Distinct licensing of IL-18 and IL-1β secretion in response to NLRP3 inflammasome activation

PLoS One. 2012;7(9):e45186. doi: 10.1371/journal.pone.0045186. Epub 2012 Sep 18.

Abstract

Inflammasome activation permits processing of interleukins (IL)-1β and 18 and elicits cell death (pyroptosis). Whether these responses are independently licensed or are "hard-wired" consequences of caspase-1 (casp1) activity has not been clear. Here, we show that that each of these responses is independently regulated following activation of NLRP3 inflammasomes by a "non-canonical" stimulus, the secreted Listeria monocytogenes (Lm) p60 protein. Primed murine dendritic cells (DCs) responded to p60 stimulation with reactive oxygen species (ROS) production and secretion of IL-1β and IL-18 but not pyroptosis. Inhibitors of ROS production inhibited secretion of IL-1β, but did not impair IL-18 secretion. Furthermore, DCs from caspase-11 (casp11)-deficient 129S6 mice failed to secrete IL-1β in response to p60 but were fully responsive for IL-18 secretion. These findings reveal that there are distinct licensing requirements for processing of IL-18 versus IL-1β by NLRP3 inflammasomes.

Publication types

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

MeSH terms

  • Animals
  • Bacterial Proteins / pharmacology
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology
  • Caspase 1 / genetics
  • Caspase 1 / immunology
  • Caspases / deficiency
  • Caspases / genetics
  • Caspases, Initiator
  • Cell Death / drug effects
  • Dendritic Cells / cytology
  • Dendritic Cells / drug effects*
  • Dendritic Cells / immunology
  • Gene Expression / drug effects
  • Inflammasomes / drug effects*
  • Inflammasomes / immunology
  • Inflammasomes / metabolism
  • Interleukin-18 / metabolism*
  • Interleukin-1beta / metabolism*
  • Listeria monocytogenes / chemistry
  • Mice
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects

Substances

  • 60 kDa protein, Listeria monocytogenes
  • Bacterial Proteins
  • Carrier Proteins
  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Reactive Oxygen Species
  • Casp4 protein, mouse
  • Caspases
  • Caspases, Initiator
  • Caspase 1