Early tyrosine phosphorylation events following adenosine A2Areceptor in human neutrophils: identification of regulated pathways.
Activation of the adenosine2Areceptor (A2AR) elevates intracellular levels of cAMP and acts as a physiologic inhibitor of inflammatory neutrophil functions. In this study, we looked into the impact of A2AR engagement on early phosphorylation events. Neutrophils were stimulated with well-characterized proinflammatory agonists in the absence or presence of an A2AR agonist {3-[4-[2-[ [6-amino-9-[(2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxy-oxolan-2-yl]purin-2-yl]amino] ethyl] phenyl] propanoic acid (CGS 21680)}, PGE2, or a mixture of the compounds RO 20-1724 and forskolin. As assessed by immunoblotting, several proteins were tyrosine phosphorylated; CGS 21680 markedly decreased tyrosine phosphorylation levels of 4 regions (37-45, 50-55, 60, and 70 kDa). Key signaling protein kinases-p38 MAPK, Erk-1/2, PI3K/Akt, Hck, and Syk-showed decreased phosphorylation, whereas Lyn, SHIP-1, or phosphatase and tensin homolog (PTEN) was spared. PGE2or the intracellular cAMP-elevating combination of RO 20-1724 and forskolin mostly mimicked the effect of CGS 21680. Together, results unveil intracellular signaling pathways targeted by the A2AR, some of which might be key in modulating neutrophil functions.
Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, Centre de Recherche du CHU de Québec-Université Laval, Quebec City, Canada.
Miriam S
MS
Giambelluca
Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, Centre de Recherche du CHU de Québec-Université Laval, Quebec City, Canada marc.pouliot@crchul.ulaval.ca.
Marc
M
Pouliot
D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D015232:Dinoprostone / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D043705:Receptor, Adenosine A2A / Q000276:immunology*; D014443:Tyrosine / Q000276:immunology
D058908:Adenosine A2 Receptor Agonists; D043705:Receptor, Adenosine A2A; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C000606430:INPP5D protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D015232:Dinoprostone
cyclic AMP; granulocytes; inflammation; signal transduction