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 B(4) from the 5-lipoxygenase pathway and prostaglandin E(2) through the inducible cyclooxygenase-2 pathway. Adenosine, an endogenous autacoid with several anti-inflammatory properties, blocks the synthesis of leukotriene B(4) 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 E(2) 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.
Cadieux
Jean-Sébastien
JS
Centre de Recherche en Rhumatologie et Immunologie du CHUQ (CHUL), and Department of Anatomy-Physiology, Faculty of Medicine, Laval University, Quebec, Canada, G1V 4G2.
Leclerc
Patrick
P
St-Onge
Mireille
M
Dussault
Andrée-Anne
AA
Laflamme
Cynthia
C
Picard
Serge
S
Ledent
Catherine
C
Borgeat
Pierre
P
Pouliot
Marc
M
D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology* / Q000276:immunology; D007279:Injections, Subcutaneous; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects* / Q000276:immunology; D043705:Receptor, Adenosine A2A / Q000172:deficiency / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D043705:Receptor, Adenosine A2A; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D000241:Adenosine