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25-Hydroxycholesterol suppresses interleukin-1–driven inflammation downstream of type I interferon

Science  08 Aug 2014:
Vol. 345, Issue 6197, pp. 679-684
DOI: 10.1126/science.1254790

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Bad cholesterol: Bad for bacteria, too?

Why do viral infections, such as the common cold, leave people more susceptible to bacterial pneumonia? One reason is that type I interferons, secreted proteins that initiate antiviral immune responses, suppress other inflammatory molecules that protect against bacterial infection. Reboldi et al. investigated how this suppression occurs on a molecular level in mice. Interferons stimulated expression of a particular enzyme that catalyzes the production of the oxysterol 25-hydroxycholesterol (25-HC). 25-HC inhibits the function of the transcription factor SREBP, which normally drives expression of the gene that encodes interleukin-1, a secreted inflammatory protein with wide-ranging antibacterial functions.

Science, this issue p. 679

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.

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