Evidence that biosynthesis of platelet‐activating factor (paf‐acether) by human neutrophils occurs in an intracellular membrane

Ribbes, Gérard; Ninio, Ewa; Fontan, Pascal; Record, Michel; Chap, Hugues; Benveniste, Jacques; Douste‐Blazy, Louis

doi:10.1016/0014-5793(85)80007-7

Cited by 47 publications

(22 citation statements)

References 20 publications

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“…Our findings lead us to conclude that protein kinase C does not activate the acetyltransferase in intact neutrophils. The findings fit a model in which both cPLA2 (30,32) and acetyltransferase are activated in concert by the p38 kinase cascade in response to TNF-␣ and other cytokines.…”

Section: Table Imentioning

confidence: 74%

“…We employed microsomes from unstimulated cells as our acetyltransferase source and evaluated the effect of various recombinant, constitutively activated MAP kinases on acetyltransferase activity. It has been recognized for some time that the acetyltransferase is localized in an internal membrane source (32,33), and although the compartment has not been unequivocally determined, it has been suggested that it resides in either the tertiary granule or endoplasmic reticulum membranes (34). Regardless of the exact source, microsomal fractions were found to contain the highest specific activity of acetyltransferase activity.…”

Section: Activation Of Map Kinase(s) and Acetyltransferase By Tnf-␣ mentioning

confidence: 89%

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Acetyl-CoA:1-O-Alkyl-2-lyso-sn-glycero-3-phosphocholine Acetyltransferase Is Directly Activated by p38 Kinase

Nixon¹,

O’Flaherty²,

Salyer³

et al. 1999

Journal of Biological Chemistry

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Acetyl-CoA:1-O-alkyl-2-lyso-sn-glycero-3-phosphocholine acetyltransferase, along with phospholipase A 2 , is a key regulator of platelet-activating factor biosynthesis via the remodeling pathway. We have now obtained evidence in human neutrophils indicating that this enzyme is regulated by a specific member of the mitogenactivated protein kinases, namely the p38 kinase. We earlier demonstrated that tumor necrosis factor-␣ (TNF-␣) as well as N-formyl-methionyl-leucyl-phenylalanine treatment leads to increased phosphorylation and activation of p38 kinase in human neutrophils. Strikingly, in the present study these stimuli increased the catalytic activity of acetyltransferase up to 3-fold, whereas 4-phorbol 12-myristate 13-acetate, which activates the extracellular-regulated kinases (ERKs) but not p38 kinase, had no effect. Furthermore, a selective inhibitor of p38 kinase, SB 203580, was able to abolish the TNF-␣-and N-formyl-methionyl-leucyl-phenylalanineinduced activation of acetyltransferase. The same effect was not observed in the presence of an inhibitor that blocked ERK activation (PD 98059). Complementing the findings in intact cells, we have shown that recombinant, activated p38 kinase added to microsomes in the presence of Mg 2؉ and ATP increased acetyltransferase activity to the same degree as in microsomes obtained from TNF-␣-stimulated cells. No activation of acetyltransferase occurred upon treatment of microsomes with either recombinant, activated ERK-1 or ERK-2. Finally, the increases in acetyltransferase activity induced by TNF-␣ could be ablated by treating the microsomes with alkaline phosphatase. Thus acetyltransferase appears to be a downstream target for p38 kinase but not ERKs. These data from whole cells as well as cell-free systems fit a model wherein stimulus-induced acetyltransferase activation is mediated by a phosphorylation event catalyzed directly by p38 kinase.

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Section: Table Imentioning

confidence: 74%

Section: Activation Of Map Kinase(s) and Acetyltransferase By Tnf-␣ mentioning

confidence: 89%

Acetyl-CoA:1-O-Alkyl-2-lyso-sn-glycero-3-phosphocholine Acetyltransferase Is Directly Activated by p38 Kinase

Nixon¹,

O’Flaherty²,

Salyer³

et al. 1999

Journal of Biological Chemistry

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“…Human ECs do not appear to use the DTT-insensitive cholinephosphotransferase pathway (Blank et al, 1986;Bussolino, 1987a), but instead synthesize PAF in a two-step reaction in which a phospholipid precursor, 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine, is hydrolyzed by a phospholipase A2 yielding 1-O-alkyl-snglycero-3-phosphocholine, which is then acetylated at the sn-2 position by an acetyltransferase to yield PAF (Prescott et al, 1984;Whatley et al, 1989). Although we cannot exclude the possibility that PAF is synthesized in the plasma membrane, we assume that the major site of PAF synthesis in ECs is the endoplasmic reticulum based on the location of phospholipid synthesis in mammalian cells (Bishop and Bell, 1988), and the localization of PAF acetyltransferase in microsomes from several cells and tissues (Ribbes et al, 1985;Snyder, 1987;Mollinedo et al, 1988). In human PMNs, both PLA2 and acetyltransferase activities are found in intracellular organdies; the acetyltransferase is localized in microsomal and granular fractions (Mollinedo et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

Endothelial cell-associated platelet-activating factor: a novel mechanism for signaling intercellular adhesion.

Zimmerman

McIntyre

Mehra

et al. 1990

The Journal of Cell Biology

358

153

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Abstract. The binding of neutrophils (polymorphonuclear leukocytes [PMNs]) to endothelial cells (ECs) presents special requirements in the regulation of intercellular adhesion. ECs that are stimulated by certain agonists, including thrombin and cytokines (tumor necrosis factor or, interleukin-1), generate molecular signals that induce the adhesion of PMNs (endothelial cell-dependent neutrophil adhesion). Our experiments demonstrate that the mechanism of binding induced by thrombin is distinct from that induced by the cytokines based on the time courses, the requirement for protein synthesis, and differential binding of HL60 promyelocytic leukemia cells to ECs activated by the two classes of agonists. The rapid EC-dependent PMN adhesion (initiated in minutes) that occurs when the ECs are stimulated by thrombin is temporally coupled with the accumulation of platelet-activating factor, a biologically active phosphoglyceride that remains associated with ECs and that activates PMNs by binding to a cell surface receptor. A portion of the newly synthesized plateletactivating factor (PAF) is on the EC surface, as demonstrated by experiments in which the rate of hydrolysis of PAF synthesized by activated ECs was accelerated by extracellular PAF acetylhydrolase. When ECs were treated with exogenous PAF they became adhesive for PMNs; the PMN binding was prevented by incubating the ECs with PAF acetylhydrolase or by treating the PMNs with competitive PAF receptor antagonists. Thus PAF associated with the EC plasma membrane induces PMN binding, an observation supported by experiments in which PAF in model membranes (liposomes) stimulated rapid PMN adhesion to ECs and to cell-free surfaces. In addition, competitive antagonists of the PAF receptor inhibited the binding of PMNs to ECs activated by thrombin and other rapidly acting agonists, but not to ECs activated by tumor necrosis factor c~, indicating that PAF that is endogenously synthesized by ECs can mediate neutrophil adhesion. These experiments demonstrate a novel mechanism by which a cell-associated phospholipid, PAF, can serve as a signal for an intercellular adhesive event.

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“…Cells (lO'/ml in 137 mM NaCl, 2.7 mM KCl, 5.5 mM glucose, 20 mM Hepes, pH 7.4) were isolated on Percoll [16,17]. Cells were then incubated for 15 min at 37°C with ['H]PAF (7-14 nM, 1 ,&i/10' cells) and washed twice with Hepes buffer containing 2.5% (w/v) bovine serum albumin.…”

Section: Cell Incubationmentioning

confidence: 99%

Differential activation by fMet‐Leu‐Phe and phorbol ester of a plasma membrane phosphatidylcholine‐specific phospholipase D in human neutrophil

et al. 1989

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Signal transduction involving phosphatidylcholine hydrolysis has been investigated in human neutrophils (PMN) after in situ generation of PH]alkylacyl-sn-glycero-3-phosphocholine (PHlalkylacyl-GPC) by cell incubation with PH]alkylacetyl-GPC. When PMN were stimulated with the chemotactic peptide N-formyl-Met-Leu-Phe (fMLP) or phorbol myristate acetate (PMA) in the presence of cytochalasin B, both I-0-alkyl-2-acyl-sn-glycero-3-phosphate (PA) and 1-0-alkyl-2-acyl-sn-glycerol (AAG) were generated. On addition of the agonists in the presence of ethanol, phosphatidylethanol (PE) was formed with a concomitant decrease in PA and AAG. These results indicate the presence of a phospholipase D (PLD) acting on phosphatidylcholine in human PMN. The kinetics of hydrolysis were quite different according to the stimulus. Whereas NLP induced a maximum rise in PA and AAG at 3&45 s, these products began to appear only after 1 min upon cell incubation with PMA. Similar amounts of products were formed at 1 mm with !MLP and only at 5 min with PMA. Although similar time courses of PA generation were obtained in the absence of cytochalasin B, AAG were no longer involved and therefore cannot account for intracellular second messenger under physiological conditions. Subcellular distribution studies demonstrated the exclusive location of PA and PE in the plasma membrane. The possible involvement of PA in respiratory burst activation is discussed.

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Evidence that biosynthesis of platelet‐activating factor (paf‐acether) by human neutrophils occurs in an intracellular membrane

Cited by 47 publications

References 20 publications

Acetyl-CoA:1-O-Alkyl-2-lyso-sn-glycero-3-phosphocholine Acetyltransferase Is Directly Activated by p38 Kinase

Acetyl-CoA:1-O-Alkyl-2-lyso-sn-glycero-3-phosphocholine Acetyltransferase Is Directly Activated by p38 Kinase

Endothelial cell-associated platelet-activating factor: a novel mechanism for signaling intercellular adhesion.

Differential activation by fMet‐Leu‐Phe and phorbol ester of a plasma membrane phosphatidylcholine‐specific phospholipase D in human neutrophil

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