title: Adenosine-activated mast cells induce IgE synthesis by B lymphocytes: an A2B-mediated process involving Th2 cytokines IL-4 and IL-13 with implications for asthma.
abstract: 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 A(2A), A(2B), and A(3) adenosine receptors. The adenosine analog 5'-N-ethylcarboxamidoadenosine (NECA) (10 microM) increased mRNA expression of IL-1beta, IL-3, IL-4, IL-8, and IL-13, but not IL-2 and IFN-gamma. Up-regulation of IL-4 and IL-13 was verified using RT-PCR and ELISA; 10 microM 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 A(2B) receptors because neither the selective A(2A) agonist 2-p-(2-carboxyethyl)phenethylamino-NECA nor the selective A(3) agonist N(6)-(3-iodobenzyl)-N-methyl-5'-carbamoyladenosine reproduced it, and the selective A(2B) 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 10(6) 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.
authors.affiliation: Division of Clinical Pharmacology, Department of Pharmacology, Vanderbilt University, 1500 21st Avenue South, Nashville, TN 37232, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Ryzhov
authors.forename: Anna E
authors.initials: AE
authors.lastname: Goldstein
authors.forename: Anton
authors.initials: A
authors.lastname: Matafonov
authors.forename: Dewan
authors.initials: D
authors.lastname: Zeng
authors.forename: Italo
authors.initials: I
authors.lastname: Biaggioni
authors.forename: Igor
authors.initials: I
authors.lastname: Feoktistov
mesh_terms: D000241:Adenosine / Q000494:pharmacology*; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D001249:Asthma / Q000209:etiology; D001402:B-Lymphocytes / Q000276:immunology* / Q000502:physiology; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000235:genetics; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis*; D018793:Interleukin-13 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008407:Mast Cells / Q000276:immunology* / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D043704:Receptor, Adenosine A2B / Q000502:physiology*; D018418:Th2 Cells / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D016207:Cytokines; D018793:Interleukin-13; D012333:RNA, Messenger; D043704:Receptor, Adenosine A2B; D015847:Interleukin-4; D019830:Adenosine-5'-(N-ethylcarboxamide); D007073:Immunoglobulin E; D000241:Adenosine