The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response

    Research output: Contribution to journalArticle

    Abstract

    Recent studies suggest that the sterol metabolic network participates in the interferon (IFN) antiviral response. However, the molecular mechanisms linking IFN with the sterol network and the identity of sterol mediators remain unknown. Here we report a cellular antiviral role for macrophage production of 25-hydroxycholesterol (cholest-5-en-3β,25-diol, 25HC) as a component of the sterol metabolic network linked to the IFN response via Stat1. By utilizing quantitative metabolome profiling of all naturally occurring oxysterols upon infection or IFN-stimulation, we reveal 25HC as the only macrophage-synthesized and -secreted oxysterol. We show that 25HC can act at multiple levels as a potent paracrine inhibitor of viral infection for a broad range of viruses. We also demonstrate, using transcriptional regulatory-network analyses, genetic interventions and chromatin immunoprecipitation experiments that Stat1 directly coupled Ch25h regulation to IFN in macrophages. Our studies describe a physiological role for 25HC as a sterol-lipid effector of an innate immune pathway.
    LanguageEnglish
    Pages106-118
    JournalImmunity
    Volume38
    Issue number1
    DOIs
    Publication statusPublished - Jan 2013

    Fingerprint

    STAT Transcription Factors
    Sterols
    Interferons
    Antiviral Agents
    Macrophages
    Metabolic Networks and Pathways
    Genetic Engineering
    Metabolome
    Gene Regulatory Networks
    Chromatin Immunoprecipitation
    Virus Diseases
    25-hydroxycholesterol
    Viruses
    Lipids
    Infection

    Keywords

    • Animals
    • Antiviral Agents
    • Antiviral Agents: pharmacology
    • Binding Sites
    • Bone Marrow Cells
    • Bone Marrow Cells: drug effects
    • Bone Marrow Cells: immunology
    • Bone Marrow Cells: metabolism
    • Bone Marrow Cells: virology
    • Gene Expression Regulation
    • Genetic
    • Hydroxycholesterols
    • Hydroxycholesterols: metabolism
    • Hydroxycholesterols: pharmacology
    • Interferons
    • Interferons: pharmacology
    • Macrophage Activation
    • Macrophage Activation: drug effects
    • Macrophage Activation: immunology
    • Macrophages
    • Macrophages: drug effects
    • Macrophages: immunology
    • Macrophages: metabolism
    • Macrophages: virology
    • Mevalonic Acid
    • Mevalonic Acid: metabolism
    • Mice
    • Orphan Nuclear Receptors
    • Orphan Nuclear Receptors: metabolism
    • Promoter Regions
    • Protein Binding
    • STAT1 Transcription Factor
    • STAT1 Transcription Factor: metabolism
    • Steroid Hydroxylases
    • Steroid Hydroxylases: genetics
    • Virus Replication
    • Virus Replication: drug effects

    Cite this

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    title = "The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response",
    abstract = "Recent studies suggest that the sterol metabolic network participates in the interferon (IFN) antiviral response. However, the molecular mechanisms linking IFN with the sterol network and the identity of sterol mediators remain unknown. Here we report a cellular antiviral role for macrophage production of 25-hydroxycholesterol (cholest-5-en-3β,25-diol, 25HC) as a component of the sterol metabolic network linked to the IFN response via Stat1. By utilizing quantitative metabolome profiling of all naturally occurring oxysterols upon infection or IFN-stimulation, we reveal 25HC as the only macrophage-synthesized and -secreted oxysterol. We show that 25HC can act at multiple levels as a potent paracrine inhibitor of viral infection for a broad range of viruses. We also demonstrate, using transcriptional regulatory-network analyses, genetic interventions and chromatin immunoprecipitation experiments that Stat1 directly coupled Ch25h regulation to IFN in macrophages. Our studies describe a physiological role for 25HC as a sterol-lipid effector of an innate immune pathway.",
    keywords = "Animals, Antiviral Agents, Antiviral Agents: pharmacology, Binding Sites, Bone Marrow Cells, Bone Marrow Cells: drug effects, Bone Marrow Cells: immunology, Bone Marrow Cells: metabolism, Bone Marrow Cells: virology, Gene Expression Regulation, Genetic, Hydroxycholesterols, Hydroxycholesterols: metabolism, Hydroxycholesterols: pharmacology, Interferons, Interferons: pharmacology, Macrophage Activation, Macrophage Activation: drug effects, Macrophage Activation: immunology, Macrophages, Macrophages: drug effects, Macrophages: immunology, Macrophages: metabolism, Macrophages: virology, Mevalonic Acid, Mevalonic Acid: metabolism, Mice, Orphan Nuclear Receptors, Orphan Nuclear Receptors: metabolism, Promoter Regions, Protein Binding, STAT1 Transcription Factor, STAT1 Transcription Factor: metabolism, Steroid Hydroxylases, Steroid Hydroxylases: genetics, Virus Replication, Virus Replication: drug effects",
    author = "Steven Watterson",
    year = "2013",
    month = "1",
    doi = "10.1016/j.immuni.2012.11.004",
    language = "English",
    volume = "38",
    pages = "106--118",
    journal = "Immunity",
    issn = "1074-7613",
    publisher = "Elsevier",
    number = "1",

    }

    The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response. / Watterson, Steven.

    In: Immunity, Vol. 38, No. 1, 01.2013, p. 106-118.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response

    AU - Watterson, Steven

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    N2 - Recent studies suggest that the sterol metabolic network participates in the interferon (IFN) antiviral response. However, the molecular mechanisms linking IFN with the sterol network and the identity of sterol mediators remain unknown. Here we report a cellular antiviral role for macrophage production of 25-hydroxycholesterol (cholest-5-en-3β,25-diol, 25HC) as a component of the sterol metabolic network linked to the IFN response via Stat1. By utilizing quantitative metabolome profiling of all naturally occurring oxysterols upon infection or IFN-stimulation, we reveal 25HC as the only macrophage-synthesized and -secreted oxysterol. We show that 25HC can act at multiple levels as a potent paracrine inhibitor of viral infection for a broad range of viruses. We also demonstrate, using transcriptional regulatory-network analyses, genetic interventions and chromatin immunoprecipitation experiments that Stat1 directly coupled Ch25h regulation to IFN in macrophages. Our studies describe a physiological role for 25HC as a sterol-lipid effector of an innate immune pathway.

    AB - Recent studies suggest that the sterol metabolic network participates in the interferon (IFN) antiviral response. However, the molecular mechanisms linking IFN with the sterol network and the identity of sterol mediators remain unknown. Here we report a cellular antiviral role for macrophage production of 25-hydroxycholesterol (cholest-5-en-3β,25-diol, 25HC) as a component of the sterol metabolic network linked to the IFN response via Stat1. By utilizing quantitative metabolome profiling of all naturally occurring oxysterols upon infection or IFN-stimulation, we reveal 25HC as the only macrophage-synthesized and -secreted oxysterol. We show that 25HC can act at multiple levels as a potent paracrine inhibitor of viral infection for a broad range of viruses. We also demonstrate, using transcriptional regulatory-network analyses, genetic interventions and chromatin immunoprecipitation experiments that Stat1 directly coupled Ch25h regulation to IFN in macrophages. Our studies describe a physiological role for 25HC as a sterol-lipid effector of an innate immune pathway.

    KW - Animals

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    KW - Antiviral Agents: pharmacology

    KW - Binding Sites

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    KW - Bone Marrow Cells: drug effects

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    KW - Macrophages: immunology

    KW - Macrophages: metabolism

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    KW - Mice

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    KW - Steroid Hydroxylases: genetics

    KW - Virus Replication

    KW - Virus Replication: drug effects

    U2 - 10.1016/j.immuni.2012.11.004

    DO - 10.1016/j.immuni.2012.11.004

    M3 - Article

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    JO - Immunity

    T2 - Immunity

    JF - Immunity

    SN - 1074-7613

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