CYCLIC AMP-ELEVATING AGENTS DOWN-REGULATE THE OXIDATIVE BURST INDUCEDBY GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR (GM-CSF) IN ADHERENT NEUTROPHILS

Human neutrophils, plated on fibronectin-precoated wells, were found t o release large quantities of superoxide anion (O-2(-)) in response to GM-CSF. O(2)(-)production was reduced by prostaglandin E(2) (PGE(2)) 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 (PGE(2)) or blocking its catabolism (RO 20-17 24). When added in combination. PGE(2) and RO 20-1724 had a marked syn ergistic inhibitory effect, which was reproduced by replacing PGE(2) w ith a direct activator of adenylate cyclase, i.e. forskolin (FK). More over, the neutrophil response to GM-CSF was inhibited by a membrane-pe rmeable analogue of cAMP in a dose-dependent manner. As GM-CSF and PGE (2) are known to be generated at tissue sites of inflammation, the res ults suggest the existence of a PGE(2)-dependent regulatory pathway po tentially capable of controlling the neutrophil response to GM-CSF, in turn limiting the risk of local oxidative tissue injury. Moreover, ow ing to its susceptibility to amplification by RO 20-1724, the PGE(2)-d ependent pathway and in particular PDE-IV may represent a pharmacologi cal target to reduce the generation of histotoxic oxidants by GM-CSF-r esponding neutrophils.