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

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 A_2A receptor. Using the murine air pouch model of inflammation, we observed that inflammatory leukocytes from mice lacking the A_2A receptor have less cyclooxygenase-2 induction than wild-type animals. In human leukocytes, A_2A 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 A_2A receptor activation, observed particularly in neutrophils, may take part in an early modulatory mechanism promoting anti-inflammatory activities of adenosine.