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Published online before print May 15, 2007

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(Journal of Leukocyte Biology. 2007;82:392-402.)
© 2007 by Society for Leukocyte Biology

Adenosine A_2a 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^*,1 and Lorenza Tacchini^*

^* Istituto di Patologia Generale, Università di Milano, Italy;
Dipartimento di Scienze Mediche, Università "A. Avogadro," Novara, Italy;
Dipartimento di Medicina Sperimentale, Università di Genova, Italy; and
Istituto Clinico Humanitas, IRCCS, Rozzano, Italy

¹ Correspondence: Istituto di Patologia Generale, University of Milan School of Medicine, Via Mangiagalli 31, 20133 Milano, Italy. E-mail: gaetano.cairo{at}unimi.it

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- 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.

Key Words: hypoxia • inflammation • kinases

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