Adenosine A2a receptor-mediated, normoxic induction of HIF-1 through PKC and PI-3K-dependent pathways in macrophages

Cristina De Ponti, Rita Carini, Elisa Alchera, Maria Paola Nitti, Massimo Locati, Emanuele Albano, Gaetano Cairo, Lorenza Tacchini

Research output: Contribution to journalArticle

Abstract

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 A2A 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 A2A 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 A2A receptors may contribute to the anti-inflammatory and tissue-protecting activity of adenosine.

Original languageEnglish
Pages (from-to)392-402
Number of pages11
JournalJournal of Leukocyte Biology
Volume82
Issue number2
DOIs
Publication statusPublished - Aug 1 2007

Keywords

  • Hypoxia
  • Inflammation
  • Kinases

ASJC Scopus subject areas

  • Cell Biology

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