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Blood, Vol. 95 No. 2 (January 15), 2000:
pp. 519-527
Adenosine receptor occupancy suppresses chemoattractant-induced
phospholipase D activity by diminishing membrane recruitment of small
GTPases
Nathalie Thibault,
Danielle Harbour,
Pierre Borgeat,
Paul H. Naccache, and
Sylvain G. Bourgoin
From the MRC Group on the Molecular Mechanisms of Inflammation,
Centre de Recherche en Rhumatologie et Immunologie, Centre Hospitalier
Universitaire de Québec, Pavillon C.H.U.L. et Université
Laval, Départements de Physiologie et Médecine,
Québec, Canada.
Adenosine (Ado) is an important autocrine modulator of neutrophil
functions. In this study, we determined the effects of endogenous Ado
on fMet-Leu-Phe (fMLP)-induced phospholipase D (PLD) activity in
neutrophils. The removal of extracellular Ado by Ado deaminase (ADA) or
the blockade of its action by the A2a receptor antagonists 8-(3-chlorostyryl) caffeine (CSC) or CGS15943 markedly increased fMLP-induced PLD activation. The concentration-dependent stimulatory effects of CSC and CGS15943 were abolished by a pretreatment of neutrophil suspensionswith ADA. In contrast, the selective A2a receptor
agonist CGS21680 suppressed fMLP-induced PLD activation. Furthermore,
inhibition by CGS21680 of fMLP-induced PLD activity was reversed by CSC
or CGS15943. The removal of Ado by ADA or the blockade of its action by
CSC or CGS15943, markedly increased the membrane recruitment of
cytosolic protein kinase C (PKC), RhoA, and ADP-ribosylation
factor (ARF) in response to fMLP. As shown for PLD activity, the
stimulatory effect of Ado receptor antagonists on PLD cofactors
translocation was abolished by a pretreatment of the cells with ADA.
Moreover, the membrane translocation of both PKC, RhoA, and ARF in
response to fMLP was attenuated by CGS21680 and this effect of the A2a
receptor agonist was antagonized by CSC or CGS15943. These data
demonstrate that Ado released by neutrophils in the extracellular
milieu inhibits PLD activation by blocking membrane association of ARF,
RhoA, and PKC through Ado A2a receptor occupancy.
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