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
Open Access
- 11 March 2011
- journal article
- Published by Wiley in Journal of Neurochemistry
- Vol. 117 (4), 712-723
- https://doi.org/10.1111/j.1471-4159.2011.07240.x
Abstract
J. Neurochem. (2011) 117, 712â723. Abstract The potent proâinflammatory cytokine, interleukinâ1β (ILâ1β), is synthesized as an inactive 33âkDa precursor (proâILâ1β) and is processed by caspase 1 into the bioactive 17âkDa mature form. The P2X7 receptor, an ATPâgated cation channel, plays an essential role in caspase 1 activation, production and release of mature bioactive 17âkDa form. We recently reported ATP induces the release of an unconventional 20âkDa form of ILâ1β (p20âILâ1β) from lipopolysaccharideâprimed microglial cells. Emerging evidence suggests physiological relevance for p20âILâ1β; however, the underlying mechanisms for its production and release remain unknown. Here, we investigated the pathways involved in the ATPâinduced production of p20âILâ1β using lipopolysaccharideâprimed mouse microglial cells. The activation of P2X7 receptor by ATP triggered p20âILâ1β production under acidic extracellular conditions. ATPâinduced p20âILâ1β production was blocked by pepstatin A, a potent inhibitor of the lysosomal protease, cathepsin D. The removal of extracellular Ca2+ inhibited the p20âILâ1β production as well as ATPâinduced 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 proâILâ1β leakage, our data suggest the leaked proâILâ1β is processed into p20âILâ1β by cathepsin D released after ATP stimulation under acidic extracellular conditions.Keywords
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