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Effect of A_2B Adenosine Receptor Gene Ablation on Proinflammatory Adenosine Signaling in Mast Cells¹

Sergey Ryzhov^*,, Rinat Zaynagetdinov^*,, Anna E. Goldstein^,¶, Sergey V. Novitskiy^,, Mikhail M. Dikov^,, Michael R. Blackburn^||, Italo Biaggioni^,,¶ and Igor Feoktistov^2,*,,¶

^* Division of Cardiovascular Medicine, Division of Clinical Pharmacology, Division of Hematology/Oncology, and Department of Medicine and ^¶ Department of Pharmacology, Vanderbilt University, Nashville, TN 37232; and ^|| Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston TX 77030

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 FcRI 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 A₃ 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants R01 HL070952 and R01 HL076306 from the National Institutes of Health.

² Address correspondence and reprint requests Dr. Igor Feoktistov, Division of Cardiovascular Medicine, 360 Preston Research Building, Vanderbilt University, 2220 Pierce Avenue, Nashville, TN 37232-6300. E-mail address: igor.feoktistov{at}vanderbilt.edu

³ Abbreviations used in this paper: ADA, adenosine deaminase; KO, knockout; BMMC, bone marrow-derived mast cell; HSA, human serum albumin; VEGF, vascular endothelial growth factor; WT, wild type.