title: Activation of the A(3) adenosine receptor suppresses superoxide production and chemotaxis of mouse bone marrow neutrophils.
abstract: Adenosine is formed in injured/ischemic tissues, where it suppresses the actions of essentially all cells of the immune system. Most of the anti-inflammatory actions of adenosine have been attributed to signaling through the G(s) protein-coupled A(2A) adenosine receptor (AR). Here, we report that the A(3)AR is highly expressed in murine neutrophils isolated from bone marrow. Selective activation of the A(3)AR with (2S,3S,4R,5R)-3-amino-5-[6-(2,5-dichlorobenzylamino)purin-9-yl]-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide (CP-532,903) potently inhibited mouse bone marrow neutrophil superoxide generation and chemotaxis induced by various activating agents. The selectivity of CP-532,903 was confirmed in assays using neutrophils obtained from A(2A)AR and A(3)AR gene "knockout" mice. In a model of thioglycollate-induced inflammation, treating mice with CP-532,903 inhibited recruitment of leukocytes into the peritoneum by specifically activating the A(3)AR. Collectively, our findings support the theory that the A(3)AR contributes to the anti-inflammatory actions of adenosine on neutrophils and provide a potential mechanistic explanation for the efficacy of A(3)AR agonists in animal models of inflammation (i.e., inhibition of neutrophil-mediated tissue injury).
authors.affiliation: Department of Pharmacology and Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Dharini
authors.initials: D
authors.lastname: van der Hoeven
authors.forename: Tina C
authors.initials: TC
authors.lastname: Wan
authors.forename: John A
authors.initials: JA
authors.lastname: Auchampach
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects; D002469:Cell Separation; D002633:Chemotaxis / Q000187:drug effects; D005663:Furans / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects; D010538:Peritonitis / Q000473:pathology; D010627:Phenethylamines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000235:genetics / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*
chemical_list: C479779:CP-532,903; D005663:Furans; D010627:Phenethylamines; D011687:Purines; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D043704:Receptor, Adenosine A2B; D043684:Receptor, Adenosine A3; D013481:Superoxides; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000241:Adenosine