Priming of human neutrophil superoxide generation by tumour necrosis factor‐α is signalled by enhanced phosphatidylinositol 3,4,5‐trisphosphate but not inositol 1,4,5‐trisphosphate accumulation

Condliffe, Alison M.; Hawkins, Phillip T.; Stephens, Len R.; Haslett, Christopher; Chilvers, Edwin R.

doi:10.1016/s0014-5793(98)01358-1

Cited by 41 publications

(32 citation statements)

References 41 publications

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“…Ins (1,3,4,5) 6 ) were primed with TNF-␣ (200 U/ml) or GM-CSF (100 ng/ml) for 30 min. Vehicle or fMLP (100 nM) was added for the indicated times and the reactions were stopped by the addition of methanol/chloroform (2:1, v/v).…”

Section: O 2 ϫ Release Assaymentioning

confidence: 99%

“…N eutrophil priming refers to a process whereby exposure of these cells to various inflammatory mediators (e.g., LPS, TNF-␣, or GM-CSF) greatly enhances subsequent agonist-induced respiratory burst activity and degranulation responses (1). While this event improves the ability of neutrophils to locate and kill invading microorganisms, priming is also implicated in neutrophil-mediated tissue injury both in vitro and in vivo (2,3).…”

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confidence: 99%

“…Hence, the recruitment of large numbers of such hyperresponsive cells at an inflammatory focus may predispose to tissue injury and contribute to a variety of neutrophil-mediated diseases, including acute respiratory distress syndrome, rheumatoid arthritis, and ischemia-reperfusion injury (4). Priming also has a direct effect on neutrophil shape, deformability, integrin/selectin expression, and longevity (1,5), and, as a consequence, has a profound effect on the rheological, adhesive, and survival properties of these cells in vivo (6). More recently we have shown that priming is a reversible process and that neutrophils can cycle among unprimed, primed, deprimed, and reprimed states (7), underscoring the dynamic nature of this process.…”

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confidence: 99%

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

Cadwallader

Condliffe

McGregor

et al. 2002

The Journal of Immunology

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Neutrophil priming by agents such as TNF-α and GM-CSF causes a dramatic increase in the response of these cells to secretagogue agonists and affects the capacity of neutrophils to induce tissue injury. In view of the central role of phosphatidylinositol 3-kinase (PI3-kinase) in regulating NADPH oxidase activity we examined the influence of priming agents on agonist-stimulated phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) accumulation in human neutrophils. Pretreatment of neutrophils with TNF-α or GM-CSF, while not influencing fMLP-stimulated PtdIns(3,4,5)P3 accumulation at 5 s, caused a major increase in PtdIns(3,4,5)P3 at later times (10–60 s), which paralleled the augmented superoxide anion (O2−) response. The intimate relationship between PtdIns(3,4,5)P3 accumulation and O2− release was confirmed using platelet-activating factor, which caused full but transient priming of both responses. Likewise, LY294002, a PI3-kinase inhibitor, and genistein, a tyrosine kinase inhibitor, caused parallel inhibition of O2− generation and PtdIns(3,4,5)P3 accumulation; in contrast, radicicol, which inhibits receptor-mediated activation of p85 PI3-kinase, had no effect on either response. Despite major increases in PI3-kinase activity observed in p85 and anti-phosphotyrosine immunoprecipitates in growth factor-stimulated smooth muscle cells, no such increase was observed in primed/stimulated neutrophils. In contrast, both fMLP and TNF-α alone caused a 3-fold increase in PI3-kinase activity in p110γ PI3-kinase immunoprecipitates. p21ras activation (an upstream regulator of PI3-kinase) was unaffected by priming. These data demonstrate that timing and magnitude of PtdIns(3,4,5)P3 accumulation in neutrophils correlate closely with O2− generation, that PI3-kinase-γ is responsible for the enhanced PtdIns(3,4,5)P3 production seen in primed cells, and that factors other than activation of p21ras underlie this response.

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Section: O 2 ϫ Release Assaymentioning

confidence: 99%

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confidence: 99%

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

Cadwallader

Condliffe

McGregor

et al. 2002

The Journal of Immunology

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“…p40 phox and p47 phox contain PX domains that bind to PI(3)P and PI(3,4)P 2 , respectively (28). Inhibition of PI3K through wortmannin treatment inhibits the oxidative burst in neutrophils (29). The p40 phox -dependent activation of NOX2 during Fc receptor-mediated phagocytosis requires the presence of PI(3)P on phagosome membranes (26,30).…”

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confidence: 99%

SHIP-1 Increases Early Oxidative Burst and Regulates Phagosome Maturation in Macrophages

Kamen

Levinsohn

Cadwallader

et al. 2008

The Journal of Immunology

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Although the inositol phosphatase SHIP-1 is generally thought to inhibit signaling for Fc receptor-mediated phagocytosis, the product of its activity, phosphatidylinositol 3,4 bisphosphate (PI(3,4)P2), has been implicated in activation of the NADPH oxidase. This suggests that SHIP-1 positively regulates the generation of reactive oxygen species after phagocytosis. To examine how SHIP-1 activity contributes to Fc receptor-mediated phagocytosis, we measured and compared phospholipid dynamics, membrane trafficking, and the oxidative burst in macrophages from SHIP-1-deficient and wild-type mice. SHIP-1-deficient macrophages showed significantly elevated ratios of PI(3,4,5)P3 to PI(3,4)P2 on phagosomal membranes. Imaging reactive oxygen intermediate activities in phagosomes revealed decreased early NADPH oxidase activity in SHIP-1-deficient macrophages. SHIP-1 deficiency also altered later stages of phagosome maturation, as indicated by the persistent elevation of PI(3)P and the early localization of Rab5a to phagosomes. These direct measurements of individual organelles indicate that phagosomal SHIP-1 enhances the early oxidative burst through localized alteration of the membrane 3′-phosphoinositide composition.

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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).…”

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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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Priming of human neutrophil superoxide generation by tumour necrosis factor‐α is signalled by enhanced phosphatidylinositol 3,4,5‐trisphosphate but not inositol 1,4,5‐trisphosphate accumulation

Cited by 41 publications

References 41 publications

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

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

SHIP-1 Increases Early Oxidative Burst and Regulates Phagosome Maturation in Macrophages

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

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