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Immunity. 2013 Jan 24;38(1):106-18. doi: 10.1016/j.immuni.2012.11.004. Epub 2012 Dec 27.

The transcription factor STAT-1 couples macrophage synthesis of 25-hydroxycholesterol to the interferon antiviral response.

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1
Division of Pathway Medicine and Edinburgh Infectious Diseases, University of Edinburgh, Edinburgh EH16 4SB, UK.

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.

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PMID:
23273843
PMCID:
PMC3556782
DOI:
10.1016/j.immuni.2012.11.004
[Indexed for MEDLINE]
Free PMC Article

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