and IRF-9 are comparable in the structure. Synteny analysis revealed that the gene loci for the ten IRF family members in vertebrates were also quite conservative, but in zebrafish conserved genes were distributed in a much longer distance in chromosomes. Furthermore, all ten different members are clustered in respectively different clades; but the IRF-11 was clustered with one in sea urchin.ConclusionsIn vertebrates, the ten well-characterized IRF family members shared a relatively high degree of similarity in genomic structure and syntenic gene arrangement, implying that they might have been evolved in a similar pattern and with similar selective pressure in different classes of vertebrates. Genome and/or gene duplication, and probably gene shuffling or gene loss might have occurred during the evolution of these IRF family members, but arrangement of chromosome or its segment might have taken place in zebrafish. However, the ten IRF family members in vertebrates and those IRF-like genes in non-vertebrate deuterostomes were quite different in those analyzed characters, as they might have undergone different patterns of evolution.

Dataset Information

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

Publications

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

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