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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bacterial Proteins / pharmacology
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Carrier Proteins / genetics
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Carrier Proteins / immunology
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Caspase 1 / genetics
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Caspase 1 / immunology
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Caspases / deficiency
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Caspases / genetics
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Caspases, Initiator
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Cell Death / drug effects
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Dendritic Cells / cytology
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Dendritic Cells / drug effects*
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Dendritic Cells / immunology
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Gene Expression / drug effects
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Inflammasomes / drug effects*
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Inflammasomes / immunology
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Inflammasomes / metabolism
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Interleukin-18 / metabolism*
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Interleukin-1beta / metabolism*
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Listeria monocytogenes / chemistry
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Mice
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Mice, Knockout
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NLR Family, Pyrin Domain-Containing 3 Protein
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Reactive Oxygen Species / metabolism
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Signal Transduction / drug effects
Substances
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60 kDa protein, Listeria monocytogenes
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Bacterial Proteins
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Carrier Proteins
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Inflammasomes
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Interleukin-18
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Interleukin-1beta
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Reactive Oxygen Species
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Casp4 protein, mouse
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Caspases
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Caspases, Initiator
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Caspase 1