Adenosine A2a receptor-mediated, normoxic induction of HIF-1 through PKC and PI-3K-dependent pathways in macrophages.
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-alpha 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.
De Ponti
Cristina
C
Istituto di Patologia Generale, Università di Milano, Italy.
Carini
Rita
R
Alchera
Elisa
E
Nitti
Maria Paola
MP
Locati
Massimo
M
Albano
Emanuele
E
Cairo
Gaetano
G
Tacchini
Lorenza
L
D000818:Animals; D002460:Cell Line; D005260:Female; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms
D051793:Hypoxia-Inducible Factor 1; D043705:Receptor, Adenosine A2A; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C