1,2‐Diacylglycerol accumulation in human neutrophils does not correlate with respiratory burst activation

Koenderman, Leo; Tool, Anton T.J.; Roos, Dirk; Verhoeven, Arthur J.

doi:10.1016/0014-5793(89)80170-x

Cited by 30 publications

(8 citation statements)

References 25 publications

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“…Thus, if Ras and/or Rap1 are indeed unable to activate Ral, calcium may be responsible for fMLP-and PAF-induced Ral activation. This would be compatible with the notion that GM-CSF does not induce an increase in [Ca 2ϩ ] i (30,40). Indeed, in neutrophils the calcium ionophore ionomycin induces Ral activation, showing that a rise in [Ca 2ϩ ] i is sufficient to activate Ral.…”

Section: Discussionsupporting

confidence: 74%

“…Since an increase in [Ca 2ϩ ] i has been implicated in the activation of Ral (23,24) and GM-CSF does not give rise to [Ca 2ϩ ] i (30) in neutrophils, we have investigated whether calcium is involved in Ral activation in neutrophils. Indeed, the calcium ionophore ionomycin did induce the activation of Ral, showing that changes in [Ca 2ϩ ] i are sufficient to induce Ral activation (Fig.…”

Section: Fig 1 Fmlp-and Paf-induced Activation Of the Smallmentioning

confidence: 99%

“…-Neutrophils were Ca 2ϩ depleted as described before (30). Neutrophils were suspended in Ca 2ϩ -free incubation buffer supplemented with 1 mM EGTA.…”

Section: Depletion Of Intracellular Free Ca 2ϩmentioning

confidence: 99%

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Differential fMet-Leu-Phe- and Platelet-activating Factor-induced Signaling Toward Ral Activation in Primary Human Neutrophils

M’Rabet¹,

Coffer²,

Wolthuis³

et al. 1999

Journal of Biological Chemistry

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We have measured the activation of the small GTPase Ral in human neutrophils after stimulation with fMetLeu-Phe (fMLP), platelet activating factor (PAF), and granulocyte macrophage-colony stimulating factor and compared it with the activation of two other small GTPases, Ras and Rap1. We found that fMLP and PAF, but not granulocyte macrophage-colony stimulating factor, induce Ral activation. All three stimuli induce the activation of both Ras and Rap1. Utilizing specific inhibitors we demonstrate that fMLP-induced Ral activation is mediated by pertussis toxin-sensitive G-proteins and partially by Src-like kinases, whereas fMLP-induced Ras activation is independent of Src-like kinases. PAFinduced Ral activation is mediated by pertussis toxininsensitive proteins, Src-like kinases and phosphatidylinositol 3-kinase. Phosphatidylinositol 3-kinase is not involved in PAF-induced Ras activation. The calcium ionophore ionomycin activates Ral, but calcium depletion partially inhibits fMLP-and PAF-induced Ral activation, whereas Ras activation was not affected. In addition, 12-O-tetradecanoylphorbol-13-acetate-induced activation of Ral is completely abolished by inhibitors of protein kinase C, whereas 12-O-tetradecanoylphorbol-13-acetate-induced Ras activation is largely insensitive. We conclude that in neutrophils Ral activation is mediated by multiple pathways, and that fMLP and PAF induce Ral activation differently.Neutrophils play an important role in the host defense to invading microbial pathogens. Upon infection neutrophils become activated through interaction with chemoattractants and cytokines. These ligands bind to a variety of cell surface receptors, including heterotrimeric G-protein-coupled receptors for fMet-Leu-Phe (fMLP) 1 and platelet activating factor (PAF), and tyrosine kinase-associated receptors for granulocyte-macrophage colony stimulating factor (GM-CSF). Receptor activation triggers intracellular signal transduction pathways, resulting in the correct biological response, for instance, migration, phagocytosis, antibody-dependent cell-mediated cytotoxicity, degranulation, and superoxide production. Improper functioning of neutrophils is implicated in the pathogenesis of a variety of inflammatory diseases resulting in tissue damage (1-5).Activation of small GTPases of the Ras superfamily is thought to play a critical role in the regulation of neutrophil function (6). For instance, Rac1 is implicated in the assembly of the NADPH oxidase complex which generates the respiratory burst and has been demonstrated to be activated (7). Also Ras and its close relative Rap1 are rapidly activated after stimulation of primary human neutrophils with fMLP, PAF, and GM-CSF (8, 9), suggesting a role in initial events of neutrophil activation. Ras controls the Raf-MEK-ERK kinase cascade and, in addition, the regulation of the actin cytoskeleton (10, 11). The function of Rap1 is still largely unclear, although for neutrophils it has been suggested that Rap1 plays a role in the regulation of the respiratory burst (12, 13)....

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Section: Discussionsupporting

confidence: 74%

Section: Fig 1 Fmlp-and Paf-induced Activation Of the Smallmentioning

confidence: 99%

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Differential fMet-Leu-Phe- and Platelet-activating Factor-induced Signaling Toward Ral Activation in Primary Human Neutrophils

M’Rabet¹,

Coffer²,

Wolthuis³

et al. 1999

Journal of Biological Chemistry

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“…In intact PMN, Ohtsuka et al (4) showed that exogenous DG did not stimulate°2 production in guinea pig PMN and Koenderman et al (23) reported that DG accumulation in human PMN stimulated with FMLP did not correlate with 02 consumption. Rossi and his colleagues (24)(25)(26) and Tyagi et al (27), by inhibiting the turnover of phosphoinositides in Ca2+-depleted, FMLP-stimulated PMN, indirectly dissociated PLC-generated DG from NADPH oxidase activation.…”

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confidence: 99%

Phosphatidic acid as a second messenger in human polymorphonuclear leukocytes. Effects on activation of NADPH oxidase.

Agwu¹,

McPhail²,

Sozzani³

et al. 1991

J. Clin. Invest.

161

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IntroductionReceptor-mediated agonists, such as FMLP, induce an early, phospholipase D (PLD)-mediated accumulation of phosphatidic acid (PA) which may play a role in the activation of NADPH oxidase in human PMN. We have determined the effect of changes in PA production on 02 consumption in intact PMN and the level of NADPH oxidase activity measured in a cell-free assay. (13, 14) and others (15-18) have demonstrated that FMLP also activates a phospholipase D (PLD) that hydrolyzes choline-containing phosphoglycerides (PC) such that PA is the first metabolite formed. In this pathway, DG is generated by PA phosphohydrolase (PAP)-catalyzed dephosphorylation of PA (19). The differences in the temporal sequence of formation ofPA and DG via these pathways and the fact that interconversions between these metabolites modulates their accumulation during stimulation, complicate efforts aimed at understanding the individual involvement of PA or DG in the activation of PMN NADPH oxidase.A role for DG (6)(7)(8)(20)(21)(22)

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“…The mechanism of superoxide synthesis in neutrophils has been intensively examined during the past 10 years [Tauber, 1987;Nishizuka, 1988;Sha'afi and Molski, 19881, and NADPH oxidase is known to be a key enzyme of superoxide synthesis. There are two major signaling pathways in the formylmethionyl-leucyl-phenylalanine (fMLP)-induced activation of NADPH oxidase, namely phorbol myristate acetate (PKC)-dependent and PKCindependent pathways [Gerard and McPhail, 1986;Berkow et al, 1987;Nishizuka, 1988;Ohsaka et al, 1988;Watoson et al, 1988;Koenderman et al, 1989;Dusi et al, 19931. The activation of NADPH oxidase in the PKC-dependent pathway was reported to be mediated by the signal transduction mechanism composed of a receptor-linked GTP-binding protein, phospholipase C (PLC), and PKC [Tauber, 1987;Grinstein and Furuya, 1988;Nishizuka, 1988;Combadiere et al, 19901. In fMLP stimulation, activated PLC produced inositol trisphosphate UP31 and diacylglycerol (DAG).…”

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confidence: 99%

Involvement of protein phosphatase 2A in PKC-independent pathway of neutrophil superoxide generation by fMLP

et al. 1996

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We examined the effects of okadaic acid, a protein phosphatase 1 and 2A inhibitor, on superoxide generation in human neutrophils. Superoxide generation induced by fMLP was inhibited by low-dose okadaic acid (10-100 nM), but it had no effect on superoxide synthesis by PMA, and the fMLP-induced rise of the intracellular Ca2+ concentration was not affected by low-dose okadaic acid. These findings suggested that the inhibitory mechanism of okadaic acid might involve PKC-independent and Ca(2+)-independent pathways in fMLP induced NADPH oxidase activation. Both fMLP-stimulated phosphorylation of serine residues in p47phox and its translocation to the plasma membrane were suppressed by low-dose okadaic acid. On the other hand, PMA-induced phosphorylation and translocation of p47phox were not affected by such a low dose of okadaic acid. These findings suggested that fMLP induced phosphorylation of serine residues in p47phox was regulated by protein phosphatase 2A, and its phosphorylation was necessary for translocation and superoxide generation in fMLP-activated human neutrophils.

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1,2‐Diacylglycerol accumulation in human neutrophils does not correlate with respiratory burst activation

Cited by 30 publications

References 25 publications

Differential fMet-Leu-Phe- and Platelet-activating Factor-induced Signaling Toward Ral Activation in Primary Human Neutrophils

Differential fMet-Leu-Phe- and Platelet-activating Factor-induced Signaling Toward Ral Activation in Primary Human Neutrophils

Phosphatidic acid as a second messenger in human polymorphonuclear leukocytes. Effects on activation of NADPH oxidase.

Involvement of protein phosphatase 2A in PKC-independent pathway of neutrophil superoxide generation by fMLP

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