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A putative osmoreceptor system that controls neutrophil function through the release of ATP, its conversion to adenosine, and activation of A2 adenosine and P2 receptors
Author(s) -
Chen Yu,
Shukla Alok,
Namiki Sachiko,
Insel Paul A.,
Junger Wolfgang G.
Publication year - 2004
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0204066
Subject(s) - adenosine , adenosine a3 receptor , biology , purinergic signalling , adenosine receptor , receptor , adenosine a1 receptor , adenosine a2b receptor , p2 receptor , purinergic receptor , adenosine deaminase inhibitor , xanthine , adenosine deaminase , microbiology and biotechnology , biochemistry , medicine , agonist , enzyme
We have previously shown that hypertonic stress (HS) can suppress chemoattractant‐induced neutrophil responses via cyclic adenosine monophosphate and enhance these responses through p38 mitogen‐activated protein kinase (MAPK) activation. The underlying mechanisms are unknown. Here, we report that HS dose‐dependently releases adenosine 5′‐triphosphate (ATP) from neutrophils and that extracellular ATP is rapidly converted to adenosine or activates p38 MAPK and enhances N‐formyl‐methionyl‐leucyl‐phenylalanine‐induced superoxide formation. In contrast, adenosine suppresses superoxide formation. Adenosine deaminase treatment abolished the suppressive effect of HS, indicating that HS inhibits neutrophils through adenosine generation. Neutrophils express mRNA, encoding all known P1 adenosine receptors (A1, A2a, A2b, and A3) and the nucleotide receptors P2Y2, P2Y4, P2Y6, P2Y11, and P2X7. A2 receptor agonists mimicked the suppressive effects of HS; the A2 receptor antagonists 8‐(p‐sulfophenyl)theophylline, 3,7‐dimethyl‐1‐(2‐propynyl)xanthine, 1,3,7‐trimethyl‐8‐(3‐chlorostyryl)xanthine, and 3‐propylxanthine, but not A1 and A3 receptor antagonists, decreased the suppressive effect of HS, indicating that HS suppresses neutrophils via A2 receptor activation. Antagonists of P2 receptors counteracted the enhancing effects of ATP, suggesting that HS costimulates neutrophils by means of P2 receptor activation. We conclude that hypertonic stress regulates neutrophil function via a single molecule (ATP) and its metabolite (adenosine), using positive‐ and negative‐feedback mechanisms through the activation of P2 and A2 receptors, respectively.