John Owen - Stress-induced platelet-activating factor synthesis in human neutrophils.

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      Publication Details (including relevant citation   information):

      Biochim Biophys Acta 1733:120-129

      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.

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