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.
Adenosine A2a receptor-mediated, normoxic induction of HIF-1 through PKC and PI-3K-dependent pathways in macrophages / C. De Ponti, R. Carini, E. Alchera, M.P. Nitti, M. Locati, E. Albano, G. Cairo, L. Tacchini. - In: JOURNAL OF LEUKOCYTE BIOLOGY. - ISSN 0741-5400. - 82:2(2007 Aug), pp. 392-402.
|Titolo:||Adenosine A2a receptor-mediated, normoxic induction of HIF-1 through PKC and PI-3K-dependent pathways in macrophages|
DE PONTI, CRISTINA (Primo)
CAIRO, GAETANO (Penultimo)
TACCHINI, LORENZA (Ultimo)
|Parole Chiave:||Hypoxia; Inflammation; Kinases|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||ago-2007|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1189/jlb.0107060|
|Appare nelle tipologie:||01 - Articolo su periodico|