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* CIHR Group on the Molecular Mechanisms of Inflammation, Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du CHUL, CHUQ et Université Laval, Départements
d’Anatomie-Physiologie et
Médecine, Québec, Canada
Correspondence: Sylvain G. Bourgoin, Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du CHUL, CHUQ, 2705 Blvd. Laurier, Sainte-Foy, Québec, G1V 4G2, Canada. E-mail: Sylvain.bourgoin{at}crchul.ulaval.ca
The aim of this study was to assess in human neutrophils the implication of an adenosine 3',5'-cyclic monophosphate (cAMP)-dependent pathway in the inhibitory effects of A2a receptor engagement. We found that Ro20-1724, a cAMP phosphodiesterase inhibitor, in the presence of adenosine deaminase (ADA) or A2a receptor antagonists rendered transient the fMLP-induced sustained increases in cAMP levels. The role of A2a receptor stimulation was demonstrated by the ability of the A2a receptor agonist, CGS21680, to prevent ADA-mediated reduction of the persistent cAMP elevation induced by fMLP. Persistent cAMP elevation correlated with inhibition of fMLP-induced PLD activation and recruitment of Arf, RhoA, and PKC to membranes. The suppressive effect of CGS21680 or isoproterenol, a ß-adrenergic receptor agonist, was increased by Ro20-1724 or by the adenylyl cyclase activator, forskolin, and reversed, at least in part, by the inhibitor of adenylyl cyclase, 2',5'-dideoxyadenosine. The activator of protein kinase A (PKA), Sp-cAMP inhibited fMLP-induced PLD activation and translocation of Arf and RhoA to membranes. In contrast, the suppression by A2a receptor stimulation of fMLP-induced PLD activation and cofactor recruitment was antagonized by PKA inhibitors, Rp-cAMP and H89. In conclusion, A2a receptor occupancy by extracellular adenosine inhibits fMLP-induced neutrophil activation via cAMP and PKA-regulated events.
Key Words: protein kinase C • phosphodiesterase • ADA • cAMP
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