Cyclic AMP-elevating agents down-regulate the oxidative burst induced by granulocyte-macrophage colony-stimulating factor (GM-CSF) in adherent neutrophils

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.

Prostaglandin A2triggers a strong oxidative burst in Laminaria: a novel defense inducer in brown algae?

“…To our knowledge, only one case of an oxidative burst triggered by a prostaglandin has been reported in eukaryotes, that of 15-deoxydelta(12,14)-prostaglandin J 2 , an agonist of peroxisome proliferator activated receptor gamma, which induces superoxide anion production in human cells, with an efficacy similar to its action on ERK phosphorylation (Huang et al 2002). In contrast, some prostaglandins have been reported to inhibit the oxidative burst (e.g., Ottonello et al 1995). Also, the oxidative burst observed here is among the strongest in amplitude ever observed in a brown algal system: The PGA 2 -triggered oxidative burst is considerably stronger with up to 5 µmol H 2 O 2 g -1 FW observed, in contrast to around 1 mol H 2 O 2 g -1 FW for oligoguluronates (Küpper et al 2001(Küpper et al , 2002, lipopolysaccharides , polyunsaturated free fatty acids and methyl jasmonate ).…”

Exendin-4 inhibits interleukin-1β-induced iNOS expression at the protein level, but not at the transcriptional and posttranscriptional levels, in RINm5F β-cells

“…Growing evidence suggests that cAMP inhibits most inflammatory reactions such as the production of inflammatory cytokines and oxidative burst (Ottonello et al 1995, Willis & Nisen 1995. However, the role of cAMP in iNOS expression is different depending on the cell types (Galea & Feinstein 1999).…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…However, PGE 2 may also contribute to dysregulated inflammatory responses by increasing vascular permeability that facilitates influx of pro-inflammatory polypeptides. While PGE 2 prolongs neutrophil half-life through upregulation of intracellular cAMP levels and inhibition of apoptosis [113], it also attenuates PMA-, fMLP-or GM-CSF-stimulated ROS and LTB 4 production in neutrophils [114][115][116][117]. The Th2 cytokine IL-13 was found to increase neutrophil PGE 2 production concomitant with increased expression of complement receptor type 1 (CR1) and type 3 (CR3), and increased neutrophil phagocytosis [118].…”