Cyclic AMP-elevating agents down-regulate the oxidative burst induced by granulocyte-macrophage colony-stimulating factor (GM-CSF) in adherent neutrophils.
Human neutrophils, plated on fibronectin-precoated wells, were found to release large quantities of superoxide anion (O2-) in response to GM-CSF. O2- production was reduced by prostaglandin E2 (PGE2) and the phosphodiesterase type IV (PDE IV) inhibitor RO 20-1724. Both agents are known to increase intracellular cyclic AMP (cAMP) levels by inducing its production (PGE2) or blocking its catabolism (RO 20-1724). When added in combination, PGE2 and RO 20-1724 had a marked synergistic inhibitory effect, which was reproduced by replacing PGE2 with a direct activator of adenylate cyclase, i.e. forskolin (FK). Moreover, the neutrophil response to GM-CSF was inhibited by a membrane-permeable analogue of cAMP in a dose-dependent manner. As GM-CSF and PGE2 are known to be generated at tissue sites of inflammation, the results suggest the existence of a PGE2-dependent regulatory pathway potentially capable of controlling the neutrophil response to GM-CSF, in turn limiting the risk of local oxidative tissue injury. Moreover, owing to its susceptibility to amplification by RO 20-1724, the PGE2-dependent pathway and in particular PDE-IV may represent a pharmacological target to reduce the generation of histotoxic oxidants by GM-CSF-responding neutrophils.
Ottonello
L
L
Department of Internal Medicine, University of Genova Medical School, Italy.
Morone
M P
MP
Dapino
P
P
Dallegri
F
F
D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D002448:Cell Adhesion; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D015536:Down-Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009504:Neutrophils / Q000502:physiology*; D016897:Respiratory Burst / Q000187:drug effects*
D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000242:Cyclic AMP; D015232:Dinoprostone