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Divisions of
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Cardiovascular Medicine and
Clinical Pharmacology, and Departments of
Medicine and
Pharmacology, Vanderbilt University, Nashville, TN 37232; and
¶ Department of Drug Research and Pharmacological Sciences, CV Therapeutics, Inc., Palo Alto, CA 94304
Adenosine provokes bronchoconstriction in asthmatics through acute activation of mast cells, but its potential role in chronic inflammation has not been adequately characterized. We hypothesized that adenosine up-regulates Th2 cytokines in mast cells, thus promoting IgE synthesis by B lymphocytes. We tested this hypothesis in human mast cells (HMC-1) expressing A2A, A2B, and A3 adenosine receptors. The adenosine analog 5'-N-ethylcarboxamidoadenosine (NECA) (10 µM) increased mRNA expression of IL-1
, IL-3, IL-4, IL-8, and IL-13, but not IL-2 and IFN-
. Up-regulation of IL-4 and IL-13 was verified using RT-PCR and ELISA; 10 µM NECA increased IL-13 concentrations in HMC-1 conditioned medium 28-fold, from 7.6 ± 0.3 to 215 ± 4 pg/ml, and increased IL-4 concentrations 6-fold, from 19.2 ± 0.1 to 117 ± 2 pg/ml. This effect was mediated by A2B receptors because neither the selective A2A agonist 2-p-(2-carboxyethyl)phenethylamino-NECA nor the selective A3 agonist N6-(3-iodobenzyl)-N-methyl-5'-carbamoyladenosine reproduced it, and the selective A2B antagonist 3-isobutyl-8-pyrrolidinoxanthine prevented it. Constitutive expression of CD40 ligand on HMC-1 surface was not altered by NECA. Human B lymphocytes cocultured for 12 days with NECA-stimulated HMC-1 produced 870 ± 33 pg IgE per 106 B cells, whereas lymphocytes cocultured with nonstimulated HMC-1, or cultured alone in the absence or in the presence of NECA, produced no IgE. Thus, we demonstrated induction of IgE synthesis by the interaction between adenosine-stimulated mast cells and B lymphocytes, and suggest that this mechanism is involved in the amplification of the allergic inflammatory responses associated with asthma.
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