title: Distinct licensing of IL-18 and IL-1β secretion in response to NLRP3 inflammasome activation.
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.
authors.affiliation: Integrated Department of Immunology, National Jewish Health, Denver, Colorado, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Schmidt
authors.forename: Laurel L
authors.initials: LL
authors.lastname: Lenz
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology; D020169:Caspases / Q000172:deficiency / Q000235:genetics; D053471:Caspases, Initiator; D016923:Cell Death / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D058847:Inflammasomes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D008089:Listeria monocytogenes / Q000737:chemistry; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C078516:60 kDa protein, Listeria monocytogenes; D001426:Bacterial Proteins; D002352:Carrier Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1