Adenosine A2a receptors induce heterologous desensitization of chemokine receptors.
Adenosine, released by cells in an injurious or hypoxic environment, possesses potent anti-inflammatory effects by inhibiting the production of proinflammatory cytokines and superoxide anions (O2-). We hypothesized that adenosine compounds also induced heterologous desensitization of chemokine receptors, which played a critical role in leukocyte trafficking. Our studies using adenosine receptor subtype-specific agonists revealed that pretreatment with adenosine compounds suppressed RANTES-induced chemotaxis and Ca2+ flux through activation of A2a adenosine receptor. Adenosine compounds also desensitized IL-8- and MCP-1-induced chemotaxis, but not that induced by fMLP. Activation of protein kinase A (PKA), a component of the signaling pathway induced by the A2a receptor, was sufficient to desensitize RANTES-induced chemotaxis. Inhibition of PKA reversed the desensitization effects of adenosine compounds, suggesting that PKA was necessary for A2a receptor-mediated heterologous desensitization. In a mouse model, prior activation of A2a receptors blocked RANTES-induced recruitment of leukocytes in an air pouch. Moreover, the A2a receptor-induced cross-desensitization also reduced the susceptibility of monocytes to infection by an R5 strain of HIV-1. Our results suggest that activation of A2a adenosine receptors suppresses chemokine receptor function, and such receptor cross-talk was based on the simple mechanism of PKA-mediated heterologous desensitization, thus contributing to the antiinflammatory activity of adenosine.
Zhang
Ning
N
Laboratory of Molecular Immunoregulation, Center for Cancer Research and Basic Research Program, Science Applications International-Frederick, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Yang
De
D
Dong
Huifang
H
Chen
Qian
Q
Dimitrova
Dessislava I
DI
Rogers
Thomas J
TJ
Sitkovsky
Michail
M
Oppenheim
Joost J
JJ
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D018946:Chemokine CCL5 / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D002633:Chemotaxis / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010627:Phenethylamines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism; D019707:Receptors, Chemokine / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship
D058908:Adenosine A2 Receptor Agonists; D018946:Chemokine CCL5; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; D019707:Receptors, Chemokine; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D017868:Cyclic AMP-Dependent Protein Kinases; D000241:Adenosine