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(Journal of Leukocyte Biology. 2002;71:695-700.)
© 2002 by Society for Leukocyte Biology

Contribution of phopholipase D and a brefeldin A-sensitive ARF to chemoattractant-induced superoxide production and secretion of human neutrophils

Krisztina Káldi*, Júlia Szeberényi*, Balázs K. Rada*, Péter Kovács{dagger}, Miklós Geiszt*, Attila Mócsai* and Erzsébet Ligeti*

Departments of
* Physiology, and
{dagger} Genetics, Cell and Immunobiology, Semmelweis University, Budapest, Hungary

Correspondence: Dr. Erzsébet Ligeti, Department of Physiology, Semmelweis University, Puskin u.9., H-1088 Budapest, Hungary. E-mail: ligeti{at}puskin.sote.hu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We show that blockers of phospholipase D (PLD) reduce fMLP-triggered exocytosis of secretory vesicles effectively. In accordance with this, the PLD product phosphatidic acid (PA) was able to induce mobilization of secretory vesicles. Although PLD seems to play a role in the release of all neutrophil granule types, exogenous PA alone was not sufficient to activate the exocytosis of primary and secondary granules, suggesting that in the case of these granules, additional signaling factors are required to initiate the secretory responses. The ADP-ribosylation factor (ARF)-inhibitor brefeldin A (BFA) inhibited the fMLP-stimulated O2·- production strongly, whereas it did not influence any of the exocytic responses, and no significant effect of BFA was detected on the O2·- generation induced by other stimuli. On the basis of these results, we propose that upon chemoattractant stimulation, PLD activity is involved in induction of degranulation and O2·- production, but a BFA-sensitive ARF is only required to the activation of the NADPH oxidase. This ARF action seems to participate exclusively in the signaling pathway between the fMLP receptor and the oxidase.

Key Words: phagocytes • NADPH oxidase • fMLP receptor • secretory vesicles


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Stimulation of neutrophil granulocytes by chemotactic agents leads to the induction of multiple microbicidal reactions including the generation of reactive oxygen intermediates and the secretion of granule constituents. Among the mobilizable intracellular membrane compartments of neutrophils secretory vesicles become released most rapidly following activation by inflammatory stimuli. Exocytosis of secretory-vesicle membrane content, including integrins, different chemotactic receptors, and the cytochrome component of the O2·--producing reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, strongly augments the responsiveness of neutrophils at all stages of their microbicidal action [1 ]. Although the contribution of secretory-vesicle release to the neutrophil-effector reactions was indicated in many cases (e.g., refs. [2 3 4 ]; for review, see ref. [1 ]), very little is known about the signaling pathways regulating the process. It is important that although chelation of intracellular calcium [5 ], inhibition of phosphatidylinositol-3-kinases [6 ], or pretreatment with broad-spectrum or Src-family tyrosine-kinase inhibitors or with inhibitors of the p38 mitogen-activated protein kinase pathway [7 ] strongly inhibit the O2·- production and exocytosis of primary and secondary granules, none of these interventions causes any significant inhibition of the formyl-Met-Leu-Phe (fMLP)-induced release of secretory vesicles.

A role for phospholipase D (PLD) was suggested in the signal transduction from the chemotactic receptor to a variety of responses. PLD catalyzes the hydrolysis of phosphatidylcholine to produce phosphatidic acid (PA), which is converted into diradylglycerol subsequently. Ethanol, an inhibitor of PA formation, and propranolol, a blocker of diradylglycerol production, were shown to reduce fMLP-induced NADPH oxidase activation [8 , 9 ] and exocytosis of specific granules in human neutrophils [9 ]. Ethanol also inhibits secretion of primary granule constituents in fMLP-stimulated HL60 cells and rabbit neutrophils [10 , 11 ], but propranolol has no influence on this process, indicating that PA is a more important regulator of this secretory function than diradylglycerol [11 ].

As shown in different cell types, PLD may be a downstream effector of the small GTPase adenosine 5'-diphosphate (ADP)-ribosylation factor (ARF; e.g., refs. [12 , 13 ]). In neutrophils and neutrophil-like HL60 cells, ARF1 was suggested to control PLD activity. In HL60 cells depleted of freely diffusible cytosolic proteins, recombinant ARF1 was shown to restore guanosine 5'-triphosphate (GTP){gamma}S-stimulated PLD activity and the secretion of primary granules [14 ]. In cytosol-depleted human neutrophils, the ability of fMLP to stimulate PLD was dependent on the readdition of ARF1 to the cells [15 ]. In the same study, fMLP-induced translocation of endogenous ARF to membranes was demonstrated. In a recent study performed on neutrophil-like PLB-985 cells, a regulatory role for ARF6 in the fMLP-induced stimulation of the NADPH oxidase was proposed [16 ]. Unfortunately, only the effect of the overexpression of ARF1 and ARF6 mutants was investigated in this paper, and influence of deletion of the endogenous ARFs was not shown.

Although many data support the view that ARF proteins contribute to the PLD activity in phagocytes, our knowledge about the functional role of the putative ARF-PLD pathway in the mediation of the neutrophil-effector reactions is poor. The aim of the present study was to analyze the participation of ARF and PLD in the chemoattractant-induced activation of neutrophils. By using different inhibitors, we show that exocytosis of secretory vesicles following chemotactic stimulus depends on PLD activity. In contrast to the release of other neutrophil granule types, the PLD product PA is sufficient to induce this secretory response. Brefeldin A (BFA), a specific blocker of ARF action (e.g., refs. [17 18 19 ]), inhibits fMLP-stimulated O2·- production effectively, but it has no, or minor, influence on the degranulation and O2·- production induced by other stimuli. Our results suggest that upon activation of the fMLP receptor, partially different signaling events lead to the stimulation of the various effector reactions. Although PLD is involved in the induction of O2·- production and degranulation, a BFA-sensitive ARF-guanine nucleotide-exchange factor (GEF) complex regulates the NADPH oxidase exclusively.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Materials
Dextran T-500 and Ficoll-Paque were obtained from Pharmacia (Uppsala, Sweden). fMLP, cytochalasin B (CB), 4-methylumbelliferyl-ß-D-glucuronide, L-{alpha}-phosphatidylserine, and BFA were from Sigma Chemical Co. (St. Louis, MO). Human lactoferrin (Lfr), human serum albumin (HSA), anti-human Lfr (rabbit), and anti-HSA (goat) antibodies were from Sigma Chemical Co. Horseradish peroxidase-labeled antibodies were obtained from Nordic Immunological Laboratories (Tilburg, The Netherlands). 1-O-[3H]Octadecyl lyso platelet-activating factor (PAF) was purchased from Amersham Pharmacia Biotech (Little Chalfont, UK). Incubation media were prepared using sterile and endotoxin-free water. For preparation of the stock solution, L-{alpha}-phosphatidic acid (1,2-diacyl-sn-glycero-3-phosphate; Sigma Chemical Co.) was solved in chloroform (25 mg/ml), added to Hanks’ balanced saline solution (HBSS; 5 mg/ml), and sonicated.

Preparation of human neutrophils
Venous blood was drawn from healthy volunteers who gave written, informed consent and were treated according to the prescriptions of the Journal of Physiology and the Ethical Committee of the Semmelweis University (Budapest, Hungary). After dextran sedimentation at room temperature, neutrophils were obtained by centrifugation at 4°C through Ficoll-Paque followed by hypotonic lysis of erythrocytes [7 ]. Cells were resuspended in ice-cold HBSS and kept on ice until use. The preparations usually contained >98% polymorphonuclear cells; the viability, as determined by the erythrosin B dye-exclusion test, was >98%. Preparation was carried out under sterile conditions by using media prepared with endotoxin-free water. Where indicated, nonsterile cells were used, which were prepared in a similar way but without using endotoxin-free water.

Viability of the cells was also controlled following alcohol treatment and incubation with fMLP. Primary alcohols did not influence the ability of the cells to exclude erythrosin B significantly (unpublished results).

Degranulation of human neutrophils
Human neutrophils at 106/ml were incubated in HBSS with or without the indicated inhibitors and/or 10 µM CB for 10 min on ice and for a further 10 min at 37°C. The cells were then stimulated for 10 min with 500 nM fMLP or 50 nM phorbol 12-myristate 13-acetate (PMA). The reaction was stopped by cooling, and the suspension was centrifuged for 10 min at 2000 g at 4°C. The extent of degranulation was determined by measuring the concentration of the different granule markers in the supernatant. Controls were carried out with the same amount of the solvents of inhibitors and stimulators.

The activity of the primary granule marker ß-glucuronidase (ß-GU) was determined by a fluorimetric assay as described previously [20 ]. Total cellular ß-GU activity was also measured, using suspensions treated with 0.02% cetyl-trimethyl-ammonium bromide as detergent. Concentration of the secondary granule marker Lfr [1 ] and of HSA, a marker of secretory vesicles [21 ], was determined by enzyme-linked immunosorbent assay as described in [7 ].

Formation of PA from 1-O-[;3H]octadecyl lyso PAF under conditions of the degranulation assay was monitored according to ref. [15 ].

Measurement of O2·- production
O2·- production of human neutrophil granulocytes was determined by the superoxide-dismutase-inhibitable reduction of ferricytochrome c as described [20 ]. Absorption of unstimulated samples was substracted, and O2·- production was calculated using an absorption coefficient of 21.1 mM-1 · cm-1. Alternatively, O2 consumption in response to opsonized Escherichia coli (ML-35) was measured under similar conditions with a Clark-type oxygen electrode [22 , 23 ]. O2·- production in the cell-free system was determined by combining neutrophil cytosol and membrane fractions in the presence of arachidonic acid as described [24 ].

Presentation of data and statistical analysis
Assays were performed in triplicates or quadriplicates. In case of stimulation in the presence of CB, nonstimulated cells were also pretreated with CB. Nonstimulated values were subtracted from the stimulated ones, and in some cases, the obtained data were expressed in percent of similarly calculated values in the absence of inhibitors (control). Mean ± SE of these values from the indicated number of parallel measurements or experiments is provided.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Conditions of preparation determine responsiveness of human neutrophils to fMLP
In human neutrophil granulocytes prepared under nonsterile conditions, only a negligible amount of secretory-vesicle content HSA can be detected (unpublished results), indicating that these cells lose their secretory vesicles during the preparation process. To avoid this spontaneous release of secretory vesicles and possible priming of the cells, degranulation experiments were carried out with human neutrophils prepared under sterile and pyrogen-free conditions [7 ]. However, chemoattractant-induced O2·- production of these cells was only about 20% of that measured on nonsterile cells, whereas upon PMA stimulation or after pretreatment with CB, the differently prepared cells produced a comparable amount of O2·- (Table 1) . Apparently, activation of NADPH oxidase initiated by ligand binding to the fMLP receptors requires priming effects and/or translocation of elements from primary or secondary granules mobilized by CB. This is in accordance with the previous observation that no fMLP-activated exocytosis of primary granules and only minimal mobilization of secondary granules could be detected in the absence of CB [7 ]. Thus, throughout this paper, O2·- production and release of primary and secondary granules of cells are shown, which were prepared under sterile conditions and pretreated with CB. None of these responses were activated by CB alone.


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  		Table 1. Influence of Conditions of Preparation on the O2·- Production of Neutrophils

 
PLD blockers inhibit chemoattractant-induced release of secretory vesicles
PLD activity is increased after chemotactic stimulation, and PLD was shown to mediate the effect of fMLP on the release of primary and secondary granules and superoxide production [8 , 9 , 11 ]. To determine the involvement of PLD in the activation of the release of secretory vesicles, we applied different primary alcohols to reduce PA production by PLD. The PLD blocker, ethanol, inhibited the fMLP-induced release of the secretory vesicle marker, HSA (Fig. 1A ), whereas it had weak influence on the PMA-activated response.The experiments summarized in Figure 1A were carried out in the presence of the microfilament-disrupting agent CB, but identical results were obtained in the absence of CB (unpublished results). Surprisingly, ethanol was found by other authors (unpublished results mentioned in ref. [25 ]) not to inhibit the fMLP-stimulated mobilization of secretory vesicles. To confirm that the action of ethanol in our experiments can be attributed to the inhibition of PLD, we tested the effect of 1-butanol, which also serves as a substrate for PLD, leading to the formation of phosphatidylbutanol instead of PA [16 ]. As a control, we used tert-butanol, which is not a substrate, and thus not a competitive inhibitor of PLD. We compared the effect of both butanol forms on the HSA release to that on the exocytosis of the primary and secondary granule markers, ß-GU and Lfr. 1-Butanol, added in a relatively low concentration (0.2%), reduced the fMLP-stimulated exocytosis of all three granule markers, whereas tert-butanol had little effect on these processes (Fig. 1B) . In a PLD assay, the same amount of 1-butanol suppressed the fMLP-induced PA formation by about 90%. These findings suggest that similar to the release of other granule types, PA formation is important for the fMLP-dependent stimulation of the release of secretory vesicles.



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  		Figure 1. Effect of PLD inhibitors on the fMLP (A and B) and PMA (A)-induced release of ß-GU (B), Lfr (B), and HSA (A and B) from human neutrophils. CB-treated cells were preincubated with or without 1% ethanol (A), 0.2% 1-butanol (B), or 0.2% tert-butanol (B), followed by stimulation for 10 min with 500 nM fMLP or 50 nM PMA, respectively. (A) Results are mean ± SE of three parallels and are representative of three similar experiments, each performed in triplicates. (B) Data represent the mean ± SE of results from three experiments, each performed in quadriplicates. Control values (100%) corresponded to 35 ± 5% of the total cellular ß-GU content in the case of primary granules, 4.93 ± 1.0 µg Lfr/106 cells in the case of secondary granules, and 65 ± 10 ng HSA/106 cells in the case of secretory vesicles (n=3).

 
Exogenous PA can induce the release of secretory vesicles and O2·- production
To further analyze the role of PA in the mediation of neutrophil-effector reactions, we added exogenous PA to the cells, which stimulated the exocytosis of the secretory-vesicle marker HSA in a dose-dependent manner (Fig. 2 ). As Table 2 shows, 45 µg/ml PA and 500 nM fMLP released comparable amounts of HSA from the cells. The ability of PA to induce the exocytosis of secretory-vesicle content was independent of the presence of CB. Similar to the release of HSA and in accordance with the results of Tokumura et al. [26 ], the same amount of exogenous PA activated the O2·- production (up to 15 nmol O2·-/10 min/106 cells). In contrast to this, under the same experimental conditions, PA did not induce significant release of the markers of primary and secondary granules (Table 2) , pointing to differential requirements for the release of the three compartments and also indicating that the effect of PA on HSA release was not a result of nonspecific lysis of the cells. To further confirm the specificity of the action of PA on the exocytosis of secretory vesicles, the effect of other lipids was also tested. Applied in comparable concentrations, linolenic acid stimulated no measurable HSA release. Treatment of the cells with the same amount of phosphatidylserine, which similar to PA, contains a negatively charged head, resulted in only 25.2 ± 2.7% (n=3) of the PA-induced response.



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  		Figure 2. Stimulation of HSA secretion by exogenous PA. Human neutrophils were preincubated with 10 µM CB and were stimulated with the indicated concentrations of PA for 10 min. Maximum corresponded to the amount of HSA released by 100 µg/ml PA. Data are mean ± SE of three parallel measurements and representative of three similar experiments performed on separate neutrophil preparations.

 

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  		Table 2. Effect of PA on the Degranulation of Neutrophils

 
BFA blocks fMLP-induced O2·- production
Because data from our above experiments and from others suggest that PLD plays a central role in the mediation of chemoattractant-dependent activation of neutrophils [8 9 10 11 ] and because ARF was shown to control fMLP-induced PLD stimulation in these cells [14 , 15 ], we investigated the possible involvement of ARF in the regulation of O2·- production and secretion of fMLP-stimulated neutrophils. For blocking ARF, BFA was used, which interacts with several ARF-GEF complexes directly [18 , 19 ]. BFA, applied in similar amounts, which were found to block ARF action specifically in different systems [27 28 29 ], inhibited the fMLP-induced O2·- production effectively and in a concentration-dependent manner (Fig. 3 ). BFA (60 µg/ml) reduced the O2·- formation to 12.4 ± 5.45% (n=4) of the control. In the next experiments, we investigated the effect of BFA on other signaling routes activating the NADPH oxidase. As shown in Figure 3B , BFA had hardly any effect on the O2·- production stimulated by PMA or opsonized bacteria. Because PA was shown to activate the NADPH oxidase under in vitro conditions [30 ], we also tested the action of BFA in a cell-free activation system. Preincubation of the reaction mixture with BFA did not significantly alter the O2·- generation induced by arachidonic acid as amphiphil (unpublished results).



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  		Figure 3. Effect of BFA on the O2·- production of human neutrophils. Human neutrophils were preincubated with or without BFA at the indicated concentrations followed by stimulation with 500 nM fMLP (A and B), 50 nM PMA (B), or 10 opsonized E. coli /cell (B). Cells were treated with 10 µM CB before stimulation with fMLP or PMA. (A) Data are mean ± SE of three parallel measurements and representative of three similar experiments, each performed in triplicates on separate neutrophil preparations. (B) Data represent the mean ± SE of results from the indicated number of experiments, each performed in quadriplicates. Control values (100%) corresponded to 8.89 ± 3.48 nmol O2·-/10 min/106 cells (n=5) in the case of fMLP stimulation, 25.58 ± 8.14 nmol O2·-/10 min/106 cells (n=3) in the case of PMA stimulation, and 3.7 ± 2.6 nmol O2/10 min/106 cells (n=3) in the case of bacterial stimulation.

 
Because fMLP-stimulated exocytosis of all three granule types was found to be PLD-dependent, the effect of ARF inhibition on the chemoattractant-activated degranulation was also investigated. BFA, applied in a concentration inhibiting the fMLP-induced O2·- production almost completely, did not influence the release of primary and secondary granules and secretory vesicles (Fig. 4 ).



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  		Figure 4. Influence of BFA on the chemoattractant-induced degranulation. Human neutrophils were preincubated with or without 60 µg/ml BFA in the presence of 10 µM CB, followed by stimulation with 500 nM fMLP for 10 min. Data are mean ± SE of four parallel measurements and representative of six similar experiments performed on separate neutrophil preparations in triplicates.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although secretory vesicles were described as intracellular compartments that become mobilized upon chemoattractant stimulation of the cells [31 ], information is still lacking about the signal-transducing steps leading from the chemotactic receptors to the exocytosis of these vesicles. In fact, a number of inhibitors targeting different intracellular signaling pathways had been shown to have no, or negligible, effects on the chemoattractant-induced release of secretory vesicles [5 6 7 ]. In this study, we show that primary alcohols, inhibitors of PLD, block the fMLP receptor-mediated release of secretory vesicles effectively in human neutrophils. Capability of exogenous PA to induce HSA secretion supports the suggestion that PLD participates in the regulation of this secretory response. Taken together, these findings suggest that the PLD-generated PA plays a central role in signaling the release of secretory vesicles, being necessary and sufficient for this response. To our knowledge, the PLD signaling pathway is the first to be likely to participate in the fMLP-induced exocytosis of secretory vesicles.

Although inhibitors of the PLD pathway also reduced the exocytosis of primary and secondary granules, exogenously added PA alone did not induce any release of these compartments, indicating that in contrast to the secretory vesicles, formation of PA by PLD must be supplemented by other signaling events to cause release of primary and secondary granules.

We found that the ARF blocker BFA very effectively inhibited the O2·- generation stimulated by the chemoattractant. In contrast to PLD, which seems to be involved in most responses initiated by ligand binding to the chemoattractant receptor, a BFA-sensitive ARF-GEF interaction seems to mediate only the fMLP-induced activation of the NADPH oxidase but not the degranulation response. O2·- production induced by PMA or opsonized bacteria was influenced only marginally by BFA, indicating that a significant part of the signaling pathways leading from PKC or the opsonin receptors to NADPH oxidase bypasses the BFA-sensitive ARF-GEF complex. The finding that BFA did not influence O2·- generation in the in vitro activation system also suggests that the BFA-inhibitable ARF mediates the signal transduction related specifically to the fMLP receptor. This is the first presentation of the fact that a microbicidal reaction of neutrophils is mediated by a pathway containing a BFA-sensitive step.

The ARF action demonstrated in our experiments is probably different from that described by Dana et al. [16 ], because ARF6, which they proposed to enhance NADPH oxidase activity in PLB-985 cells, is considered to be controlled by BFA-insensitive GEFs [32 , 33 ]. BFA-sensitive PLD activation was described in several systems and was suggested to be mediated by class I ARFs, such as ARF1 and -3 (e.g., refs. [28 , 29 , 34 ]). Mitchell et al. [28 ] showed that upon binding of agonists, a subgroup of rhodopsin-family receptors forms BFA-sensitive, functional complexes with ARF and Rho. Interaction of the receptor with the small GTPases was suggested to be dependent on the presence of a NPXXY motif in the seventh transmembrane domain of the receptor. The fMLP receptor also carries this amino acid sequence, thus its similar interaction with a BFA-sensitive ARF can be assumed. Whether the PLD involved in the fMLP-activated O2·- production is coupled to the BFA-inhibitable ARF remains to be determined. Concentration dependence of the BFA sensitivity of receptor-mediated PLD activation [28 , 29 ] corresponded to that found for the fMLP-stimulated O2·- production (Fig. 3A) . However, in HL60 cells, fMLP-dependent PLD activity was shown to be BFA-insensitive [35 ]. This discrepancy may result from the fact that whole-cell measurement of PLD activity does not necessarily reflect local activities, which may also regulate important cellular functions, in this case, O2·- production. Alternatively, BFA-sensitive ARF may act independently of PLD. Recent data indicate that binding ARF proteins and Rac to Arfaptin is mutually exclusive, and it has been suggested that activation of ARF leads to its binding to Arfaptin and releasing of Rac for signaling activity [36 ]. In neutrophils, the released Rac could react subsequently with the oxidase and in this way, contribute to the stimulation of O2·- generation. Activation of NADPH oxidase by this mechanism may represent a new example of cross-talk between different subfamilies of the small GTPase superfamily.

In conclusion, we suggest that upon activation of the fMLP receptor, the signaling pathway diverges at a certain level: A BFA-sensitive ARF action is involved in the stimulation of the O2·- production, whereas this small G protein does not seem to participate in inducing exocytosis.


   ACKNOWLEDGEMENTS
 
This work was supported by the Hungarian National Scientific Research Fund (OTKA, T 025078 and F 034204), the Hungarian Ministry of Education (0156/2001), and the Hungarian Ministry of Health (316/2000). K. K. was supported by a postdoctoral fellowship (Bolyai) of the Hungarian Academy of Sciences. We thank Erzsébet Seres-Horváth and Edit Fedina for expert technical assistance.

Received July 16, 2001; revised November 8, 2001; accepted November 29, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Borregaard, N., Lollike, K., Kjeldsen, L., Sengelov, H., Bastholm, L., Nielsen, M. H., Bainton, D. F. (1993) Human neutrophil granules and secretory vesicles Eur. J. Haematol. 51,187-198[Medline]
  2. Dahlgren, C., Karlsson, A., Sendo, F. (2001) Neutrophil secretory vesicles are the intracellular reservoir for GPI-80, a protein with adhesion-regulating potential J. Leukoc. Biol. 69,57-62[Abstract/Free Full Text]
  3. Sengelov, H., Boulay, F., Kjeldsen, L., Borregaard, N. (1994) Subcellular localization and translocation of the receptor for N-formylmethionyl-leucyl-phenylalanine in human neutrophils Biochem. J. 299,473-479
  4. Plesner, T., Ploug, M., Ellis, V., Ronne, E., Hoyer-Hansen, G., Wittrup, M., Pedersen, T. L., Tscherning, T., Dano, K., Hansen, N. E. (1994) The receptor for urokinase-type plasminogen activator and urokinase is translocated from two distinct intracellular compartments to the plasma membrane on stimulation of human neutrophils Blood 83,808-815[Abstract/Free Full Text]
  5. Sengelov, H., Kjeldsen, L., Borregaard, N. (1993) Control of exocytosis in early neutrophil activation J. Immunol. 150,1535-1543[Abstract]
  6. Capodici, C., Hanft, S., Feoktistov, M., Pillinger, M. H. (1998) Phosphatidylinositol 3-kinase mediates chemoattractant-stimulated, CD11b/CD18-dependent cell-cell adhesion of human neutrophils: evidence for an ERK-independent pathway J. Immunol. 160,1901-1909[Abstract/Free Full Text]
  7. Mócsai, A., Jakus, Z., Vántus, T., Berton, G., Lowell, C. A., Ligeti, E. (2000) Kinase pathways in chemoattractant-induced degranulation of neutrophils. The role of p38 MAP kinase activated by Src family kinases J. Immunol. 164,4321-4331[Abstract/Free Full Text]
  8. Agwu, D. E., McPhail, L. C., Sozzani, S., Bass, D. A., McCall, C. E. (1991) Phosphatidic acid as a second messenger in human polymorphonuclear leukocytes. Effects on activation of NADPH oxidase J. Clin. Investig. 88,531-539
  9. Suchard, S. J., Nakamura, T., Abe, A., Shayman, J. A., Boxer, L. A. (1994) Phospholipase D-mediated diradylglycerol formation coincides with H2O2 and lactoferrin release in adherent human neutrophils J. Biol. Chem. 269,8063-8068[Abstract/Free Full Text]
  10. Stutchfield, J., Cockcroft, S. (1993) Correlation between secretion and phospholipase D activation in differentiated HL60 cells Biochem. J. 293,649-655
  11. Kanaho, Y., Kanoh, H., Saitoh, K., Nozawa, Y. (1991) Phospholipase D activation by platelet-activating factor, leukotriene B4, and formyl-methionyl-leucyl-phenylalanine in rabbit neutrophils. Phospholipase D activation is involved in enzyme release J. Immunol. 146,3536-3541[Abstract]
  12. Brown, H. A., Gutowski, S., Moomaw, C. R., Slaughter, C., Sternweis, P. C. (1993) ADP-ribosylation factor, a small GTP-dependent regulatory protein, stimulates phospholipase D activity Cell 75,1137-1144[Medline]
  13. Exton, J. H. (2000) Phospholipase D Ann. N. Y. Acad. Sci. 905,61-68[Medline]
  14. Fensome, A., Cunningham, E., Prosser, S., Tan, S. K., Swigart, P., Thomas, G., Hsuan, J., Cockcroft, S. (1996) ARF and PITP restore GTP gamma S-stimulated protein secretion from cytosol-depleted HL60 cells by promoting PIP2 synthesis Curr. Biol. 6,730-738[Medline]
  15. Fensome, A., Whatmore, J., Morgan, C., Jones, D., Cockcroft, S. (1998) ADP-ribosylation factor and Rho proteins mediate fMLP-dependent activation of phospholipase D in human neutrophils J. Biol. Chem. 273,13157-13164[Abstract/Free Full Text]
  16. Dana, R. R., Eigsti, C., Holmes, K. L., Leto, T. (2000) A regulatory role for ADP-ribosylation factor 6 (ARF6) in activation of the phagocyte NADPH oxidase J. Biol. Chem. 275,32566-32571[Abstract/Free Full Text]
  17. Helms, J. B., Rothman, J. E. (1992) Inhibition by brefeldin A of a Golgi membrane enzyme that catalyses exchange of guanine nucleotide bound to ARF Nature 360,352-354[Medline]
  18. Peyroche, A., Antonny, B., Robineau, S., Acker, J., Cherfils, J., Jackson, C. L. (1999) Brefeldin A acts to stabilize an abortive ARF-GDP-Sec7 domain protein complex, involvement of specific residues of the Sec7 domain Mol. Cell 3,275-285[Medline]
  19. Mansour, S. J., Skaug, J., Zhao, X. H., Giordano, J., Scherer, S. W., Melancon, P. (1999) p200 ARF-GEP1, a Golgi-localized guanine nucleotide exchange protein whose Sec7 domain is targeted by the drug brefeldin A Proc. Natl. Acad. Sci. USA 96,7968-7973[Abstract/Free Full Text]
  20. Mócsai, A., Bánfi, B., Kapus, A., Farkas, G., Geiszt, M., Buday, L., Faragó, A., Ligeti, E. (1997) Differential effects of tyrosine kinase inhibitors and inhibitor of the mitogen-activated protein kinase cascade on the degranulation and superoxide production of human neutrophil granulocytes Biochem. Pharmacol. 54,781-789[Medline]
  21. Borregaard, N., Kjeldsen, L., Rygaard, K., Bastholm, L., Nielsen, M. H., Sengelov, H., Bjerrum, O. W., Johnsen, A. H. (1992) Stimulus-dependent secretion of plasma proteins from human neutrophils J. Clin. Investig. 90,86-96
  22. Bolscher, B. G., van Zwieten, R., Kramer, I. M., Weening, R. S., Verhoeven, A. J., Roos, D. (1989) A phosphoprotein of Mr 47,000, defective in autosomal chronic granulomatous disease, copurifies with one of two soluble components required for NADPH:O2 oxidoreductase activity in human neutrophils J. Clin. Investig. 83,757-763
  23. Estabrook, R. W. (1967) Mitochondrial respiratory control and the polarographic measurement of ADP:O ratios Methods Enzymol. 10,41-47
  24. Ligeti, E., Doussiere, J., Vignais, P. V. (1988) Activation of the O2(·-)-generating oxidase in plasma membrane from bovine polymorphonuclear neutrophils by arachidonic acid, a cytosolic factor of protein nature, and nonhydrolyzable analogues of GTP Biochemistry 27,193-200[Medline]
  25. Morgan, C. T., Sengelov, H., Whatmore, J., Borregaard, N., Cockroft, S. (1997) ADP-ribosylation-factor-regulated phospholipase D activity localizes to secretory vesicles and mobilizes to the plasma membrane following N-formylmethionyl-leucyl-phenylalanine stimulation of human neutrophils Biochem. J. 325,581-585
  26. Tokumura, A., Moriyama, T., Minamino, H., Hayakawa, T., Tsukatani, H. (1997) Exogenous phosphatidic acid with saturated short-chain fatty acyl groups induces superoxide anion release from guinea pig peritoneal polymorphonuclear leukocytes by three different mechanisms Biochim. Biophys. Acta 1344,87-102[Medline]
  27. Orci, L., Perrelet, A., Ravazzola, M., Wieland, F. T., Schekman, R., Rothman, J. E. (1993) "BFA bodies", a subcompartment of the endoplasmic reticulum Proc. Natl. Acad. Sci. USA 90,11089-11093[Abstract/Free Full Text]
  28. Mitchell, R., McCulloch, D., Lutz, E., Johnson, M., MacKenzie, C., Fennell, M., Fink, G., Zhou, W., Sealfon, S. C. (1998) Rhodopsin-family receptors associate with small G proteins to activate phospholipase D Nature 392,411-414[Medline]
  29. McCulloch, D. A., Lutz, E. M., Johnson, M. S., Robertson, D. N., MacKenzie, C. J., Holland, P. J., Mitchell, R. (2001) ADP-ribosylation factor-dependent phospholipase D activation by VPAC receptors and a PAC(1) receptor splice variant Mol. Pharmacol. 59,1523-1532[Abstract/Free Full Text]
  30. Qualliotine-Mann, D., Agwu, D. E., Ellenburg, M. D., McCall, C. E., McPhail, L. C. (1993) Phosphatidic acid and diacylglycerol synergize in a cell-free system for activation of NADPH oxidase from human neutrophils J. Biol. Chem. 268,23843-23849[Abstract/Free Full Text]
  31. Borregaard, N., Miller, L., Springer, T. A. (1987) Chemoattractant-regulated mobilization of a novel intracellular compartment in human neutrophils Science 237,1204-1206[Abstract/Free Full Text]
  32. Cavenagh, M. M., Whitney, J. A., Carroll, K., Zhang, C., Boman, A. L., Rosenwald, A. G., Mellman, I., Kahn, R. A. (1996) Intracellular distribution of Arf proteins in mammalian cells. Arf6 is uniquely localized to the plasma membrane J. Biol. Chem. 271,21767-21774[Abstract/Free Full Text]
  33. Zhang, Q., Cox, D., Tseng, C. C., Donaldson, J. G., Greenberg, S. (1998) A requirement for ARF6 in Fcgamma receptor-mediated phagocytosis in macrophages J. Biol. Chem. 273,19977-19981[Abstract/Free Full Text]
  34. Shome, K., Nie, Y., Romero, G. (1998) ADP-ribosylation factor proteins mediate agonist-induced activation of phospholipase D J. Biol. Chem. 273,30836-30841[Abstract/Free Full Text]
  35. Guillemain, I., Exton, J. H. (1997) Effects of brefeldin A on phosphatidylcholine phospholipase D and inositolphospholipid metabolism in HL-60 cells Eur. J. Biochem. 249,812-819[Medline]
  36. Tarricone, C., Xiao, B., Justin, N., Walker, P. A., Rittinger, K., Gamblin, S. J., Smerdon, S. J. (2001) The structural basis of Arfaptin-mediated cross-talk between Rac and Arf signalling pathways Nature 411,215-219[Medline]



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