Regulation of Phosphatidylinositol 3-Kinase Activity and Phosphatidylinositol 3,4,5-Trisphosphate Accumulation by Neutrophil Priming Agents

Cadwallader, Karen A.; Condliffe, Alison M.; McGregor, Alex; Walker, Trevor R.; White, Jim; Stephens, Len R.; Chilvers, Edwin R.

doi:10.4049/jimmunol.169.6.3336

Cited by 58 publications

(60 citation statements)

References 38 publications

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“…However, this mechanism does not appear to pertain to the neutrophil. We have previously shown that while TNF- § priming enhances fMLP receptorstimulated PtdIns(3,4,5)P 3 accumulation, TNF- § alone has no effect on PtdIns(3,4,5)P 3 accumulation [8], and we now show that LY294002 has no effect on TNF- § -stimulated I ‹ B loss. In contrast, GM-CSF, which activates PI3-kinase and elevates PtdIns(3,4,5)P 3 in human neutrophils, was unable to initiate I ‹ B degradation.…”

Section: Discussionmentioning

confidence: 60%

“…M) that did not affect the intrinsic rate of apoptosis. In contrast, BAY11-7085 over the same concentration range caused a significant increase in early TNF- § -stimulated apoptosis (% apoptosis at 6 h, control 8 Fig. 2A-C).…”

Section: The Role Of the Nf-‹ B Pathway In Gm-csfand Tnf-> -Stimulatementioning

confidence: 88%

“…Cytokinestimulated accumulation of phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P 3 ] [8] activates a number of downstream targets including Akt [9,10]. Akt in turn phosphorylates effector proteins, among these the proapoptotic factor Bad, pro-caspase-9 and the forkhead transcription factors [11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

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The survival effect of TNF‐α in human neutrophils is mediated via NF‐κB‐dependent IL‐8 release

et al. 2004

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The capacity of cytokines to modulate neutrophil apoptosis is thought to be a major factor influencing the resolution of granulocytic inflammation. We have previously shown that the late survival effect of TNF‐α in human neutrophils involves activation of both NF‐κB and phosphoinositide 3‐kinase (PI3‐kinase) pathways. In this study, we address how these pathways integrate to prevent cell death. In human neutrophils, TNF‐α (200 U/ml) induced rapid IκB‐α degradation, NF‐κB activation and IL‐8 release (31.8±5.4 pg/105 cells/2 h), whereas GM‐CSF (10 ng/ml) stimulated an equivalent IL‐8 release (26.5±4.5 pg/105 cells/2 h) without enhanced IκB‐α degradation or NF‐κB activation compared to control. Importantly, inhibition of PI3‐kinase did not modify TNF‐α ‐induced IκB‐α degradation, yet fully inhibited the survival effect of both cytokines. Inhibition of IκB‐α phosphorylation, PI3‐kinase or ERK1/2 activation blocked IL‐8 release by both cytokines. Blocking IL‐8 activity by inhibiting its synthesis or by using a neutralizing antibody enhanced the early pro‐apoptotic effectof TNF‐α and inhibited its late survival effect without affecting GM‐CSF‐induced survival. These data suggest that cross‐talk between NF‐κB and PI3‐kinase pathways in TNF‐α ‐stimulated neutrophils results from NF‐κB/ERK1/2‐dependent IL‐8 production which acts in an autocrine manner to drive PI3‐kinase‐dependent survival. In contrast, GM‐CSF‐mediated survival does not involve NF‐κB activation or IL‐8 release.

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Section: Discussionmentioning

confidence: 60%

Section: The Role Of the Nf-‹ B Pathway In Gm-csfand Tnf-> -Stimulatementioning

confidence: 88%

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The survival effect of TNF‐α in human neutrophils is mediated via NF‐κB‐dependent IL‐8 release

et al. 2004

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“…Ca 2ϩ , PKC, as well as alternative mechanisms stimulate phospholipase D and phospholipase A 2 , which can further feedback on activation of PKC (4 -6). More recently, activation of the ␥ isoform of PI3K (PI3KIB) by the ␤␥ subunits of G␣i, with the consequent increase in phosphorylation of the 3 position in the inositol ring of phosphatidylinositol, has been demonstrated to play an essential role in stimulation of some PMNs responses by fMLP and other chemoattractants (7)(8)(9).…”

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confidence: 99%

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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“…A number of signaling pathways have been implicated in the priming process including the phosphatidylinositol 3-kinase pathway (67,68) and several MAP kinase pathways (69 -76). The involvement of p38 MAPK in priming has been particularly contentious with some groups claiming that p38 MAPK plays a critical role (69,70,72,73), whereas others claim that it plays no role in priming whatsoever, and instead is involved only in the oxidase activation step (77).…”

mentioning

confidence: 99%

Distinct Ligand-dependent Roles for p38 MAPK in Priming and Activation of the Neutrophil NADPH Oxidase

Brown

Stewart

Bissonnette

et al. 2004

Journal of Biological Chemistry

103

108

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In response to certain cytokines and inflammatory mediators, the activity of the neutrophil NADPH oxidase enzyme is primed for enhanced superoxide production when the cells receive a subsequent oxidase-activating stimulus. The relative role of p38 MAPK in the priming and activation processes is incompletely understood. We have developed a 2-step assay that allows the relative contributions of p38 MAPK activity in priming to be distinguished from those involved in oxidase activation. Using this assay, together with in vitro kinase assays and immunochemical studies, we report that p38 MAPK plays a critical role in TNF␣ priming of the human and porcine NADPH oxidase for superoxide production in response to complement-opsonized zymosan (OpZ), but little, if any, role in neutrophil priming by platelet-activating factor (PAF) for OpZ-dependent responses. The OpZ-mediated activation process per se is independent of p38 MAPK activity, in contrast to oxidase activation by fMLP, where 70% of the response is eliminated by p38 MAPK inhibitors regardless of the priming agent. We further report that incubation of neutrophils with TNF␣ results in the p38 MAPK-dependent phosphorylation of a subpopulation of p47 phox and p67 phox molecules, whereas PAF priming results in phosphorylation only of p67 phox . Despite these phosphorylations, TNF␣ priming does not result in significant association of either of these oxidase subunits with neutrophil membranes, demonstrating that the molecular basis for priming does not appear to involve preassembly of the NADPH oxidase holoenzyme/cytochrome complex prior to oxidase activation.The neutrophil NADPH oxidase is a multiprotein enzyme that catalyzes the production of O 2 Ϫ from oxygen using NADPH as an electron donor (1, 2). The O 2 Ϫ is subsequently converted to powerful oxidizing agents such as hypohalides, singlet oxygen, peroxides, and chloramines, which together with proteases and ions, are primarily responsible for neutrophil-mediated killing of microorganisms (2-4). These oxidase products, however, are also highly destructive to nearby tissues (see Refs. 5-7). Consequently, tight temporal and spatial regulation of the oxidase is required so that it is activated only under appropriate circumstances.The NADPH oxidase holoenzyme consists of 6 subunits. In resting cells in which the oxidase is dormant, 4 of the subunits, p47 phox , p67 phox , p40 phox , and the small GTPase Rac2 are localized exclusively in the cytoplasm whereas the remaining two subunits, p22 phox and gp91 phox form a heterodimeric membrane-bound flavocytochrome known as cytochrome b 558 . Exposure of neutrophils to a variety of diverse stimuli results in translocation and docking of the cytosolic subunits with the membrane subunits (3, 8 -19), allowing electrons to flow from p67 phox -bound NADPH to molecular oxygen via an FAD moiety and two heme groups in the membrane-bound cytochrome (20). The subunit translocation and oxidase activation process is complex and requires multisite phosphorylation of the cytosolic subuni...

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Regulation of Phosphatidylinositol 3-Kinase Activity and Phosphatidylinositol 3,4,5-Trisphosphate Accumulation by Neutrophil Priming Agents

Cited by 58 publications

References 38 publications

The survival effect of TNF‐α in human neutrophils is mediated via NF‐κB‐dependent IL‐8 release

The survival effect of TNF‐α in human neutrophils is mediated via NF‐κB‐dependent IL‐8 release

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

Distinct Ligand-dependent Roles for p38 MAPK in Priming and Activation of the Neutrophil NADPH Oxidase

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