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Adenosine A 2a receptor‐mediated, normoxic induction of HIF‐1 through PKC and PI‐3K‐dependent pathways in macrophages
Author(s) -
De Ponti Cristina,
Carini Rita,
Alchera Elisa,
Nitti Maria Paola,
Locati Massimo,
Albano Emanuele,
Cairo Gaetano,
Tacchini Lorenza
Publication year - 2007
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.0107060
Subject(s) - adenosine , biology , transactivation , adenosine a3 receptor , microbiology and biotechnology , adenosine receptor , adenosine a2b receptor , signal transduction , receptor , agonist , endocrinology , transcription factor , biochemistry , gene
Adenosine released by cells in injurious or hypoxic environments has tissue‐protecting and anti‐inflammatory effects, which are also a result of modulation of macrophage functions, such as vascular endothelial growth factor (VEGF) production. As VEGF is a well‐known target of hypoxia‐inducible factor 1 (HIF‐1), we hypothesized that adenosine may activate HIF‐1 directly. Our studies using subtype‐specific adenosine receptor agonists and antagonists showed that by activating the A 2A receptor, adenosine treatment induced HIF‐1 DNA‐binding activity, nuclear accumulation, and transactivation capacity in J774A.1 mouse macrophages. Increased HIF‐1 levels were also found in adenosine‐treated mouse peritoneal macrophages. The HIF‐1 activation induced by the A 2A receptor‐specific agonist CGS21680 required the PI‐3K and protein kinase C pathways but was not mediated by changes in iron levels. Investigation of the molecular basis of HIF‐1 activation revealed the involvement of transcriptional and to a larger extent, translational mechanisms. HIF‐1 induction triggered the expression of HIF‐1 target genes involved in cell survival (aldolase, phosphoglycerate kinase) and VEGF but did not induce inflammation‐related genes regulated by HIF‐1, such as TNF‐α or CXCR4. Our results show that the formation of adenosine and induction of HIF‐1, two events which occur in response to hypoxia, are linked directly and suggest that HIF‐1 activation through A 2A receptors may contribute to the anti‐inflammatory and tissue‐protecting activity of adenosine.