Purinergic Modulation of Interleukin-1β Release from Microglial Cells Stimulated with Bacterial Endotoxin

Abstract

Microglial cells express a peculiar plasma membrane receptor for extracellular ATP, named P2Z/P2X7 purinergic receptor, that triggers massive 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. Science (Wash. DC). 272:735–737) cytolytic receptor is unknown. In vitro and in vivo activation of the macrophage and microglial cell P2Z/P2X7 receptor by exogenous ATP causes a large and rapid release of mature IL-1β. In the present report we investigated the role of microglial P2Z/P2X7 receptor in IL-1β release triggered by LPS. Our data suggest that LPS-dependent IL-1β release involves activation of this purinergic receptor as it is inhibited by the selective P2Z/P2X7 blocker oxidized ATP and modulated by ATP-hydrolyzing enzymes such as apyrase or hexokinase. Furthermore, microglial cells release ATP when stimulated with LPS. LPS-dependent release of ATP is also observed in monocyte-derived human macrophages. It is suggested that bacterial endotoxin activates an autocrine/paracrine loop that drives ATP-dependent IL-1β secretion.

The effects of P2X7 receptor antagonists on the formation and function of human osteoclasts in vitro

“…One possible explanation for the lack of effect with A-438079 is that it is a competitive and reversible antagonist [34]. Oxidised ATP is an irreversible P2X7R inhibitor [35,36], whilst KN62 and the cyclic imide group of antagonists are non-competitive allosteric inhibitors [37,38]. Given that these cultures were performed over a three week period and we have measured a long-term response, it could be possible that A-438079 has been competed off the receptor during this time, thus reducing its efficacy.…”

The role of P2X7 receptors in tissue fibrosis: a brief review

“…In many cases, pathogen elimination requires the damage-associated molecular patterns (DAMPs) that include endogenous intracellular molecules released by activated or necrotic cells [37]. PAMPs such as lipopolysaccharide (LPS) can induce the synthesis of pro-inflammatory cytokines such as pro-interleukin (IL)-1β [38], and its release occurs after NALP-3 inflammasome complex activation [39]. Extracellular ATP is a potent DAMP molecule [40] that exerts its effects by binding to the P2X 7 R [4].…”

The estrogen-responsive B box protein: a novel enhancer of interleukin-1β secretion

“…Secretion is independent of the Golgi apparatus and can be stimulated by exogenous ATP via the P2X7 receptor. [3][4][5] Processing and activation of proIL-1b is strictly dependent on the protease caspase-1, which cleaves proIL-1b after the aspartic acid residue at position 116, generating active IL-1b. 6,7 Consequently, macrophages from caspase-1 knockout mice cannot produce mature IL-1b.…”