RRC ID |
18208
|
著者 |
Takenouchi T, Iwamaru Y, Sugama S, Tsukimoto M, Fujita M, Sekigawa A, Sekiyama K, Sato M, Kojima S, Conti B, Hashimoto M, Kitani H.
|
タイトル |
The activation of P2X7 receptor induces cathepsin D-dependent production of a 20-kDa form of IL-1β under acidic extracellular pH in LPS-primed microglial cells.
|
ジャーナル |
J Neurochem
|
Abstract |
The potent pro-inflammatory cytokine, interleukin-1β (IL-1β), is synthesized as an inactive 33-kDa precursor (pro-IL-1β) 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-1β (p20-IL-1β) from lipopolysaccharide-primed microglial cells. Emerging evidence suggests physiological relevance for p20-IL-1β; 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-1β using lipopolysaccharide-primed mouse microglial cells. The activation of P2X7 receptor by ATP triggered p20-IL-1β production under acidic extracellular conditions. ATP-induced p20-IL-1β 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-1β 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-1β leakage, our data suggest the leaked pro-IL-1β is processed into p20-IL-1β by cathepsin D released after ATP stimulation under acidic extracellular conditions.
|
巻・号 |
117(4)
|
ページ |
712-23
|
公開日 |
2011-5-1
|
DOI |
10.1111/j.1471-4159.2011.07240.x
|
PMID |
21395581
|
MeSH |
Adenosine Triphosphate / pharmacology
Animals
Blotting, Western
Caspase 1 / metabolism
Cathepsin D / pharmacology*
Cell Line
Exocytosis / drug effects
Extracellular Space / metabolism*
Hydrogen-Ion Concentration
Immunohistochemistry
Interleukin-1beta / biosynthesis*
Lipopolysaccharides / pharmacology*
Lysosomes / drug effects
Lysosomes / metabolism
Mice
Mice, Inbred C57BL
Microglia / drug effects
Microglia / metabolism*
Nerve Tissue Proteins / biosynthesis
Pepstatins / pharmacology
Receptors, Purinergic P2X7 / drug effects*
|
IF |
4.066
|
引用数 |
24
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
NEUROSCIENCES
|
リソース情報 |
ヒト・動物細胞 |
MG6(RCB2403) |