Participation of c-FLIP in NLRP3 and AIM2 inflammasome activation.
Cell Death Differ
; 21(3): 451-61, 2014 Mar.
Article
em En
| MEDLINE
| ID: mdl-24270411
ABSTRACT
Cellular FLICE-inhibitory protein (c-FLIP) is an inhibitor of caspase-8 and is required for macrophage survival. Recent studies have revealed a selective role of caspase-8 in noncanonical IL-1ß production that is independent of caspase-1 or inflammasome. Here we demonstrated that c-FLIP(L) is an unexpected contributor to canonical inflammasome activation for the generation of caspase-1 and active IL-1ß. Hemizygotic deletion of c-FLIP impaired ATP- and monosodium uric acid (MSU)-induced IL-1ß production in macrophages primed through Toll-like receptors (TLRs). Decreased IL-1ß expression was attributed to a reduced activation of caspase-1 in c-FLIP hemizygotic cells. In contrast, the production of TNF-α was not affected by downregulation in c-FLIP. c-FLIP(L) interacted with NLRP3 or procaspase-1. c-FLIP is required for the full NLRP3 inflammasome assembly and NLRP3 mitochondrial localization, and c-FLIP is associated with NLRP3 inflammasome. c-FLIP downregulation also reduced AIM2 inflammasome activation. In contrast, c-FLIP inhibited SMAC mimetic-, FasL-, or Dectin-1-induced IL-1ß generation that is caspase-8-mediated. Our results demonstrate a prominent role of c-FLIP(L) in the optimal activation of the NLRP3 and AIM2 inflammasomes, and suggest that c-FLIP could be a valid target for treatment of inflammatory diseases caused by over-activation of inflammasomes.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Transporte
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Proteínas de Ligação a DNA
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Interleucina-1beta
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Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD
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Inflamassomos
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Macrófagos
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article