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

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• 作者：Mathieu Blanc¹ ; ⁹ ; Wei Yuan Hsieh¹ ; ⁹ ; Kevin A. Robertson¹ ; ² ; Kai A. Kropp¹ ; Thorsten Forster¹ ; Guanghou Shui³ ; Paul Lacaze¹ ; Steven Watterson¹ ; ² ; Samantha J. Griffiths¹ ; Nathanael J. Spann⁴ ; Anna Meljon⁵ ; Simon Talbot¹ ; Kathiresan Krishnan⁶ ; Douglas F. Covey⁶ ; Markus R. Wenk³ ; Marie Craigon¹ ; Zsolts Ruzsics⁷ ; Jü ; rgen Haas¹ ; Ana Angulo⁸ ; William J. Griffiths⁵ ; Christopher K. Glass⁴ ; Yuqin Wang⁵ ; Peter Ghazal¹ ; ² ; ^{p.ghazal@ed.ac.uk}
• 刊名：Immunity
• 出版年：2013
• 出版时间：24 January, 2013
• 年：2013
• 卷：38
• 期：1
• 页码：106-118
• 全文大小：1706 K

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Summary

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-3¦Â,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.