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Published online before print May 15, 2007

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0107060

Received for publication January 24, 2007.
Revised March 28, 2007.
Accepted for publication April 13, 2007.

Article

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 ^*@, 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

^@ To whom correspondence should be addressed. E-mail: gaetano.cairo{at}unimi.it.

	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 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, is linked directly and suggests 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