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Blood, Vol. 91 No. 12 (June 15), 1998:
pp. 4770-4775
The Bactericidal/Permeability-Increasing Protein (BPI) Is Present
in Specific Granules of Human Eosinophils
By
Jero Calafat,
Hans Janssen,
Anton Tool,
Mieke A. Dentener,
Edward
F. Knol,
Helene F. Rosenberg, and
Arne Egesten
From the Division of Cell Biology, The Netherlands Cancer Institute,
Amsterdam, The Netherlands; the Central Laboratory of The Netherlands
Red Cross Blood Transfusion Service, Amsterdam, The Netherlands; the
Department of Pulmonology, Maastricht University, Maastricht, The
Netherlands; the Laboratory of Host Defenses, NIAID, National
Institutes of Health, Bethesda, MD; and the Department of Medicine,
Lund University, University Hospital MAS, Malmö, Sweden.
 |
ABSTRACT |
Eosinophils participate in the inflammatory response seen in allergy
and parasitic infestation, but a role in host defense against bacterial
infection is not settled. The bactericidal/permeability-increasing protein (BPI) has been demonstrated in neutrophils and it exerts bacteriostatic and bactericidal effects against a wide variety of
Gram-negative bacterial species. Using the Western blot technique, a
55-kD band, corresponding to BPI, was detected in lysates from both
neutrophils and eosinophils. The localization of BPI in immature and
mature eosinophils was investigated using immunoelectron microscopy. BPI was found in immature and mature specific granules of eosinophils and was detected in phagosomes as well, indicating release of the
protein from the granules into the phagosomes. Using a specific enzyme-linked immunosorbent assay, eosinophils were shown to contain 179 ng of BPI/5 × 106 eosinophils compared with 710 ng
BPI/5 × 106 neutrophils. The presence of BPI in
eosinophils suggests a role for these cells in host defense against
Gram-negative bacterial invasion or may suggest a role for BPI against
parasitic infestation.
| |
INTRODUCTION |
EOSINOPHILS ARE believed to participate
in host defense against helminthic infections and play a
pathophysiological role in asthma and allergy.1 They have a
characteristic content of highly cationic proteins in their cytoplasmic
granules1 and bactericidal effects have been shown for
three of these: eosinophil cationic protein, major basic protein, and
eosinophil peroxidase.2 However, the eosinophil count of
peripheral blood is not typically raised in bacterial infection, but
eosinophils may be recruited to sites of bacterial invasion, whereas
serum concentration of characteristic eosinophil proteins are raised in
patients with bacterial infection.3
The bactericidal/permeability-increasing protein (BPI) is a 55-kD
highly cationic protein4 that is stored in the population of azurophil granules of neutrophils.5 BPI has a high
target cell specificity for Gram-negative bacteria and binds to the
lipopolysaccharides (LPS)6 present in the outer envelope of
these bacteria. Through this binding, it exerts immediate
bacteriostatic effects and, later, bactericidal effects.7
Both isolated BPI and intact neutrophils have similar actions on target
bacteria, suggesting that BPI is of major importance in the host
defense functions of neutrophils against BPI-sensitive Gram-negative
bacteria.8 BPI is thought to be stored in association with
the granule membrane of azurophil granules, and transmembranous
anchoring by the hydrophobic carboxy-terminal portion has been
suggested.5,9
In the present study, we show that BPI is present in both neutrophils
and eosinophils. We also show the subcellular distribution of BPI in
eosinophils. Our finding suggests a role for eosinophils in host
defense against Gram-negative infection.
| |
MATERIALS AND METHODS |
Serum-treated zymosan (STZ) was prepared as described
before.10 Interleukin-5 (IL-5) was from Amersham
(Buckinghamshire, UK). Incubation medium for the cell incubations
contained 132 mmol/L NaCl, 6.0 mmol/L KCl, 1.0 mmol/L
CaCl2, 1.0 mmol/L MgSO4, 1.2 mmol/L potassium
phosphate, 20 mmol/L HEPES, 5.5 mmol/L glucose, and 0.5% (wt/vol)
human albumin, pH 7.4.
Cell isolation.
Blood was obtained from healthy volunteers and was collected in 13 mmol/L trisodium citrate (pH 7.4) for immediate anticoagulation.
Granulocytes were obtained as described11 and then
incubated with isotonic NH4Cl-solution to lyse the
erythrocytes. The remaining leukocytes were washed twice in cold
phosphate-buffered saline (PBS) containing 0.5% human serum albumin.
The polymorphonuclear cells (PMN) had a purity of greater than 95%,
consisting mainly of neutrophils, and a viability of greater than 98%.
Cell viability was tested by lactate dehydrogenase release or Trypan
blue exclusion.
Eosinophils were isolated as previously described,12 with
slight modifications. In short, the mononuclear cells were separated from the granulocytes by centrifugation of the blood over Ficoll-Paque (Pharmacia Biotech, Uppsala, Sweden). The granulocytes were washed twice in incubation medium and resuspended. For the immunomagnetic isolation,12 the cells were incubated with MACS microbeads
conjugated to a monoclonal antibody to CD16 (Miltenyi Biotec GmbH,
Bergish Gladbach, Germany) at 4°C for 30 minutes. Thereafter, the
cell-suspension was run through a magnetic column (VarioMACS; Miltenyi
Biotec GmbH) to remove neutrophils from the cell suspension. The
eosinophils (purity, > 98%; contaminating cells were mainly
lymphocytes) were washed and suspended in incubation medium.
To purify lymphocytes, the mononuclear cells obtained after
Ficoll-Paque separation were washed and incubated in RPMI 1640 supplemented with 10% fetal bovine serum (Biofluids, Rockville, MD) on
plastic Petri dishes to let the monocytes adhere. After 1 hour of
incubation at 37°C, the nonadherent lymphocytes were poured off and
collected for lysis as described below. The lymphocytes had a purity of
greater than 99%.
In initial experiments, lysis of neutrophils by Triton X-100 was
compared with lysis by sonication and repeated freeze/thaw cycles.
Lysis using Triton X-100 gave the highest yield of BPI and results
similar to the detergent Igepal (Sigma, St Louis, MO) used at the same
concentration. Therefore, in subsequent experiments, 1% Triton X-100
in PBS was used. To inhibit proteases and possible degradation of BPI,
benzamidine was added at 10 mmol/L. Lysis of cells was performed for 20 minutes on ice. The lysates were stored at  80°C until
analyzed by enzyme-linked immunosorbent assay (ELISA).
Some cells were collected for electron microscopy, and a part of these
cells were pretreated with IL-5 at 10 10 mol/L and
subsequent addition of STZ. All the cells were fixed in a mixture of
0.5% glutaraldehyde and 4% paraformaldehyde (PFA) in 0.1 mol/L
phosphate buffer (pH 7.2) for 2 hours.
Immature myeloid cells were obtained from bone marrow aspirate after
enrichment by density gradient centrifugation over Percoll (density of
1.074 g/mL) as described.13 The cells at the interphase were collected and, after washing, fixed as described above.
Immunoelectron microscopy.
Fixed cells were pelleted in 10% gelatin in PBS. Approximately 80-nm
cryosections were made on an MT-7 ultracryomicrotome (Research and
Manufacturing Co, Tucson, AZ) and incubated at room temperature with
rabbit anti-BPI (dilution 1/600), followed by incubation with 10-nm
gold-conjugated goat antirabbit IgG (dilution 1/40). Both incubations
were for 1 hour. As control, the primary antiserum was replaced by a
nonrelevant rabbit antiserum. After immunolabeling, the cryosections
were embedded in a mixture of methylcellulose and uranyl acetate. All
sections were examined with a Philips CM 10 electron microscope
(Eindhoven, The Netherlands).
Antibodies.
A polyclonal rabbit antibody to BPI was supplied by Dr Inge Olsson
(Lund, Sweden). The production and characterization of this antibody
has been described.5 Goat antirabbit IgG linked to 10-nm
gold was from Amersham Nederland ('s-Hertogenbosch, The Netherlands).
BPI ELISA.
A previously described sandwich ELISA, specific for BPI,14
was used to determine BPI in cell lysates.
Western blot.
Eosinophils obtained by immunomagnetic isolation (purity, >98%;
contaminating cells were mainly lymphocytes), neutrophils (purity,
>98%), and lymphocytes (purity, >99%) were lysed with Triton
X-100 at a final concentration of 1 × 107 cells/mL
and subsequently subject to sodium dodecyl sulfate-polyacrylamide gel
electrophoresis (SDS-PAGE) on 14% tris-glycine gels
(Novel Experimental Technologies, San Diego, CA) followed by Western blotting using standard procedures15; the primary antibody
was used at a 1:1,000 dilution followed by a 1:1,000 dilution of goat
antirabbit IgG (Biorad, Richmond, CA).
In some experiments, eosinophils, at a final concentration of
106 eosinophils/mL, were prewarmed for 10 minutes at
37°C before incubation with IL-5 at 1010 mol/L
for 20 minutes and subsequent incubation with STZ at a final
concentration of 1 mg/mL. Cells were collected at different time points
and treated as described above.
| |
RESULTS |
Detection of BPI in eosinophil lysates by Western blotting.
Western blot technique was used to detect BPI in lysates from highly
purified neutrophils, eosinophils, and lymphocytes
(Fig 1). A doublet 55-kD band,
corresponding to BPI, was detected in the lanes of neutrophils and
eosinophils, but not in lymphocytes. The immunoreactive band in the
lane of eosinophils was less intense than that of neutrophils. This
could correspond to a lower content of the protein in eosinophils
compared with neutrophils. The doublet pattern of the 55-kD band has
been shown to be due to variable glycosylation of BPI in
neutrophils.16
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| Fig 1.
A doublet 55-kD immunoreactive band corresponding to BPI
is present in neutrophils (lane 1) and eosinophils (lane 3), but not in
lymphocytes (lane 2). Highly purified cells were lysed and subject to
SDS-PAGE/Western blotting. The primary antibody was detected by a
secondary goat antirabbit antibody conjugated with alkaline
phosphatase.
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Localization of BPI in eosinophils from human peripheral blood and in
eosinophil progenitors.
To determine the subcellular localization of BPI in eosinophils,
cryosections of eosinophils isolated from peripheral blood and immature
cells from bone marrow were incubated with anti-BPI serum. Compared
with neutrophils, eosinophils showed less intense labeling for BPI. In
mature eosinophils (Fig 2), BPI was present in the specific granules. The majority of these granules possess crystalloids. The cell surface was also weakly labeled, as has been
demonstrated for neutrophils.16 In eosinophil promyelocytes and myelocytes of the bone marrow, the granules are round and do not
yet possess crystalloids (promyelocytes) or have few (myelocytes) and
the endoplasmic reticulum is abundant. The BPI in these cells was
localized to some granules and in the endoplasmic reticulum (Fig 3). Lymphocytes, monocytes, and
platelets present in the same sections were unlabeled. No labeling was
found in the control of each experiment in which the primary antibody
was replaced by a nonrelevant rabbit antiserum.
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| Fig 2.
Localization of BPI in eosinophils. Cryosections of
eosinophils labeled to detect BPI. Labeling of the core-containing
specific granules of eosinophils was heterogeneous. The top of the
micrograph shows an eosinophil with labeled granules (large arrows);
however, the labeling was less intense than in the neutrophil at the
bottom. Some labeling (small arrows) was also observed on the surface membrane of the eosinophil (insert). The nucleus (n) was unlabeled. Bars = 200 nm.
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| Fig 3.
Localization of BPI in eosinophilic myelocytes.
Cryosections of bone marrow cells incubated with anti-BPI and
visualized by secondary gold-conjugated antibody. An area of an
eosinophilic myelocyte is shown. Most of the granules do not possess a
crystalloid, but two crystalloid-containing mature specific granules
are present (c). BPI (arrows) is present in almost all granules and in
the endoplasmic reticulum (er). Bars = 400 nm.
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|
Measurement of the BPI content in neutrophils and eosinophils.
Using specific ELISA for measurement of BPI, the content in highly
purified preparations of neutrophils and eosinophils was determined
from whole cell extracts. Eosinophils were found to hold 179 ± 44 ng (mean ± SEM; range, 77 to 280 ng, n = 4)/5 × 106 eosinophils compared with 710 ± 83 ng (mean ± SEM; range, 510 to 901 ng, n = 4)/5 × 106
neutrophils. In the literature, varying amounts of BPI in neutrophils have been reported: 1,650 ± 125 ng (mean ± SEM, range, 435 to 2,200 ng, n = 17)/5 × 106 neutrophils17;
910 ± 505 ng (mean ± SEM, n = 4)/5 × 106
neutrophils18; and 3,250 ± 315 ng (mean ± SEM, range, 2,050 to 4,400 ng, n = 5)/5 × 106
neutrophils.5 Although the extraction procedure is
principally the same in these studies, the variation most likely is due
to variations in the sensitivity and calibration of the methods of measurement used. There also seems to be a large donor variation in the
BPI content of neutrophils. In any case, our data show that the BPI
content of eosinophils is about one fourth of that found in
neutrophils.
Redistribution of BPI in eosinophils stimulated with STZ.
Highly purified eosinophils were prewarmed and preincubated with IL-5
at 1010 mol/L for 20 minutes at 37°C before the
addition of STZ for 10 minutes. The pretreatment with IL-5 activates
eosinophils and increase their interaction with STZ.19
After incubations, cells were fixed and processed for immunoelectron
microscopy. Electron microscopic investigation show extensive
phagocytosis of STZ (Fig 4). Detection of
BPI by immunogold technique show BPI present within phagosomes (Fig 4),
indicating release into the phagosome.
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| Fig 4.
Localization of BPI in eosinophils after coincubation
with STZ. Cells were prewarmed for 10 minutes at 37°C and activated with IL-5 at 0.1 nmol/l for 20 minutes before the addition of STZ and
coincubation for 10 minutes. Ultrathin cryosections were incubated with
anti-BPI and visualized by secondary gold-conjugated antibody. Area of
an eosinophil showing a phagosome with a STZ containing BPI. Granules
are seen fusing with the phagosome (arrowheads), whereas some intact
granules (g) are seen close to the membrane of the phagosome. Bar = 400 nm.
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| |
DISCUSSION |
It is a novel finding that eosinophils possess BPI. About one fourth of
the amount was found in eosinophils compared with neutrophils. BPI was
detected in the specific crystalloid-containing granules of
eosinophils.
In a previous study, using immunofluorescence for the detection of BPI,
it was not possible to detect the presence of BPI in eosinophils due to
their autofluorescent properties.5 In the present study,
this problem was circumvented by the use of immunoelectron microscopy.
The finding of BPI in both immature and mature eosinophils by
immunoelectron microscopy suggests that the protein is synthesized at
the promyelocytic stage of differentiation in the bone marrow, because
we were able to detect BPI in both core-less and core-containing
specific granules. The core-less granules of eosinophil promyelocytes
have been suggested to mature into the core-containing specific
granules of mature eosinophils.20
Eosinophils are generally considered to be effector cells in host
defense against parasitic infection.1 However, the presence of BPI in eosinophils suggests an additional role for this cell in host
defense to some bacterial infections. Beside the bactericidal activity
from BPI, the characteristic cationic proteins of eosinophil granules,
such as major basic protein (MBP), eosinophil cationic protein (ECP),
and eosinophil peroxidase (EPO), do possess bactericidal activity
beside their activity shown in vitro against several parasites and
mammalian cells.2 Taken together, this further indicates
that eosinophils may have an additional role in host defense to
bacterial infection. On the other hand, the presence of BPI in
eosinophils could suggest a function for BPI in the defense against
parasitic infestation. To our knowledge, possible effects from BPI on
parasites have not been investigated.
Eosinophils have been regarded as poor phagocytes, but this might be
because, in previous studies, mainly resting populations of eosinophils
have been investigated. In one study, normal human eosinophils were
shown to ingest and kill Escherichia coli less efficiently than
neutrophils.21 Recently, it was shown that, after
incubation with granulocyte-macrophage colony-stimulating factor
(GM-CSF), IL-3, or IL-5, their phagocytic capacity increases dramatically.22 In fact, tissue-derived eosinophils, which
presumably are activated, were more efficient in phagocytosing E
coli than either neutrophils or macrophages.23 In mice,
E coli attracts eosinophils to inflammatory
sites,24 and in guinea pigs, LPS was shown to induce
accumulation of eosinophils in vivo in guinea pig skin,25
speaking for a role for eosinophils against Gram-negative infection in
these animals.
The biological effects of BPI can be exerted by a 25-kD N-terminal
fragment,26,27 and the C-terminal hydrophobic portion of
BPI has been suggested to serve as an anchor into the granule membrane.9 Moreover, the middle of the BPI molecule
contains a hydrophilic proline-rich region that is protease-sensitive
and provides potential cleavage sites for elastase.9 We
were not able to detect a smaller fragment of BPI in lysates from
activated and phagocytosing eosinophils (data not shown). In line with
this is that neutrophils upon stimulation release 55-kD BPI to the supernatant, suggesting that, at least partly, BPI is not
transmembranously anchored and, furthermore, is not subject to
proteolytic cleavage.17
In conclusion, eosinophils possess BPI, suggesting a role for
eosinophils in protection against Gram-negative infection. Therefore, eosinophils may be specialized to participate in host defense against
parasites, but could have an additional role in the protection against
Gram-negative infection. Especially because eosinophils are numerous in
colonic mucosa.23 Further studies are needed to elucidate
how efficient activated eosinophils are in killing phagocytosed
Gram-negative bacteria.
| |
FOOTNOTES |
Supported by grants from the Th. C. Berg Foundation, the Greta & Johan
Kock Foundations, the Ernhold Lundström Foundation, and the
Alfred Österlund Foundation.
Submitted August 1, 1997; accepted February 10, 1998.
Address reprint requests to Arne Egesten, MD, Department of Medicine,
University Hospital MAS, S-205 02 Malmö, Sweden; e-mail: Arne.Egesten{at}medforsk.mas.lu.se.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
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O. Levy
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Abstract
Introduction
Abstract