Affiliation:
1. First Medical Clinic, Department of Internal Medicine, University of Genova Medical School, Genova, Italy
Abstract
SUMMARY
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 (PGE.) 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.
Publisher
Oxford University Press (OUP)
Subject
Immunology,Immunology and Allergy
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