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.
Bibliographical noteCopyright © 2013 Elsevier Inc. All rights reserved.
- Antiviral Agents/pharmacology
- Binding Sites
- Bone Marrow Cells/drug effects
- Gene Expression Regulation
- Liver X Receptors
- Macrophage Activation/drug effects
- Macrophages/drug effects
- Mevalonic Acid/metabolism
- Orphan Nuclear Receptors/metabolism
- Promoter Regions, Genetic
- Protein Binding
- STAT1 Transcription Factor/metabolism
- Steroid Hydroxylases/genetics
- Virus Replication/drug effects