An oxysterol produced in response to type I interferon (IFN) signaling suppresses inflammasome activation, according to a report in Science (345, 679–684).

Although IFN signaling induces antiviral activity, a negative feedback pathway is also induced downstream of IFN to quell the inflammatory response and reduce interleukin-1β (IL-1β) production. Many IFN-stimulated genes are induced during an inflammatory response, but the direct contribution of particular genes to the anti-inflammatory effects of IFN remains unclear.

Jason G. Cyster and his colleagues report that one of these IFN-stimulated genes, which encodes the enzyme cholesterol 25-hydroxylase (Ch25h), is induced in macrophages upon stimulation with lipopolysaccharide (LPS). Upon induction, Ch25h hydroxylates cholesterol, resulting in the production of the oxysterol, 25-hydroxycholsterol (25-HC). Mice deficient in Ch25h produce more IL-1β after in vivo treatment with LPS and die earlier than wild-type mice. These mice also developed more severe neuroinflammatory disease and had increased frequencies of IL-17A+ T cells. As a result of increased IL-1β production and inflammasome activity, Ch25h−/− mice are resistant to infection with Listeria monocytogenes. Mechanistically, 25-HC reduces il1b transcription and inflammasome activity. As IFN is commonly used to treat autoimmune disease, these findings provide some clues into the anti-inflammatory effects of IFN.