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Prepublished online as a Blood First Edition Paper on August 8, 2002; DOI 10.1182/blood-2002-04-1102.
PHAGOCYTES
From Children's Hospital Medical Center, Cincinnati,
OH.
Severely impaired pulmonary microbial clearance was observed in
granulocyte-macrophage colony-stimulating factor (GM-CSF)-deficient mice. To determine mechanisms by which GM-CSF mediates lung host defense, Fc The alveolar macrophage (AM) plays a central role
in lung host defense through both effector and regulatory functions. As the resident professional phagocyte, AMs provide a first line of host
defense by internalizing and degrading microbial pathogens encountered
on the respiratory surface.1 Upon pathogen exposure, AMs
express cytokines that influence recruitment and activation of
inflammatory cells and modify adaptive immune responses in a
pathogen-selective fashion.2 In this way, cytokines
released from pathogen-exposed AMs provide important molecular
"links" between innate and adaptive immunity in the lung. AMs also
present processed antigens to lymphocytes, resulting in production of opsonizing, pathogen-specific immunoglobulins (Igs).
Opsonins such as IgG further enhance phagocytic pathogen clearance and
modulate inflammatory responses through interaction with cell-surface
receptors that recognize the Fc region of pathogen-bound IgG
(Fc Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates
growth and differentiation of cultured AMs12-14
and plays a critical role in surfactant homeostasis and in lung host
defense (reviewed by Trapnell and Whitsett15). Defects in
AM functions in GM-CSF gene-targeted
(GM Interferon- Together, these observations suggest that GM-CSF might regulate both
Fc Mice
Alveolar macrophages and alveolar macrophage cell lines
Adenovirus The adenovirus used in this study is a replication-deficient derivative of human type 5 adenovirus whose structure has been previously reported.38 Methods for growth and purification of viruses in endotoxin-free media, media supplements, and solutions (supplied routinely or by special arrangement from BioWhittaker, Walkersville, MD) have been previously described.39,40 Virus concentration was determined from the optical density of the purified virions at 260 nm (OD260) using the formula 1 OD260 = 1 × 1012 particles per milliliter and expressed as optical particle units (opu) as previously described.41 Adenovirus was administered to the lungs by transoral intubation and tracheal instillation as previously described.29 In vitro infection of cultured AMs was done as previously described.40Fc R-mediated phagocytosis was quantified in primary AMs ex
vivo immediately after recovery by BAL20 and adherence to
plastic42 and in cultured AM cell lines plated the day
prior to analysis. Cells (105 per well, plated in 35-mm
dishes) were exposed to unopsonized beads or IgG-opsonized beads at a
concentration of 0.5 × 107/mL for 1 hour. In some
experiments, cells were preincubated with rat antimouse CD16/32
(Pharmingen) for 30 minutes prior to and during incubation with
IgG-opsonized beads to block Fc RII/Fc RIII-mediated opsonophagocytosis. Cells were then washed extensively in FACS buffer
to remove noninternalized particles, detached by brief trypsinization,
and evaluated by flow cytometry on a FACScan flow cytometer (Becton
Dickinson, San Jose, CA). Results were analyzed using CellQuest
software (Becton Dickinson) on a Macintosh microcomputer. The
phagocytic index was calculated from the following formula: phagocytic
index = percent of cells containing beads × mean
fluorescence of cells containing beads. All determinations
represent the mean of at least 3 separate measurements, and each
experiment was performed 2 or more times with similar results.
Fc R (rat antimouse CD16/32; Pharmingen; 30 minutes, 4°C). As controls, cells were also evaluated with primary
isotype- and species-matched antimouse immunoglobulins. After
incubation, immunostained cells were washed twice in FACS buffer and
kept on ice and then analyzed by single-color flow cytometry using a
FACScan flow cytometer as above. Fluorescence data were collected using
logarithmic amplification on 10 000 viable cells as determined by
forward light scattering. To determine if AMs in GM /
mice were capable of responding to IFN- by increasing Fc R
expression, primary AMs were obtained by BAL, collected by
centrifugation, and freed of nonadherent cells by adherence in plastic
dishes for 45 minutes as previously described.42 AMs were
then exposed to IFN- (200 U/mL, 24 hours) and detached with Versene,
and cell-surface Fc R levels were assessed by FACS as above. In other
experiments, AM Fc R levels were also similarly assessed by FACS 48 hours after intrapulmonary administration of IL-18 (100 ng per mouse in
60 µL 0.9% NaCl) to stimulate increased levels of IFN- levels in the lung. All determinations were done on primary AMs from 4 mice per
group or 4 plates of cultured AMs analyzed separately. Results were
similar in corresponding samples, and representative examples are
shown. Each experiment was done twice.
Reverse transcriptase-polymerase chain reaction amplification Messenger RNA transcript levels were quantified in primary or cultured AMs using reverse transcriptase-polymerase chain reaction (RT-PCR) as previously described.20,29 The following primer sets were used: glyceraldehyde-3-phosphate dehydrogenase [GAPDH]: 5'-ATTCTACCCACGGCAAGTTCAATGG-'3 and 5'-AGGGGCGGAGATGATGACCC-3'; IL-18: 5'-AGACCTGGAATCAGACAACTTTGG-'3 and 5'-AAACTCCATCTTGTTGTGTCCTGG-3'; Fc RIA:
5'-GAGCAGGGAAAGAAAGCAAATTCC-3' and 5'-TTAAGAGTTGCATGCCATGGTCC-3'; Fc RIIB: 5'-CCCAAGTCCAGCAGGTCTTTACC-3' and
5'-TTCTGGCTTGCTTTTCCCAATGCC-3'; and Fc RIIIA:
5'-GATCCAGCAACTACATCCTCCATC-3' and 5'-GCCTTGAACTGGTGATCCTAAGTC-3'. All
determinations were done in triplicate using either primary AMs from 3 mice analyzed separately or plates of cultured AMs. Each
experiment was done twice.
Cytokine levels IFN- , IL-18, and IL-12 concentrations in the lungs were
measured by enzyme-linked immunosorbent assay (ELISA) as previously described.29 Briefly, BAL fluid was obtained from groups
of mice (4-6 per group) and cleared of cells and debris by low-speed centrifugation (450g, 10 minutes, 4°C). Cleared BAL fluid
from each mouse was then assayed individually for various cytokines by
using the appropriate murine Quantikine kit (R&D Systems, Minneapolis, MN) as directed by the manufacturer. Assessments of IL-18 and IL-12
levels were done twice. IFN- levels in the BAL fluid were also
similarly assessed in mice 48 hours after receiving IL-18 via pulmonary
administration as described above. In vitro determination of IL-18
release by cultured AMs (MH-S, mAMGFP+, and
mAMPU.1+) was done essentially as described.40 Briefly, cells (2.5 × 105 per well in 24-well plates)
were incubated in the absence or presence of adenovirus
(1010 optical particle units [opu] per well) for 24 hours. Culture supernate was then aspirated, cleared by low-speed
centrifugation, and evaluated for the presence of IL-18 by
ELISA as above. All determinations represent the mean of 4 determinations done on separate plates of cells per group. Experiments
with mAMPU.1+ and mAMGFP+ cells were done twice.
Statistics Numeric data are presented as mean ± SEM. Statistical comparisons were made using the Student t test. Statistical calculations were performed with Sigma Plot (version 7.0) software on an IBM-compatible microcomputer.
GM-CSF is required for Fc R-mediated phagocytosis by AMs was
assessed in primary AMs from GM+/+, GM / ,
and SPC-GM+/+/GM / mice by ex vivo challenge
with fluorescent latex beads coated either with albumin alone
(unopsonized beads) or with albumin and then antialbumin antibody
(IgG-opsonized beads) followed by flow cytometry. In GM+/+
AMs, Fc R-mediated phagocytosis was demonstrated by a phagocytic index for IgG-opsonized beads 117% ± 4% greater than that for unopsonized beads (Figure 1A). In
contrast, Fc R-mediated phagocytosis was absent in
GM / AMs (Figure 1B). Phagocytosis of unopsonized beads
was also reduced in GM / AMs. Pulmonary expression of
GM-CSF restored Fc R-mediated phagocytosis as demonstrated in
SPC-GM+/+/GM / AMs, which had a phagocytic
index for IgG-opsonized beads 150% ± 23% greater than that for
unopsonized beads (Figure 1C). Thus, exposure to GM-CSF in the lung is
required for Fc R-mediated phagocytosis by primary AMs.
PU.1 expression rescues Fc R-mediated phagocytosis
by AMs, downstream of GM-CSF, was assessed as above in cultured GM / AM cell lines wherein PU.1 expression was absent
(mAMGFP+) or restored by retroviral gene transfer
(mAMPU.1+) and a cultured GM+/+ AM cell line
expressing PU.1 normally (MH-S). In MH-S cells, Fc R-mediated
phagocytosis was demonstrated by a phagocytic index for IgG-opsonized
beads 574% ± 40% greater than that for unopsonized beads (Figure
1D). Rat antimurine Fc RII/III antibody completely blocked
Fc R-dependent uptake. In GM / mAM cells,
Fc R-mediated phagocytosis did not occur in the absence of PU.1
(mAMGFP+; Figure 1E) but was restored by PU.1 expression
(mAMPU.1+; Figure 1F). Fc R-mediated phagocytosis in
mAMPU.1+ cells was completely blocked by antimurine
Fc RII/III antibody. Because pulmonary GM-CSF is required for
expression of PU.1 in AMs,20 these data indicate that
GM-CSF regulates Fc R-mediated phagocytosis by AMs via PU.1.
GM-CSF, via PU.1, regulates constitutive Fc R-mediated phagocytosis by
GM / AMs could be explained by failure to stimulate
expression of Fc Rs, levels of cell-surface Fc Rs on primary and
cultured AMs were assessed by flow cytometry. Fc Rs were present on
all primary GM+/+ AMs as demonstrated using a rat antimouse
Fc RII/III antibody (Figure 2A). In
contrast, Fc Rs were undetectable on GM / AMs but were
restored by pulmonary GM-CSF expression as demonstrated with AMs from
SPC-GM+/+/GM / mice. Because PU.1 stimulates
transcription of the human Fc RIB43 and murine
Fc RIIIA44 genes in myeloid cell lines, the role of PU.1
in regulation of AM Fc R levels was assessed using MH-S, mAMGFP+, and mAMPU.1+ cells. Fc Rs were readily
and uniformly detected on cultured MH-S cells as demonstrated using the
anti-Fc RII/III antibody (Figure 2A). In sharp contrast, Fc Rs were
absent on mAMGFP+ cells but were restored by PU.1 expression
in mAMPU.1+ cells (Figure 2A). Importantly,
mAMGFP+ cells did not contain detectable mRNA encoding
either Fc RIIIA or Fc RIIB (Figure 2B), both of which are detected
by the antimurine FcR antibody45,46 used for flow
cytometry above. Nor did these cells contain mRNA for Fc RIA. In
contrast, both wild-type (MH-S) and PU.1-expressing GM /
(mAMPU.1+) cultured AMs expressed mRNA for all 3 Fc Rs
(Figure 2B). Together with the results from primary AMs, these data
indicate that GM-CSF, via PU.1, is required for expression of both
activating FcRs (Fc RIA, Fc RIIIA) and inhibiting FcRs (Fc RIIB)
in AMs.
Fc R levels on AMs by 253% ± 95% as determined by flow
cytometry using the anti-Fc RII/III antibody (Figure 2C). In
contrast, Fc Rs were absent on GM / AMs following
pulmonary adenoviral infection. Importantly, ex vivo exposure of
GM / AMs to IFN- restored Fc R expression as
indicated by the marked increase in fluorescence of anti-Fc RII/III
antibody-stained cells (Figure 2C). Thus, enhancement of Fc R II/III
expression on AMs following adenoviral infection does not occur in
GM / mice and is not due to an inability of
GM / AMs to respond to IFN- .
Impairment of IFN-
expression by IL-18/IL-12, levels of these cytokines were quantified in
the lungs after pulmonary adenoviral infection. IFN- was not
detected in the lungs of uninfected GM+/+,
GM / , or SPC-GM+/+/GM / mice
(Figure 3A). In GM+/+ or
SPC-GM+/+/GM / mice, but not
GM / mice, high levels of IFN- were detected after
infection (392 ± 136, 384 ± 114, and 57 ± 29 pg/mL,
respectively; Figure 3A). Thus, pulmonary GM-CSF expression is required
for the high-level expression of IFN- accompanying pulmonary
adenoviral infection.
Because IL-18 and IL-12 stimulate IFN- PU.1 rescues IL-18 production in cultured GM / mice
but not GM / mice (Figure
4A). IL-18 mRNA was more abundant in
primary AMs from SPC-GM+/+/GM / than from
GM+/+ mice, likely reflecting the markedly increased
pulmonary GM-CSF levels in SPC-GM+/+/GM /
mice.34 To further assess the role of GM-CSF/PU.1 in
regulation of IL-18 expression in AMs, IL-18 release from
adenovirus-infected and uninfected MH-S, mAMGFP+, and
mAMPU.1+ cells was quantified by ELISA. Adenoviral infection
of MH-S cells, but not mAMGFP+ cells, markedly increased
IL-18 release (25.2 ± 7.9 vs 5.3 ± 1.2 pg/mL medium,
respectively; Figure 4B). PU.1 restored IL-18 release by
mAMPU.1+ cells following adenoviral infection (18.5 ± 4.5
pg/mL medium). Because pulmonary GM-CSF is required for expression of
PU.1 in primary AMs,20 these data indicate that GM-CSF
regulates IL-18 production by AMs via PU.1.
The present study was designed to determine the role of
GM-CSF in Fc The correlation between Fc The present studies support a model in which adenoviral enhancement of
Fc
Results of the present study support the concept that GM-CSF is
required for terminal differentiation of AMs in the lungs in
vivo.20 This is consistent with previous findings
demonstrating that rescue of a wild-type AM phenotype was associated
with restoration of GM-CSF only in the lungs in
SPC-GM+/+/GM
We thank Dr Harinder Singh for the gift of the PU.1/GFP- and
GFP-expressing retroviral vectors and thank Z. Chroneos, who provided
the GM
Submitted April 10, 2002; accepted July 15, 2002.
Prepublished online as Blood First Edition Paper, August 8, 2002; DOI 10.1182/blood-2002-04-1102.
Supported by the National Institutes of Health (NIH) R01 HL69549 (B.C.T.), NIH SCOR HL56387 (J.A.W.), Fondation Suisse de Bourse en Medecine et Biologie (FSBMB) (P.-Y.B.), TCHRF Procter Scholarship (P.-Y.B.), M. Carvajal Steuer (P.-Y.B.), and the Cystic Fibrosis Foundation, Research and Development Program (J.A.W. and B.C.T.).
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: Bruce C. Trapnell, Children's Hospital Medical Center, Division of Pulmonary Biology, 3333 Burnet Ave, Cincinnati, OH 45229; e-mail: bruce.trapnell{at}cchmc.org.
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M. Ochs, L. Knudsen, L. Allen, A. Stumbaugh, S. Levitt, J. R. Nyengaard, and S. Hawgood GM-CSF mediates alveolar epithelial type II cell changes, but not emphysema-like pathology, in SP-D-deficient mice Am J Physiol Lung Cell Mol Physiol, December 1, 2004; 287(6): L1333 - L1341. [Abstract] [Full Text] [PDF] |
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K. M. Empey, M. Hollifield, K. Schuer, F. Gigliotti, and B. A. Garvy Passive Immunization of Neonatal Mice against Pneumocystis carinii f. sp. muris Enhances Control of Infection without Stimulating Inflammation Infect. Immun., November 1, 2004; 72(11): 6211 - 6220. [Abstract] [Full Text] [PDF] |
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B. L. Schweitzer and R. P. DeKoter Analysis of Gene Expression and Ig Transcription in PU.1/Spi-B-Deficient Progenitor B Cell Lines J. Immunol., January 1, 2004; 172(1): 144 - 154. [Abstract] [Full Text] [PDF] |
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