RT Journal Article
SR Electronic
T1 25-Hydroxycholesterol suppresses interleukin-1–driven inflammation downstream of type I interferon
JF Science
JO Science
FD American Association for the Advancement of Science
SP 679
OP 684
DO 10.1126/science.1254790
VO 345
IS 6197
A1 Reboldi, Andrea
A1 Dang, Eric V.
A1 McDonald, Jeffrey G.
A1 Liang, Guosheng
A1 Russell, David W.
A1 Cyster, Jason G.
YR 2014
UL http://science.sciencemag.org/content/345/6197/679.abstract
AB 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 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.