Open AccessCyclic AMP‐elevating agents down‐regulate the oxidative burst induced by granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) in adherent neutrophils
Author(s) -
OTTONELLO L.,
MORONE M. P.,
DAPINO P.,
DALLEGRI F.
Publication year - 1995
Publication title -
clinical & experimental immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 135
eISSN - 1365-2249
pISSN - 0009-9104
DOI - 10.1111/j.1365-2249.1995.tb03141.x
Subject(s) - forskolin , respiratory burst , prostaglandin e2 , activator (genetics) , phosphodiesterase , granulocyte , superoxide , prostaglandin e , granulocyte macrophage colony stimulating factor , biology , adenylate kinase , cyclase , endocrinology , phosphodiesterase inhibitor , medicine , second messenger system , intracellular , microbiology and biotechnology , biochemistry , immunology , cytokine , enzyme , receptor , stimulation
SUMMARY Human neutrophils, plated on fibronectin‐precoated wells, were found to 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.) or blocking its catabolism (RO 20–1724). When added in combination, PGE 2 and RO 20–1724 had a marked synergistic inhibitory effect, which was reproduced by replacing PGE 2 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 PGE 2 are known to be generated at tissue sites of inflammation, the results suggest the existence of a PGE 2 ‐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 PGE 2 ‐dependent pathway and in particular PDE‐IV may represent a pharmacological target to reduce the generation of histotoxic oxidants by GM‐CSF‐responding neutrophils.