Cutting Edge: FAS (CD95) Mediates Noncanonical IL-1β and IL-18 Maturation via caspase-8 in an RIP3-independent Manner

J Immunol. 2012 Dec 15;189(12):5508-12. doi: 10.4049/jimmunol.1202121. Epub 2012 Nov 9.

Abstract

Fas, a TNF family receptor, is activated by the membrane protein Fas ligand expressed on various immune cells. Fas signaling triggers apoptosis and induces inflammatory cytokine production. Among the Fas-induced cytokines, the IL-1β family cytokines require proteolysis to gain biological activity. Inflammasomes, which respond to pathogens and danger signals, cleave IL-1β cytokines via caspase-1. However, the mechanisms by which Fas regulates IL-1β activation remain unresolved. In this article, we demonstrate that macrophages exposed to TLR ligands upregulate Fas, which renders them responsive to receptor engagement by Fas ligand. Fas signaling activates caspase-8 in macrophages and dendritic cells, leading to the maturation of IL-1β and IL-18 independently of inflammasomes or RIP3. Hence, Fas controls a novel noncanonical IL-1β activation pathway in myeloid cells, which could play an essential role in inflammatory processes, tumor surveillance, and control of infectious diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspase 8 / genetics
  • Caspase 8 / metabolism
  • Caspase 8 / physiology*
  • Dendritic Cells / enzymology
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Enzyme Activation / immunology
  • Fas-Associated Death Domain Protein / deficiency
  • Fas-Associated Death Domain Protein / genetics
  • Fas-Associated Death Domain Protein / physiology
  • Inflammasomes / metabolism
  • Inflammasomes / physiology
  • Interleukin-18 / biosynthesis*
  • Interleukin-1beta / biosynthesis*
  • Macrophages, Peritoneal / enzymology
  • Macrophages, Peritoneal / immunology
  • Macrophages, Peritoneal / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Receptor-Interacting Protein Serine-Threonine Kinases / deficiency
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • fas Receptor / physiology*

Substances

  • Fadd protein, mouse
  • Fas protein, mouse
  • Fas-Associated Death Domain Protein
  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • fas Receptor
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse
  • Casp8 protein, mouse
  • Caspase 8