Inhibition of the phagocytosis-induced respiratory burst by the fungal metabolite wortmannin and some analogues

Baggiolini, Marco; Dewald, Béatrice; Schnyder, J.; Ruch, W.; Cooper, Philip H.; Payne, Trevor

doi:10.1016/0014-4827(87)90201-1

Cited by 133 publications

(71 citation statements)

References 42 publications

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“…Wortmannin (1.0 PM) inhibited 0; release from neutrophils stimulated with 1.0 PM fMLP or 50 nM PMA by 81 f 8% and 8 + 8% (SD., n = 6-7), respectively. Similar observations have been published previously for human neutrophils [7,8]. Neutrophils stimulated with fMLP exhibit a rapid activation of four renaturable protein kinases with molecular masses of ca.…”

Section: Analysts Of Datasupporting

confidence: 88%

“…PMA), or the combination of these agents (e.g, [3,4,6]). Activation of these kinases was blocked by treating the cells with pertussis toxin, which indicates a role for a heterotrimeric G-protein in this response [46]_ Previous studies have shown that the microbial metabolite wortmannin blocks a signal transduction sequence in fMLP-stimulated neutrophils that is necessary for degranulation and 0; production [7,8]. This signal is dependent upon a heterotrimeric G-protein but independent of Ca2+ [8].…”

Section: Introductionmentioning

confidence: 99%

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Wortmannin and 1‐butanol block activation of a novel family of protein kinases in neutrophils

Ding

Badwey

1994

FEBS Letters

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Neutrophils contain four uncharacterized protein kinases with molecular masses of ca. 69, 63, 49 and 40 kDa that are rapidly activated upon stimulation of these cells with the chemoattractant fMet-Leu-Phe [Ding, J. and Badwey, J.A . (1993) J. Biol. Chem. 268,1732617333]. We now report that wortmannin and I-butanol block activation of all four of these kinases. These reagents are known to inhibit superoxide generation in neutrophils stimulated with this agonist. Wortmannin inhibits phosphatidylinositol3-kinase and blocks activation of phospholipase D, whereas I-butanol can reduce the generation of phosphatidate in cells by serving as a substrate for phospholipase D. These data suggest that phosphatidylinositol3-kinase and phospholipase D may be involved in the activation of several novel protein kinases in neutrophils and that one or more of these kinases is/are involved in superoxide release.

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Section: Analysts Of Datasupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Wortmannin and 1‐butanol block activation of a novel family of protein kinases in neutrophils

Ding

Badwey

1994

FEBS Letters

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“…6 B). This IC 50 is similar to that reported for the eff ect of wortmannin on oxidase activity in human and murine macrophages ingesting zymosan particles, where phagocytosis was also relatively preserved (57). Note that PI3 kinase inhibitors do not eliminate PMA-stimulated NADPH oxidase activation in COS phox Fcγ cells (not depicted) or neutrophils (58).…”

Section: Articlesupporting

confidence: 82%

The phosphoinositide-binding protein p40phox activates the NADPH oxidase during FcγIIA receptor–induced phagocytosis

Suh¹,

Stull²,

Li³

et al. 2006

The Journal of Cell Biology

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“…the PI3K-dependent signaling pathway (Fig. 6) may seem to conflict with the evidence that inhibition of PI3K activity by wortmannin or deficiency of PI3KIB results in an impairment of chemoattractant-induced respiratory burst (7,39,40). Indeed, in both mouse and human PMN, wortmannin effectively inhibited fMLPinduced superoxide generation, and in hck Ϫ/Ϫ fgr Ϫ/Ϫ PMNs the drug had a totally suppressive effect (Fig.…”

Section: Figurementioning

confidence: 96%

The Src Family Kinases Hck and Fgr Regulate Neutrophil Responses to N-Formyl-Methionyl-Leucyl-Phenylalanine

Fumagalli

Zhang

Baruzzi

et al. 2007

The Journal of Immunology

106

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The chemotactic peptide formyl-methionyl-leucyl-phenilalanine (fMLP) triggers intracellular protein tyrosine phosphorylation leading to neutrophil activation. Deficiency of the Src family kinases Hck and Fgr have previously been found to regulate fMLP-induced degranulation. In this study, we further investigate fMLP signaling in hck−/−fgr−/− neutrophils and find that they fail to activate a respiratory burst and display reduced F-actin polymerization in response to fMLP. Additionally, albeit migration of both hck−/−fgr−/− mouse neutrophils and human neutrophils incubated with the Src family kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) through 3-μm pore size Transwells was normal, deficiency, or inhibition, of Src kinases resulted in a failure of neutrophils to migrate through 1-μm pore size Transwells. Among MAPKs, phosphorylation of ERK1/2 was not different, phosphorylation of p38 was only partially affected, and phosphorylation of JNK was markedly decreased in fMLP-stimulated hck−/−fgr−/− neutrophils and in human neutrophils incubated with PP2. An increase in intracellular Ca2+ concentration and phosphorylation of Akt/PKB occurred normally in fMLP-stimulated hck−/−fgr−/− neutrophils, indicating that activation of both phosphoinositide-specific phospholipase C and PI3K is independent of Hck and Fgr. In contrast, phosphorylation of the Rho/Rac guanine nucleotide exchange factor Vav1 and the Rac target p21-activated kinases were markedly reduced in both hck−/−fgr−/− neutrophils and human neutrophils incubated with a PP2. Consistent with these findings, PP2 inhibited Rac2 activation in human neutrophils. We suggest that Hck and Fgr act within a signaling pathway triggered by fMLP receptors that involves Vav1 and p21-activated kinases, leading to respiratory burst and F-actin polymerization.

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Inhibition of the phagocytosis-induced respiratory burst by the fungal metabolite wortmannin and some analogues

Cited by 133 publications

References 42 publications

Wortmannin and 1‐butanol block activation of a novel family of protein kinases in neutrophils

Wortmannin and 1‐butanol block activation of a novel family of protein kinases in neutrophils

The phosphoinositide-binding protein p40phox activates the NADPH oxidase during FcγIIA receptor–induced phagocytosis

The Src Family Kinases Hck and Fgr Regulate Neutrophil Responses to N-Formyl-Methionyl-Leucyl-Phenylalanine

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