Adenosine up-regulates cyclooxygenase-2 in human granulocytes: impact on the balance of eicosanoid generation.
Polymorphonuclear neutrophils (granulocytes; PMNs) are often the first blood cells to migrate toward inflammatory lesions to perform host defense functions. PMNs respond to specific stimuli by releasing several factors and generate lipid mediators of inflammation from the 5-lipoxygenase and the inducible cyclooxygenase (COX)-2 pathways. In view of adenosine's anti-inflammatory properties and suppressive impact on the 5-lipoxygenase pathway, we addressed in this study the impact of this autacoid on the COX-2 pathway. We observed that adenosine up-regulates the expression of the COX-2 enzyme and mRNA. Production of PGE(2) in response to exogenous arachidonic acid was also increased by adenosine and correlated with COX-2 protein levels. The potentiating effect of adenosine on COX-2 could be mimicked by pharmacological increases of intracellular cAMP levels, involving the latter as a putative second messenger for the up-regulation of COX-2 by adenosine. Specific COX-2 inhibitors were used to confirm the predominant role of the COX-2 isoform in the formation of prostanoids by stimulated PMNs. Withdrawal of extracellular adenosine strikingly emphasized the inhibitory potential of PGE(2) on leukotriene B(4) formation and involved the EP(2) receptor subtype in this process. Thus, adenosine may promote a self-limiting regulatory process through the increase of PGE(2) generation, which may result in the inhibition of PMN functions. This study identifies a new aspect of the anti-inflammatory properties of adenosine in leukocytes, introducing the concept that this autacoid may exert its immunomodulatory activities in part by modifying the balance of lipid mediators generated by PMNs.
Pouliot
Marc
M
Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du Centre Hospitalier Universitaire de Québec, and Faculté de Médecine, Université Laval, Canada. Marc.Pouliot@crchul.ulaval.ca
Fiset
Marie-Elaine
ME
Massé
Mireille
M
Naccache
Paul H
PH
Borgeat
Pierre
P
D000241:Adenosine / Q000502:physiology*; D000276:Adjuvants, Immunologic / Q000502:physiology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology; D016718:Arachidonic Acid / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism; D015777:Eicosanoids / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism / Q000502:physiology; D007527:Isoenzymes / Q000096:biosynthesis*; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008565:Membrane Proteins; D018375:Neutrophil Activation / Q000502:physiology; D009504:Neutrophils / Q000201:enzymology* / Q000378:metabolism / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D018078:Receptors, Prostaglandin E / Q000378:metabolism / Q000502:physiology; D058307:Receptors, Prostaglandin E, EP2 Subtype; D015854:Up-Regulation / Q000502:physiology*
D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015777:Eicosanoids; D007527:Isoenzymes; D008565:Membrane Proteins; C545644:PTGER2 protein, human; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D007975:Leukotriene B4; D016718:Arachidonic Acid; D000242:Cyclic AMP; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000241:Adenosine; D015232:Dinoprostone