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Identification of a FOXO3/IRF7 circuit that limits inflammatory sequelae of antiviral responses (expression)

ABSTRACT: We have used an unbiased systems approach to predict that a member of the forkhead family of transcription factors, FOXO3, is a negative regulator of a subset of antiviral genes. This prediction was validated using macrophages isolated from Foxo3-null mice. We detected significantly increased transcription of a subset of interferon-stimulated genes (ISGs) under basal conditions in Foxo3-null macrophages when compared to their wild type (WT) counterparts, suggesting that FOXO3 functions as a repressor of these genes. Stimulation of Foxo3-null macrophages with poly-IC (PIC) further increased the levels of this subset of ISGs, and also revealed the transcription of additional ISGs. C57BL/6 mice were obtained from Jackson Laboratories. Foxo3-/- mice in the FVB background were obtained from MMRRC and were backcrossed to C57BL/6 mice at least 5 times to generate congenic mice. C57BL/6 Foxo3+/- heterozygotes were intercrossed to generate Foxo3-/- mice. Mice were maintained at the animal facility of the Institute for Systems Biology and used at 8-12 weeks of age. All animals were housed and handled according to the approved protocols of the University of Washington and Institute for Systems Biology's Institutional Animal Care and Use Committees. Bone marrow macrophages from wildtype and Foxo3 knock-out mice were stimulated with PIC or left untreated. 3 replicates per group.

ORGANISM(S): Mus musculus  

SUBMITTER: Vladimir Litvak   Ayush Raman 

PROVIDER: E-GEOD-37051 | ArrayExpress | 2012-09-19



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A FOXO3-IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses.

Litvak Vladimir V   Ratushny Alexander V AV   Lampano Aaron E AE   Schmitz Frank F   Huang Albert C AC   Raman Ayush A   Rust Alistair G AG   Bergthaler Andreas A   Aitchison John D JD   Aderem Alan A  

Nature 20120916 7420

Antiviral responses must be tightly regulated to defend rapidly against infection while minimizing inflammatory damage. Type 1 interferons (IFN-I) are crucial mediators of antiviral responses and their transcription is regulated by a variety of transcription factors; principal among these is the family of interferon regulatory factors (IRFs). The IRF gene regulatory networks are complex and contain multiple feedback loops. The tools of systems biology are well suited to elucidate the complex int  ...[more]

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