Adenosine A3 receptor expression and function in eosinophils.
The A3 adenosine receptor is widely expressed in human tissues with the most abundant expression in the lung and liver, but the predominant cellular localization and functions of this receptor in humans are unknown. Since adenosine influences the activation of circulating and resident inflammatory cells within the lung and leads to exaggerated airway narrowing in individuals with inflammatory airway disorders, we hypothesized that A3 receptor gene expression is localized to inflammatory cells and that gene expression is upregulated in airway inflammation. Lung and airway tissue were obtained at thoracotomy from nonsmoking subjects and subjects with inflammatory airway disorders associated with tobacco smoke or asthma. In situ hybridization identified A3 receptors in mesenchymal cells and eosinophils within the lamina propria of the airways and the adventitia of blood vessels, but not in mast cells. A3 receptor transcripts were highly expressed in peripheral blood eosinophils purified from atopic donors (6.36 +/- 0.60 pg/microg total RNA) in comparison with neutrophils (0.26 +/- 0.06 pg/microg) or mononuclear cells (0.9 +/- 0.15 pg/microg). Mean A3 receptor transcript abundance was greater in lung tissue from subjects with airway inflammation (0.33 +/- 0.04 pg/microg total RNA) than in normal lung (0.24 +/- 0.03 pg/microg total RNA, P = 0.035). The A3 receptor agonist N6-(4-amino-3-iodobenzyl)adenosine dose-dependently inhibited platelet activating factor-induced eosinophil chemotaxis to a maximum of 41%. This inhibitory effect was completely abolished by addition of the A3 receptor selective antagonist 3-(3-iodo-4-aminobenzyl)-8-(4-oxyacetate)phenyl-1-propylxanthine. We conclude that A3 receptors are primarily expressed on eosinophils in human lung, where they mediate inhibition of eosinophil chemotaxis. Specific A3 receptor ligands may be useful agents in the treatment of eosinophil-dependent diseases such as asthma and rhinitis.
Walker
B A
BA
University of British Columbia Pulmonary Research Laboratory, St. Paul's Hospital, Vancouver, Canada.
Jacobson
M A
MA
Knight
D A
DA
Salvatore
C A
CA
Weir
T
T
Zhou
D
D
Bai
T R
TR
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000737:chemistry; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004804:Eosinophils / Q000737:chemistry / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000276:immunology; D007462:Iodobenzenes / Q000494:pharmacology; D008168:Lung / Q000737:chemistry / Q000276:immunology*; D008173:Lung Diseases, Obstructive / Q000276:immunology; D008648:Mesoderm / Q000737:chemistry; D008969:Molecular Sequence Data; D010972:Platelet Activating Factor / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger / Q000032:analysis; D018047:Receptors, Purinergic P1 / Q000235:genetics*; D012756:Sheep; D014970:Xanthines / Q000494:pharmacology
D007462:Iodobenzenes; D010972:Platelet Activating Factor; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger; D018047:Receptors, Purinergic P1; D014970:Xanthines; C086749:BW A522; C044323:3-iodo-N(6)-4-aminobenzyladenosine; D000241:Adenosine