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PHAGOCYTES
From the Department of Molecular and Cellular Biology,
Pfizer Global Research and Development, Fresnes, France; the Department
of Medicine, Imperial College School of Medicine, London, United
Kingdom; and the Department of Immunology, the Department of Medicine
and Therapeutics, and the Division of Biochemistry and Molecular
Biology, University of Glasgow, Scotland.
Immunoglobulin G (IgG) receptors (Fc Receptors for the constant region (Fc) of
immunoglobulins play a pivotal role linking the humoral and cellular
arms of the immune system. On leukocytes, aggregation of receptors
(Fc Phosphatidylcholine-specific PLD (PC-PLD) catalyzes the
hydrolysis of the terminal diester bond of phosphatidylcholine to liberate phosphatidic acid and choline.8 PC-PLD was first
identified in plants but has subsequently been shown to be highly
conserved across all species and present in large amounts in bacteria,
yeast, and mammalian cells.9,10 In mammalian cells,
activation of PC-PLD has been proposed to control signal transduction
pathways regulating a wide range of physiological processes,
including membrane trafficking and cytoskeletal
reorganization,11-17 mitogenesis,18,19 neuronal and cardiac stimulation,20,21
phagocytosis,22 the respiratory burst in
neutrophils,23,24 inflammation, and
diabetes.25
The immediate products of PLD hydrolysis of phosphatidylcholine
are phosphatidic acid and choline.8 A role for
phosphatidic acid as a key intracellular signaling molecule has been
proposed as it has been shown to directly activate protein
kinases,18,19,26,27 protein tyrosine
phosphatase,28-30 phospholipase C,31
phosphoinositol-4-kinase,32 sphingosine
kinase,33 and small molecular weight guanosine
triphosphatase-activating proteins.34 Phosphatidic acid
has also been shown to promote the release of calcium from
intracellular compartments35,36 and, in neutrophils, to
activate the oxidative burst through nicotinamide adenine dinucleotide
phosphate (reduced form) (NADPH) oxidase.24,27 Phosphatidic acid itself can also act as a precursor for other intracellular signaling molecules. Thus, phosphatidic acid can be
converted into diacyl glycerol (DAG) by phosphatidic
acid-phosphohydrolase10,23 or to the mitogen
lyso-phosphatidic acid (LPA) by phospholipase A2.10,23
DAG is an established activator of conventional and novel protein
kinase C (PKC) isoforms37,38 and LPA, which, following
release from cells, acts on G-protein-coupled receptors to further
stimulate cells or adjacent cells.39 Phosphatidic acid can
also be subject to acid hydrolases followed by lipo-oxygenase, leading
to the formation of oxygen radicals and lipid peroxides that cause
tissue damage.40
In mammalian cells, 2 isoforms of PLD (PLD1 and PLD2) have been
cloned, sequenced, and characterized.17,41,42 Furthermore, PLD1 is expressed as 2 splice variants, namely, PLD1a and
PLD1b.43 Both PLD1 and PLD2 use phosphatidylcholine as
substrate. In previous studies, we have shown that coupling of Fc Here, we demonstrate that coupling of Fc Cell culture
Reverse-transcriptase-polymerase chain reaction
The PLD1 primers were designed against an overlapping region in the sequence of both PLD1 isoforms to yield a fragment of approximate 640 base pairs (bp) for PLD1a and another fragment of approximate 520 bp for PLD1b.43 Specific primers designed for PLD2 would yield a 450-bp fragment. The reaction was carried out as described previously.43 Receptor aggregation Cells were harvested by centrifugation and then incubated at 4°C for 45 minutes with 1 µM human monomeric IgG (Serotec, Oxford, United Kingdom) to occupy surface Fc RI in the presence or absence of
inhibitors or alcohols. Excess unbound ligand was removed by dilution
and centrifugation of the cells. Cells were resuspended in ice-cold
RPMI 1640/10 mM Hepes/0.1% bovine serum albumin (BSA) (RHB medium),
and surface immune complexes were formed by incubating with
cross-linking antibody (sheep antihuman IgG; 1:50) in the continued
presence of inhibitors or alcohols. Cells were then warmed to 37°C
for the times specified in each assay as described previously.44,45
Immunoprecipitation of PLDs PLD1 and PLD2 were immunoprecipitated from cell lysates prior to Western blot analysis of the desired proteins. Rabbit polyclonal antibody (2 µg), either anti-PLD1 or anti-PLD2 (QCB, Hopkinton, MA), were incubated with 50 µL 50% protein A-agarose and 450 µL buffer for 2 hours on a rocking platform at 4°C in order to form precipitating complexes. Then, the antibody-protein A-agarose mix was washed to remove unbound antibody. Following this, 500 µL cell lysate containing 200 µg protein was mixed with the precipitating (antibody-protein A-agarose) complex and placed in a tumbler at 4°C for 4 hours. Following incubation, the precipitating complex was centrifuged and washed prior to addition of Laemlli buffer for loading onto sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE).Gel electrophoresis and Western blots Proteins were resolved on 8% polyacrylamide gels (SDS-PAGE) under denaturing conditions and then transferred to 0.45-µm nitrocellulose membranes. After blocking overnight at 4°C with 5% nonfat milk in Tris-buffered saline and 0.1% Tween 20 and washing, the membranes were incubated with the relevant antibodies for 4 hours at room temperature. The membranes were washed extensively in the washing buffer and bands visualized by means of the appropriate horseradish peroxidase-conjugated secondary antibody and ECL Western Blotting Detection System (Amersham, Buckinghamshire, United Kingdom).Measurement of phospholipase D activity PLD activity was measured as previously described in Melendez et al,7 by means of the transphosphatidylation assay. Briefly, U937 cells were labeled (106 cells/mL) with [3H] palmitic acid (5 µCi/mL [185 kBq/mL]) (Amersham) in the cell culture medium for 16 hours. Following washing, the cells were incubated at 37°C for 15 minutes in RHB medium containing butan-1-ol (0.3% final). Following Fc RI aggregation,
cells were incubated for a further 30 minutes and then extracted by
Bligh-Dyer phase separation. The accumulated phosphatidylbutanol was
assayed as described previously.7
Measurement of rate of trafficking of immune complexes Trafficking of immune complexes was measured with a protocol similar to that used in previous studies.44,45 Fc RI was
aggregated as described above, but surface immune complexes were formed
by using radiolabeled cross-linking antibody
([125I]-rabbit antihuman IgG; 1:50) (R&D Systems,
Abington, United Kingdom). Supernatant trichloroacetic acid
(TCA)-soluble counts were measured to provide the rate of
intracellular trafficking.45,46 The results were expressed
as a percentage of the total cell surface counts at time zero.
Oxidase assays Whole cell superoxide production following Fc RI aggregation
or N-formyl-1-methionyl-1-leucyl-1-phenylalamine (f-MLP)
stimulation was measured in IFN- -primed U937 cells, pretreated or
not with butan-1-ol, butan-2-ol, or antisense oligonucleotides for PLD1 or PLD2.
Cells were assayed in RPMI-1% FCS without phenol red placed in a 96-well plate. For each well, 200 000 cells suspended in 80 µL were mixed with 20 µL luminol-based substrate (Diogenes, National Diagnostics, Atlanta, GA) at the same time as the cross-linking antibody, or f-MLP (1 µM). Luminescence was measured with a luminometer (Wallac 1420 Multilabel counter, Cambridge, United Kingdom). Cytosolic calcium assays Cytosolic calcium was measured as described previously except the cuvette buffer was calcium supplemented (final concentration, 1.5 mM Ca++).7 Briefly, cells were loaded with 1 µg/mL Fura-2-AM (Molecular Probes, Leiden, The Netherlands) and 1 µM human monomeric IgG (Serotec) in phosphate-buffered saline (PBS), 1.5 mM Ca++, and 1% BSA. After removal of excess reagents by dilution and centrifugation, the cells were resuspended in 1.5 mM calcium-supplemented PBS and warmed to 37°C in the cuvette. Cell surface-bound IgG was aggregated by the addition of goat anti-human IgG (1:50 dilution) (Sigma, Poole, United Kingdom). Fluorescence was measured at 340 and 380 nm, and the background-corrected 340:380 ratio was calibrated as previously described.6Sphingosine kinase assays Activation of sphingosine kinase was measured as described previously.7,33 Briefly, cells were resuspended in ice-cold 0.1 M phosphate buffer (pH 7.4) containing 20% glycerol, 1 mM mercaptoethanol, 1 mM EDTA, phosphatase inhibitors (20 mM ZnCL2, 1 mM sodium orthovanadate, and 15 mM sodium fluoride), protease inhibitors (10 µg/mL leupeptin, 10 µg/mL aprotinin, and 1 mM phenylmethyl sulfonyl fluoride), and 0.5 mM 4-deoxypyridoxine, disrupted by freeze-thawing and centrifuged at 105 000g for 90 minutes at 4°C. Supernatants were assayed for sphingosine kinase activity by incubating with sphingosine (Sigma) and [ 32P]-adenosine triphosphate (2 µCi, 5 mM [74
kBq]) for 30 minutes at 37°C, and products were separated
by thin-layer chromatography on silica gel G60 (Whatman,
Maidstone, United Kingdom) by means of
chloroform/methanol/acetic acid/water (90:90:15:6) and visualized by
autoradiography. The radioactive spots corresponding to sphingosine phosphate were scraped and counted in a scintillation counter. The
activity of sphingosine kinase following in vitro activation by phosphatidic acid was measured in cell lysates by addition of
L- -phosphatidic acid
(1,2-diacyl-sn-glycero-3-phosphate) (Sigma Aldrich, Paris, France) at 10 mol 1% Triton
X-100.
Both PLD1 and PLD2 are expressed in U937 cells, but only PLD1 is
coupled to Fc PLD expression profiles in the human monocytic cell line U937.
The isozymes of PLD expressed in U937 cells were determined by means of
reverse-transcriptase-polymerase chain reaction (RT-PCR), Northern
analysis, and Western analysis. Relative levels of expression were
compared in untreated cells, cytokine (IFN- -primed or
dbcAMP-differentiated cells revealed that both known PLD isozymes, PLD1
and PLD2, were present. In addition, both splice variants of PLD1
(PLD1a and PLD1b) were present.43 The profile of the
RT-PCR products was not altered by treating cells with IFN- or
following differentiation (Figure 1A). At
the protein level, Western blot analysis of immunoprecipitated PLDs
revealed immunoreactive bands corresponding to the predicted molecular weights for PLD1a, PLD1b, and PLD2. The PLD expression profile did not
alter following priming of cells with IFN- or cell differentiation by dbcAMP (Figure 1B).
Fc
Treatment of cells with the antisense oligonucleotide to PLD1 resulted in no change in basal activity. However, following aggregation of Fc RI, the increase in PLD activity was significantly reduced
compared with the control cells (P < .01) (Figure 2B). The reduction in the increase after Fc RI activation was
77% ± 8% in cells treated with antisense PLD1 compared with
control cells and was proportional to the observed reduction in protein expression by Western analysis. In contrast, treatment of cells with
the antisense oligonucleotide to PLD2 significantly reduced basal PLD
activity (P < .01). Fc RI-mediated activation of PLD was marginally reduced in cells treated with the antisense to PLD2, but
this reduction was entirely accounted for by the reduction in basal
levels; the increment over the basal level was identical in
control (untreated) cells and those pretreated with PLD2 antisense oligonucleotide (Figure 2B). In contrast to PLD activation by Fc RI,
PLD activity stimulated by PMA was significantly reduced in cells
pretreated with either of the 2 antisense oligonucleotides, indicating
that PMA is able to stimulate both forms of PLD (Figure 2C). Thus,
PMA-stimulated PLD activity was reduced by 50% ± 5% in cells
pretreated with PLD1 antisense and by 33% ± 5% in cells pretreated
with PLD2 antisense. A combination of treatment with both antisense
oligonucleotides (PLD1 and PLD2) proved toxic to the cells.
These data demonstrate that PLD2 contributes to the basal, unstimulated
PLD activity in these cells, whereas PLD1, but not PLD2, is coupled to
Fc RI activation.
PLD1 but not PLD2 is required to couple Fc RI to sphingosine
kinase6 and cytosolic calcium transients6,7
requires PLD activation, the nature of the isozyme involved in this
coupling was investigated by means of antisense oligonucleotides to
specifically downregulate either PLD1 or PLD2.
Previously, we have shown that aggregation of Fc
Previous studies have shown that sphingosine kinase is activated by
Fc To ensure that the loss of sphingosine kinase activity after Fc Thus, in keeping with the observed coupling of Fc PLD1 but not PLD2 functionally couples Fc Fc
PLD1 and not PLD2 couples Fc
PLD1 is necessary for trafficking of immune complexes for
degradation.
Formation of surface immune complexes on myeloid cells results in their
rapid internalization44 and trafficking to lysosomes for
degradation.45 We have previously shown that endocytosis (the initial internalization of immune complexes to early endosomes) mediated by Fc RI aggregation in cytokine-primed U937 cells, almost 50% of the initial radiolabel internalized as immune complexes appears
as TCA-soluble counts in the supernatant of these cells after 120 minutes' incubation at 37°C.7,47
Consistent with previous findings that PLD activation is not necessary
for the initial endocytosis of immune complexes mediated by
Fc RI,44 downregulation of either PLD1 or PLD2 by
pretreating cells with either antisense oligonucleotide did not alter
the rate of initial endocytosis of radiolabeled immune complexes (data not shown). However, pretreatment of cells with the antisense PLD1
oligonucleotide significantly changed the rate of appearance of
TCA-soluble counts in the supernatant of the cells whereas pretreatment
with antisense PLD2 did not. In control and antisense PLD2-treated
cells, 50% ± 2% and 49 ± 2% of the initial internalized counts
appeared in the supernatant in the TCA-soluble fraction after 120 minutes' incubation whereas for cells treated with antisense PLD1,
only 24% ± 1% of counts appeared in this fraction (Figure 6). These data demonstrate that PLD1 but
not PLD2 activation is required to mediate the trafficking of
Fc RI-internalized immune complexes in U937 cells.
In this study, we have shown that Fc Two forms of PLD have been characterized in mammalian cells, and
PLD1 exists as a number of splice variants although the significance of
these is not known. Here we show that both isozymes are expressed in
U937 cells and that priming with IFN- In vitro studies have shown that the activity of these 2 enzymes is
regulated differently. Both PLD1 and PLD2 have an absolute requirement
for phosphatidylinositol(4,5)P2 (PIP2) for
activation.41,42 Activity of PLD1 has been shown to be
stimulated in vitro by 3 additional factors; adenosine
diphosphate-ribosylation factor (ARF), Rho, and PKC54
through protein-protein interactions. In contrast, PLD2 is insensitive
to these 3 factors and, in the absence of other factors apart from
PIP2, PLD2 is very active.17 Consistent with
these in vitro observations, our data here indicate that, within the
intact U937 cell, PLD2 contributes to the basal activity of PLD whereas
PLD1 is coupled to cell activation through Fc Consistent with the finding that Fc The regulation of assembly of the subunits of NADPH oxidase to form
active enzyme and the subsequent oxidase burst is complex. Here, we
demonstrate a surprising absolute requirement on PLD activity for the
coupling of Fc Our findings that PLD1-mediated generation of phosphatidic acid drives
these monocyte biological responses demonstrates the pivotal role of
PLD1 in the intracellular signaling cascades initiated by Fc
We thank Drs Andrew Morris and Michael Frohman, Department of Pharmacology, State University of New York, for helpful advice in discussions of material in this manuscript.
Submitted April 11, 2001; accepted July 23, 2001.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Janet M. Allen, Inpharmatica, 60 Charlotte Street, London WIT 2NU, England, United Kingdom; e-mail: janet.allen{at}inpharmatica.co.uk.
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© 2001 by The American Society of Hematology.
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T. Hitomi, J. Zhang, L. M. Nicoletti, A. C. G. Grodzki, M. C. Jamur, C. Oliver, and R. P. Siraganian Phospholipase D1 regulates high-affinity IgE receptor-induced mast cell degranulation Blood, December 15, 2004; 104(13): 4122 - 4128. [Abstract] [Full Text] [PDF] |
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J. M. Beekman, J. E. Bakema, J. van der Linden, B. Tops, M. Hinten, M. van Vugt, J. G. J. van de Winkel, and J. H. W. Leusen Modulation of Fc{gamma}RI (CD64) Ligand Binding by Blocking Peptides of Periplakin J. Biol. Chem., August 6, 2004; 279(32): 33875 - 33881. [Abstract] [Full Text] [PDF] |
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K. H. Han, K.-H. Hong, J.-H. Park, J. Ko, D.-H. Kang, K.-J. Choi, M.-K. Hong, S.-W. Park, and S.-J. Park C-Reactive Protein Promotes Monocyte Chemoattractant Protein-1--Mediated Chemotaxis Through Upregulating CC Chemokine Receptor 2 Expression in Human Monocytes Circulation, June 1, 2004; 109(21): 2566 - 2571. [Abstract] [Full Text] [PDF] |
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H. K. Tay and A. J. Melendez Fc{gamma}RI-triggered Generation of Arachidonic Acid and Eicosanoids Requires iPLA2 but Not cPLA2 in Human Monocytic Cells J. Biol. Chem., May 21, 2004; 279(21): 22505 - 22513. [Abstract] [Full Text] [PDF] |
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F. A. J. van de Loo, M. B. Bennink, O. J. Arntz, R. L. Smeets, E. Lubberts, L. A. B. Joosten, P. L. E. M. van Lent, C. J. J. Coenen-de Roo, S. Cuzzocrea, B. H. Segal, et al. Deficiency of NADPH Oxidase Components p47phox and gp91phox Caused Granulomatous Synovitis and Increased Connective Tissue Destruction in Experimental Arthritis Models Am. J. Pathol., October 1, 2003; 163(4): 1525 - 1537. [Abstract] [Full Text] [PDF] |
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B. J. PETTUS, J. BIELAWSKI, A. M. PORCELLI, D. L. REAMES, K. R. JOHNSON, J. MORROW, C. E. CHALFANT, L. M. OBEID, and Y. A. HANNUN The sphingosine kinase 1/sphingosine-1-phosphate pathway mediates COX-2 induction and PGE2 production in response to TNF-{alpha} FASEB J, August 1, 2003; 17(11): 1411 - 1421. [Abstract] [Full Text] [PDF] |
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A. C. MacKinnon, A. Buckley, E. R. Chilvers, A. G. Rossi, C. Haslett, and T. Sethi Sphingosine Kinase: A Point of Convergence in the Action of Diverse Neutrophil Priming Agents J. Immunol., December 1, 2002; 169(11): 6394 - 6400. [Abstract] [Full Text] [PDF] |
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A. J. Melendez and A. K. Khaw Dichotomy of Ca2+ Signals Triggered by Different Phospholipid Pathways in Antigen Stimulation of Human Mast Cells J. Biol. Chem., May 3, 2002; 277(19): 17255 - 17262. [Abstract] [Full Text] [PDF] |
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