Editors' ChoiceInflammation

Potassium Efflux Stimulates Multiple Mechanisms

Science's STKE  06 Jul 2004:
Vol. 2004, Issue 240, pp. tw238-TW238
DOI: 10.1126/stke.2402004TW238

Interleukin-1β (IL-1β), a proinflammatory cytokine, lacks a signal peptide and is secreted from monocytes through a nonclassical exocytotic pathway. As part of this process, exogenous ATP activates the P2X7 receptor, a cation channel, triggering K+ efflux and Ca2+ influx. K+ efflux is required for production of caspase-1 from pro-caspase-1. Moreover, caspase-1, which cleaves pro-IL-1β to produce mature IL-1β, is secreted with IL-1β. How K+ efflux elicits caspase-1 production--and the relation between IL-1β processing and secretion--is unclear. Andrei et al. combined subcellular fractionation, immunoelectron microscopy, and Western analysis to show that, in monocytes treated with lipopolysaccharide to stimulate pro-IL-1β production, pro-caspase-1 (like pro-IL-1β) was present both in the cytosol and in lysosomes. ATP promoted processing of both proteins only in the lysosomal fraction and stimulated secretion of a lysosomal enzyme together with IL-1β and caspase-1. Whereas ATP stimulated processing and secretion of IL-1β, a calcium ionophore stimulated secretion of unprocessed IL-1β as did ATP during pharmacological inhibition of caspase-1. Blocking K+ efflux with increased [K+]o inhibited IL-1β processing and secretion, as well as the ATP-dependent rise in [Ca2+]i. Pharmacologic analysis and ion substitution indicated that K+ efflux independently stimulated phosphatidylcholine-specific phospholipase C (PC-PLC) and a Ca2+-independent form of phospholipase A2 (iPLA2). PC-PLC increased intracellular [Ca2+]i, thereby activating Ca2+-dependent PLA2, which promoted secretion. In contrast, inhibiting iPLA2 blocked caspase-1 activation and IL-1β processing. Thus, ATP-dependent K+ efflux appears to mediate IL-1β processing and secretion through two distinct pathways: Ca2+-dependent secretion of a lysosomal compartment and Ca2+-independent activation of caspase-1 through iPLA2.

C. Andrei, P. Margiocco, A. Poggi, L. V. Lotti, M. R. Torrisi, A. Rubartelli, Phospholipases C and A2 control lysosome-mediated IL-1β secretion: Implications for inflammatory processes. Proc. Natl. Acad. Sci. U.S.A. 101, 9745-9750 (2004). [Abstract] [Full Text]