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Blood, 1 July 2006, Vol. 108, No. 1, pp. 38-44.
Prepublished online as a Blood First Edition Paper on March 7, 2006; DOI 10.1182/blood-2005-06-2599.
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CHEMOKINES, CYTOKINES, AND INTERLEUKINS
Adenosine A2a receptors induce heterologous desensitization of chemokine receptors
Ning Zhang,
De Yang,
Huifang Dong,
Qian Chen,
Dessislava I. Dimitrova,
Thomas J. Rogers,
Michail Sitkovsky, and
Joost J. Oppenheim
From the Laboratory of Molecular Immunoregulation, Center for Cancer Research and Basic Research Program, Science Applications International-Frederick, National Cancer Institute at Frederick, Frederick, MD; Department of Chemical Biology, and State Key Laboratory of Molecular Dynamic and Stable Structures, College of Chemistry, Peking University, Beijing, China; Department of Pharmacology, Fels Institute for Cancer Research and Molecular Biology, Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA; and New England Inflammation and Tissue Protection Institute, a consortium at Northeastern University, Boston, MA.
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. (Blood. 2006;108:38-44)
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