title: Effect of A2B adenosine receptor gene ablation on proinflammatory adenosine signaling in mast cells.
abstract: Pharmacological studies suggest that A(2B) adenosine receptors mediate proinflammatory effects of adenosine in human mast cells in part by up-regulating production of Th2 cytokines and angiogenic factors. This concept has been recently challenged by the finding that mast cells cultured from bone marrow-derived mast cells (BMMCs) of A(2B) knockout mice display an enhanced degranulation in response to FcepsilonRI stimulation. This finding was interpreted as evidence of anti-inflammatory functions of A(2B) receptors and it was suggested that antagonists with inverse agonist activity could promote activation of mast cells. In this report, we demonstrate that genetic ablation of the A(2B) receptor protein has two distinct effects on BMMCs, one is the previously reported enhancement of Ag-induced degranulation, which is unrelated to adenosine signaling; the other is the loss of adenosine signaling via this receptor subtype that up-regulates IL-13 and vascular endothelial growth factor secretion. Genetic ablation of A(2B) receptors had no effect on A(3) adenosine receptor-dependent potentiation of Ag-induced degranulation in mouse BMMCs, but abrogated A(2B) adenosine receptor-dependent stimulation of IL-13 and vascular endothelial growth factor secretion. Adenosine receptor antagonists MRS1706 and DPCPX with known inverse agonist activity at the A(2B) subtype inhibited IL-13 secretion induced by the adenosine analog NECA, but did not mimic the enhanced Ag-induced degranulation observed in A(2B) knockout BMMCs. Thus, our study confirmed the proinflammatory role of adenosine signaling via A(2B) receptors and the anti-inflammatory actions of A(2B) antagonists in mouse BMMCs.
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt. University, Nashville, TN 37232, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Ryzhov
authors.forename: Rinat
authors.initials: R
authors.lastname: Zaynagetdinov
authors.forename: Anna E
authors.initials: AE
authors.lastname: Goldstein
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Novitskiy
authors.forename: Mikhail M
authors.initials: MM
authors.lastname: Dikov
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
authors.forename: Italo
authors.initials: I
authors.lastname: Biaggioni
authors.forename: Igor
authors.initials: I
authors.lastname: Feoktistov
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D058917:Adenosine A2 Receptor Antagonists; D000249:Adenosine Monophosphate / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells; D015550:Cell Degranulation; D002460:Cell Line; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D018793:Interleukin-13 / Q000096:biosynthesis* / Q000276:immunology; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011687:Purines / Q000494:pharmacology; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000276:immunology; D014970:Xanthines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D018793:Interleukin-13; C496145:N-(4-acetylphenyl)-2-(4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy)acetamide; D011687:Purines; D043704:Receptor, Adenosine A2B; D042461:Vascular Endothelial Growth Factor A; D014970:Xanthines; D000249:Adenosine Monophosphate; C051360:1,3-dipropyl-8-cyclopentylxanthine; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000241:Adenosine