John Owen - Regulation of platelet-activating factor synthesis in human neutrophils by MAP kinases.

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      Publication Details (including relevant citation   information):

      Biochim Biophys Acta 1592:175-184

      Abstract:

      Human neutrophils (PMN) are potentially a major source of   platelet-activating factor (PAF) produced during inflammatory   responses. The stimulated synthesis of PAF in PMN is carried out   by a phospholipid remodeling pathway involving three enzymes:   acetyl-CoA:lyso-PAF acetyltransferase (acetyltransferase), type   IV phospholipase A(2) (cPLA(2)) and CoA-independent transacylase   (CoA-IT). However, the coordinated actions and the regulatory   mechanisms of these enzymes in PAF synthesis are poorly defined.   A23187 has been widely used to activate the remodeling pathway,   but it has not been shown how closely its actions mimic those of   physiological stimuli. Here we address this important problem and   compare responses of the three remodeling enzymes and PAF   synthesis by intact cells. In both A23187- and   N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated PMN,   acetyltransferase activation is blocked by SB 203580, a p38 MAP   kinase inhibitor, but not by PD 98059, which blocks activation of   the ERKs. In contrast, either agent attenuated cPLA(2)   activation. Correlating with these results, SB 203580 decreased   stimulated PAF formation by 60%, whereas PD 98059 had little   effect. However, the combination of both inhibitors decreased PAF   formation to control levels. Although a role for CoA-IT in PAF   synthesis is recognized, we did not detect activation of the   enzyme in stimulated PMN. CoA-IT thus appears to exhibit full   activity in resting as well as stimulated cells. We conclude that   the calcium ionophore A23187 and the receptor agonist fMLP both   act through common pathways to stimulate PAF synthesis, with p38   MAP kinase regulating acetyltransferase and supplementing ERK   activation of cPLA(2).

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