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First published online 15 March 2005
doi: 10.1242/jcs.01737

Journal of Cell Science 118, 1437-1447 (2005)
Published by The Company of Biologists 2005
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Research Article

Potentiation of neutrophil cyclooxygenase-2 by adenosine: an early anti-inflammatory signal

Jean-Sébastien Cadieux1, Patrick Leclerc1, Mireille St-Onge1, Andrée-Anne Dussault1, Cynthia Laflamme1, Serge Picard1, Catherine Ledent2, Pierre Borgeat1 and Marc Pouliot1,*

1 Centre de Recherche en Rhumatologie et Immunologie du CHUQ (CHUL), and Department of Anatomy-Physiology, Faculty of Medicine, Laval University, Quebec, Canada, G1V 4G2
2 IRIBHM, Université Libre de Bruxelles, 808 route de Lennik, B-1070 Bruxelles, Belgium

* Author for correspondence (e-mail: marc.pouliot{at}crchul.ulaval.ca)

Accepted 18 January 2005

Neutrophils, which are often the first to migrate at inflamed sites, can generate leukotriene B4 from the 5-lipoxygenase pathway and prostaglandin E2 through the inducible cyclooxygenase-2 pathway. Adenosine, an endogenous autacoid with several anti-inflammatory properties, blocks the synthesis of leukotriene B4 while it potentiates the cyclooxygenase-2 pathway in fMLP-treated neutrophils, following activation of the A2A receptor. Using the murine air pouch model of inflammation, we observed that inflammatory leukocytes from mice lacking the A2A receptor have less cyclooxygenase-2 induction than wild-type animals. In human leukocytes, A2A receptor activation specifically elicited potentiation of cyclooxygenase-2 in neutrophils, but not in monocytes. Signal transduction studies indicated that the cAMP, ERK1/2, PI-3K and p38K intracellular pathways are implicated both in the direct upregulation of cyclooxygenase-2 and in its potentiation. Together, these results indicate that neutrophils are particularly important mediators of adenosine's effects. Given the uncontrolled inflammatory phenotype observed in knockout mice and in view of the potent inhibitory actions of prostaglandin E2 on inflammatory cells, an increased cyclooxygenase-2 expression resulting from A2A receptor activation, observed particularly in neutrophils, may take part in an early modulatory mechanism promoting anti-inflammatory activities of adenosine.

Key words: Polymorphonuclear leukocytes, Experimental animal models, Adenosine A2A receptor, Cyclic AMP, Resolution of inflammation




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