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)