title: Type I interferon inhibits interleukin-1 production and inflammasome activation.
abstract: Type I interferon (IFN) is a common therapy for autoimmune and inflammatory disorders, yet the mechanisms of action are largely unknown. Here we showed that type I IFN inhibited interleukin-1 (IL-1) production through two distinct mechanisms. Type I IFN signaling, via the STAT1 transcription factor, repressed the activity of the NLRP1 and NLRP3 inflammasomes, thereby suppressing caspase-1-dependent IL-1β maturation. In addition, type I IFN induced IL-10 in a STAT1-dependent manner; autocrine IL-10 then signaled via STAT3 to reduce the abundance of pro-IL-1α and pro-IL-1β. In vivo, poly(I:C)-induced type I IFN diminished IL-1β production in response to alum and Candida albicans, thus increasing susceptibility to this fungal pathogen. Importantly, monocytes from multiple sclerosis patients undergoing IFN-β treatment produced substantially less IL-1β than monocytes derived from healthy donors. Our findings may thus explain the effectiveness of type I IFN in the treatment of inflammatory diseases but also the observed "weakening" of the immune system after viral infection.
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Greta
authors.initials: G
authors.lastname: Guarda
authors.forename: Marion
authors.initials: M
authors.lastname: Braun
authors.forename: Francesco
authors.initials: F
authors.lastname: Staehli
authors.forename: Aubry
authors.initials: A
authors.lastname: Tardivel
authors.forename: Chantal
authors.initials: C
authors.lastname: Mattmann
authors.forename: Irmgard
authors.initials: I
authors.lastname: Förster
authors.forename: Matthias
authors.initials: M
authors.lastname: Farlik
authors.forename: Thomas
authors.initials: T
authors.lastname: Decker
authors.forename: Renaud A
authors.initials: RA
authors.lastname: Du Pasquier
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.forename: Jürg
authors.initials: J
authors.lastname: Tschopp
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D002176:Candida albicans / Q000502:physiology; D002177:Candidiasis / Q000209:etiology / Q000276:immunology; D002352:Carrier Proteins / Q000502:physiology; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured / Q000378:metabolism; D004198:Disease Susceptibility; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007369:Interferon Inducers / Q000494:pharmacology; D007370:Interferon Type I / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016899:Interferon-beta / Q000627:therapeutic use; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D016753:Interleukin-10 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010538:Peritonitis / Q000209:etiology / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C556062:IL10 protein, mouse; D058847:Inflammasomes; D007369:Interferon Inducers; D007370:Interferon Type I; D007375:Interleukin-1; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C509168:Nalp1b protein, mouse; C492716:Nlrp3 protein, mouse; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D016753:Interleukin-10; D016899:Interferon-beta; D020170:Caspase 1; D011070:Poly I-C