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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 21, 2003; DOI: 10.1124/jpet.103.059600

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Received for publication September 4, 2003.
Revised November 6, 2003.
Accepted for publication November 10, 2003.

MAP KINASE AND CASPASE SIGNALING PATHWAYS ARE REQUIRED FOR P2X7 RECEPTOR (P2X7R) INDUCED PORE FORMATION IN HUMAN THP-1 CELLS

Diana Donnelly-Roberts 1*, Marian Namovic 1, Connie Faltynek 1, Michael Frederick Jarvis 1

1 Abbott Laboratories

* Address correspondence to: E-mail: diana.l.donnelly-roberts{at}abbott.com

Abstract

Brief activation of the ATP-sensitive P2X7 receptor (P2X7R) stimulates the maturation and release of IL-1{beta} in macrophages, whereas prolonged agonist activation induces the formation of cytolytic pores in cell membranes. The present studies investigated potential down-stream mechanisms associated with native human P2X7R activation in lipopolysaccahride (LPS) and interferon{gamma} (IFN {gamma}) differentiated THP-1 cells. BzATP-induced pore formation (EC50 = 35 µM) was blocked by a selective P2X7R antagonist, KN-62, (IC50= 44 nM) and by PPADS, (IC50= 344 nM). KN-62 and PPADS also blocked BzATP-induced IL-1 {beta} release (EC50 = 617 µM) with IC50 values of 75 and 3500 nM, respectively. The selective p38 MAP kinase inhibitor, SB 202190, potently inhibited BzATP-induced pore formation (IC50 = 75 nM), but did not alter P2X7 mediated calcium influx or IL-1{beta} release. SB 202190 and KN62 also attenuated BzATP- mediated activation of phosphoryated p38 MAPK (pp38 MAPK). Two caspase inhibitors, YVAD and DEVD, attenuated both BzATP-induced pore formation and IL-1{beta} release in a concentration-dependent fashion. Neither DEVD nor p38-MAPK inhibitors blocked cell membrane pore formation evoked by maitotoxin or by activation of human P2X2a receptors. These results indicate that P2X7R mediated pore formation results from a coordinated cascade involving both the p38-MAPK and caspase pathways that is distinct from other cytolytic pore forming mechanisms. In contrast, P2X7R mediated IL-1{beta} release is dependent on caspase activity but not p38 MAPK. Taken together, these results support the hypothesis that down-stream cellular signaling mechanisms rather than channel dilation mediates cytolytic pore-formation following prolonged agonist activation which underlies P2X7 receptors.


Key words: IL-1b release, MAP kinase, P2X7, caspase, macrophage, pore formation


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