| Autor: |
Perregaux, David G., Labasi, Jeff, Laliberte, Ron, Stam, Ethan, Solle, Mike, Koller, Bev, Griffiths, Richard, Gabel, Christopher A. |
| Zdroj: |
Drug Development Research; June - July 2001, Vol. 53 Issue: 2-3 p83-90, 8p |
| Abstrakt: |
Cultured monocytes and macrophages stimulated with LPS produce large quantities of prointerleukin (IL)-1β, but release little mature cytokine to the medium. The efficiency at which the procytokine is converted to its active 17 kDa species and released extracellularly is enhanced by treating cytokine-producing cells with a secretion stimulus such as ATP or nigericin. Alterations to the composition of the intracellular ionic environment, including a necessary K+ efflux, accompany the stimulus-induced secretory process. Cell death also accompanies stimulus-induced IL-1 posttranslational processing and human monocytes treated with ATP generate and release mature caspase-1. ATP-treated monocytes achieve a swollen morphology and do not produce mature caspase-3; these traits are uncharacteristic of an apoptotic mechanism. Stimulus-induced secretion of IL-1β is disrupted by substitution of medium Cl- with chaotropic anions such as I- and by numerous anion transport inhibitors. These pharmacological agents block processing independently of the nature of the secretion stimulus, suggesting that a common downstream mechanism is engaged. Although sufficient to activate, the P2X7 receptor (P2X7R) is not a necessary element of the secretory mechanism. KN-62, an antagonist of P2X7R function, inhibits ATP-induced IL-1β posttranslational processing but does not inhibit processing induced by nigericin. Likewise, LPS-activated peritoneal macrophages isolated from P2X7R-deficient mice respond to nigericin and produce mature 17 kDa IL-1β. On the other hand, the receptor-deficient macrophages, in contrast to their wild-type counterparts, do not respond to ATP. These findings highlight the unusual secretory requirements of IL-1 and demonstrate that P2X7R activation represents one mechanism by which cytokine posttranslational processing can be initiated. Drug Dev. Res. 53:8390, 2001. © 2001 Wiley-Liss, Inc. |
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