title: Inflammation. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon.
abstract: Type I interferon (IFN) protects against viruses, yet it also has a poorly understood suppressive influence on inflammation. Here, we report that activated mouse macrophages lacking the IFN-stimulated gene cholesterol 25-hydroxylase (Ch25h) and that are unable to produce the oxysterol 25-hydroxycholesterol (25-HC) overproduce inflammatory interleukin-1 (IL-1) family cytokines. 25-HC acts by antagonizing sterol response element-binding protein (SREBP) processing to reduce Il1b transcription and to broadly repress IL-1-activating inflammasomes. In accord with these dual actions of 25-HC, Ch25h-deficient mice exhibit increased sensitivity to septic shock, exacerbated experimental autoimmune encephalomyelitis, and a stronger ability to repress bacterial growth. These findings identify an oxysterol, 25-HC, as a critical mediator in the negative-feedback pathway of IFN signaling on IL-1 family cytokine production and inflammasome activity.
authors.affiliation: Howard Hughes Medical Institute, Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Reboldi
authors.affiliation: Howard Hughes Medical Institute, Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA.
authors.forename: Eric V
authors.initials: EV
authors.lastname: Dang
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: McDonald
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Guosheng
authors.initials: G
authors.lastname: Liang
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Russell
authors.affiliation: Howard Hughes Medical Institute, Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA. jason.cyster@ucsf.edu.
authors.forename: Jason G
authors.initials: JG
authors.lastname: Cyster
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D025461:Feedback, Physiological; D006888:Hydroxycholesterols / Q000378:metabolism*; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D007370:Interferon Type I / Q000276:immunology*; D007375:Interleukin-1 / Q000276:immunology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020218:Response Elements / Q000235:genetics; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology; D013250:Steroid Hydroxylases / Q000235:genetics / Q000276:immunology*
chemical_list: D006888:Hydroxycholesterols; D058847:Inflammasomes; D007370:Interferon Type I; D007375:Interleukin-1; C007997:25-hydroxycholesterol; D013250:Steroid Hydroxylases; C507384:cholesterol 25-hydroxylase
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