PURINERGIC MODULATION OF INTERLEUKIN-1-BETA RELEASE FROM MICROGLIAL CELLS STIMULATED WITH BACTERIAL-ENDOTOXIN

Microglial cells express a peculiar plasma membrane receptor for extra cellular ATP, named P2Z/P2X(7) purinergic receptor, that triggers mass ive transmembrane ion fluxes and a reversible permeabilization of the plasma membrane to hydrophylic molecules of up to 900 dalton molecule weight and eventual cell death (Di Virgilio, F. 1995. Immunol. Today. 16:524-528). The physiological role of this newly cloned (Surprenant, A., F. Rassendren, E. Kawashima, R.A. North and G. Buell. 1996. Scienc e (Wash. DC). 272:735-737) cytolytic receptor is unknown. In vitro and in vivo activation of the macrophage and microglial cell P2Z/P2X(7) r eceptor by exogenous ATP causes a large and rapid release of mature IL -1 beta In the present report we investigated the role of microglial P 2Z/P2X(7) receptor in IL-1 beta release triggered by LPS. Our data sug gest that LPS-dependent IL-1 beta release involves activation of this purinergic receptor as it is inhibited by the selective P2Z/P2X(7) blo cker oxidized ATP and modulated by ATP-hydrolyzing enzymes such as apy rase or hexokinase. Furthermore, microglial cells release ATP when sti mulated with LPS. LPS-dependent release of ATP is also observed in mon ocyte-derived human macrophages. It is suggested that bacterial endoto xin activates an autocrine/paracrine loop that drives ATP-dependent IL -1 beta secretion.