Type I interferon inhibits interleukin-1 production and inflammasome activation

Immunity. 2011 Feb 25;34(2):213-23. doi: 10.1016/j.immuni.2011.02.006.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / physiology
  • Candida albicans / physiology
  • Candidiasis / etiology
  • Candidiasis / immunology
  • Carrier Proteins / physiology
  • Caspase 1 / deficiency
  • Caspase 1 / genetics
  • Caspase 1 / physiology
  • Cells, Cultured / metabolism
  • Disease Susceptibility
  • Gene Expression Regulation / drug effects
  • Humans
  • Inflammasomes / metabolism*
  • Interferon Inducers / pharmacology
  • Interferon Type I / biosynthesis
  • Interferon Type I / genetics
  • Interferon Type I / physiology*
  • Interferon-beta / therapeutic use
  • Interleukin-1 / biosynthesis*
  • Interleukin-1 / genetics
  • Interleukin-10 / physiology
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / immunology
  • Monocytes / metabolism
  • Multiple Sclerosis / drug therapy
  • Multiple Sclerosis / immunology
  • Multiple Sclerosis / pathology
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Peritonitis / etiology
  • Peritonitis / immunology
  • Poly I-C / pharmacology
  • STAT1 Transcription Factor / deficiency
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / physiology
  • STAT3 Transcription Factor / physiology

Substances

  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • IL10 protein, mouse
  • Inflammasomes
  • Interferon Inducers
  • Interferon Type I
  • Interleukin-1
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nalp1b protein, mouse
  • Nlrp3 protein, mouse
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Stat1 protein, mouse
  • Stat3 protein, mouse
  • Interleukin-10
  • Interferon-beta
  • Caspase 1
  • Poly I-C