The activation of P2X7 receptor induces cathepsin D-dependent production of a 20-kDa form of IL-1ß under acidic extracellular pH in LPS-primed microglial cells.
J Neurochem
; 117(4): 712-23, 2011 May.
Article
em En
| MEDLINE
| ID: mdl-21395581
The potent pro-inflammatory cytokine, interleukin-1ß (IL-1ß), is synthesized as an inactive 33-kDa precursor (pro-IL-1ß) and is processed by caspase 1 into the bioactive 17-kDa mature form. The P2X7 receptor, an ATP-gated cation channel, plays an essential role in caspase 1 activation, production and release of mature bioactive 17-kDa form. We recently reported ATP induces the release of an unconventional 20-kDa form of IL-1ß (p20-IL-1ß) from lipopolysaccharide-primed microglial cells. Emerging evidence suggests physiological relevance for p20-IL-1ß; however, the underlying mechanisms for its production and release remain unknown. Here, we investigated the pathways involved in the ATP-induced production of p20-IL-1ß using lipopolysaccharide-primed mouse microglial cells. The activation of P2X7 receptor by ATP triggered p20-IL-1ß production under acidic extracellular conditions. ATP-induced p20-IL-1ß production was blocked by pepstatin A, a potent inhibitor of the lysosomal protease, cathepsin D. The removal of extracellular Ca(2+) inhibited the p20-IL-1ß production as well as ATP-induced cathepsin D release via lysosome exocytosis. The acidic extracellular pH also facilitated the dilatation of membrane pore after ATP stimulation. Since facilitation of pore dilatation results in cytolysis accompanied with cytoplasmic pro-IL-1ß leakage, our data suggest the leaked pro-IL-1ß is processed into p20-IL-1ß by cathepsin D released after ATP stimulation under acidic extracellular conditions.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Lipopolissacarídeos
/
Catepsina D
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Microglia
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Espaço Extracelular
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Interleucina-1beta
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Receptores Purinérgicos P2X7
Limite:
Animals
Idioma:
En
Revista:
J Neurochem
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Japão