Faculty Collaboration Database

Stress-induced platelet-activating factor synthesis in human neutrophils. Biochim Biophys Acta 2005 Apr 15;1733(2-3):120-9

Date

05/03/2005

Pubmed ID

15863359

DOI

10.1016/j.bbalip.2004.12.016

Scopus ID

2-s2.0-18044389685 (requires institutional sign-in at Scopus site)   23 Citations

Abstract

Platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine; PAF) is a potent inflammatory mediator produced by cells in response to physical or chemical stress. The mechanisms linking cell injury to PAF synthesis are unknown. We used liquid chromatography-tandem mass spectrometry to investigate stress-induced PAF synthesis in human neutrophils. PAF synthesis induced by extracellular pH 5.4 correlated with the activation of a stress-activated kinase, p38 mitogen-activated protein kinase (MAPK), and was blocked by the p38 MAPK inhibitor SB 203580. A key enzyme of PAF synthesis, acetyl-CoA:lysoPAF acetyltransferase, which we have previously shown is a target of p38 MAPK, was also activated in an SB 203580-sensitive fashion. Another MAPK pathway, extracellular signal-regulated kinase-1/2 (ERK-1/2), was also activated. Surprisingly, the pharmacological blockade of the ERK-1/2 pathway with PD 98059 did not block, but rather enhanced, PAF accumulation. Two unexpected actions of PD 98059 may underlie this phenomenon: an augmentation of stress-induced p38 MAPK phosphorylation and an inhibition of PAF catabolism. The latter effect did not appear to be due to a direct inhibition of PAF acetylhydrolase. Finally, similar results were obtained using another form of cellular stress, hypertonic sodium chloride. These data are consistent with a model in which stress-induced PAF accumulation is regulated positively by p38 MAPK and negatively by ERK-1/2. Such a model contrasts with the PAF accumulation induced by other forms of stimulation, which we and others have found is up-regulated by both p38 MAPK and ERK-1/2.

Author List

Owen JS, Baker PR, O'Flaherty JT, Thomas MJ, Samuel MP, Wooten RE, Wykle RL

MESH terms used to index this publication - Major topics in bold

Acetyltransferases
Chromatography, Liquid
Dimethyl Sulfoxide
Enzyme Activation
Enzyme Inhibitors
Humans
Hydrogen-Ion Concentration
Imidazoles
Mass Spectrometry
Neutrophils
Osmotic Pressure
Oxidative Stress
Phosphorylation
Platelet Activating Factor
Pyridines
p38 Mitogen-Activated Protein Kinases