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or IL-101
*
The Wistar Institute, Philadelphia, PA 19104; and
Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(type 1) and IL-4/IL-13
and IL-10 (type 2) cytokines on fluid phase and mannose
receptor-mediated endocytosis were assessed by horseradish peroxidase
and colloidal gold-BSA uptake and computer-assisted morphometric
analysis. IL-4 and IL-13 enhanced fluid phase pinocytosis and mannose
receptor-mediated uptake by activation of phosphatidylinositol
3-kinase. Inhibition of actin assembly showed that both cytokines
exerted actin-dependent and -independent effects. Ultrastructurally,
IL-4 and IL-13 increased tubular vesicle formation underneath the
plasma membrane and at pericentriolar sites, concurrent with decreased
particle sorting to lysosomes. By contrast, IL-10 or IFN- decreased
both fluid phase pinocytosis and mannose receptor-mediated uptake.
IFN- stimulated increased particle sorting to perinuclear lysosomes,
while IL-10 decreased this activity. In summary, our data document
differential effects on macrophage endocytic functions by type 1 or
type 2 cytokines associated with induction and effector pathways in
immunity. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Analysis of monocytes and macrophages has indicated directly or
indirectly that T cell-derived cytokines such as IL-4, IL-13, IL-10,
and IFN- regulate endocytic functions. Long term cultures of
monocytes treated with either IL-4/GM-CSF or IL-13/GM-CSF develop a
dendritic-like cell phenotype with high rates of fluid phase and MRM
uptake and increased Ag presentation (8, 9, 10, 11). An important question
that remains is whether dendritic cell-like properties of IL-4/GM-CSF-
or IL-13/GM-CSF-differentiated monocytes are shared by macrophages
exposed to IL-4 or IL-13 alone. By contrast, IL-10, another type 2
cytokine, reduced Ag presentation by decreasing endocytic uptake and
MHC class II cell surface expression, concomitant with vesicle
accumulation underneath the plasma membrane (12). IFN-, a type I
cytokine, has been predominantly studied for its activation of endosome
proteolysis and Ag processing in macrophages (13, 14) and for its
effects on uptake and survival of intracellular pathogens (15, 16).
Although macrophage/T cell interactions can result in T cell activation
and type 1 and type 2 cytokine secretion, no study has correlated
cytokine actions with endocytic uptake and vesicle sorting in human
macrophages.
Independent reports dealing with murine bone marrow-derived macrophages
have demonstrated regulation of macropinocytosis and MRM after exposure
to phorbol esters, M-CSF, and the cytokines IL-4, IL-13, and IFN-
(17, 18, 19, 20, 21). Studies of M-CSF have shown a requirement for actin assembly
in macropinosome formation based on sensitivity to cytochalasin as well
as a role for phosphatidylinositol 3-kinase (PI3-kinase) (20).
PI3-kinase has also been associated with endocytosis in other cell
types (22) and has been implicated in signal transduction after IL-13
treatment of human epithelial cells (23).
We have studied the effects of selected cytokines (IFN-, IL-4,
IL-13, and IL-10) on fluid phase and MRM uptake in primary human
macrophages, and candidate mechanisms of action. Texas Red dextran,
horseradish peroxidase (HRP), and BSA-conjugated colloidal gold were
used as endocytic tracers to define changes in uptake, ultrastructural
morphology of endosomes, and their sorting in cytokine-treated
macrophages. We show a differential effect on pinocytic uptake and
particle sorting to lysosome-like vesicles by IL-4/IL-13 and IFN-,
whereas IL-10 inhibits both functions.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The medium used throughout was RPMI 1640 supplemented with 2 mM
L-glutamine, 100 µg/ml Pen/Strep (Life Technologies,
Grand Island, NY), and 5% autologous or pooled AB+ (Sigma,
St. Louis, MO) human serum. Human recombinant (Hr) IL-4 and IL-10 were
gifts from Kevin Moore, DNAX (Palo Alto, CA) and were purchased from
R&D Systems (Minneapolis, MN). HrIL-13 was a gift from Adrian Minty,
Sanofi-elf (Toulouse, France), and was purchased from R&D Systems.
HrIFN- was purchased from R&D Systems (Abingdon, Oxon, U.K., and
Minneapolis, MN). Cytokine stocks were tested for endotoxin by the
Limulus test to ensure contamination was <25 pg
endotoxin/mg protein. Chemicals (cytochalasin D and wortmannin),
BSA-colloidal gold conjugates (20 nm), endotoxin standard, and the
E-Toxate Kit were purchased from Sigma Scientific (Poole, U.K.). HRP
(1000 U/mg) was purchased from Serva Feinbiochimica (Heidelberg,
Germany) and Sigma. Texas Red 70-kDa dextran (TR-70DX) was purchased
from Molecular Probes (Eugene, OR). Zymosan particles were purchased
from Sigma and fluoresceinated as previously described (24).
Monocyte-derived macrophages: isolation, cultivation, and treatment
Human PBMC were isolated from healthy donors as previously
described (25); in short, Ficoll-Hypaque (Pharmacia, Uppsala,
Sweden)-isolated mononuclear cells were incubated for 1 h in 2%
gelatin (Difco, Detroit, MI)-coated plates. Adherent cells (>94%
CD14+ by FACS analysis) were cultivated in 5% autologous
or pooled AB+ (Sigma) human serum for 48 h before
transfer to 48-well plates (Nunc, Naperville, IL) at a density of
2.5 x 105 cells/well (500-ml total volume), 96-well
plates (Nunc) at 105 cells/well (200-ml total volume), or
30-mm tissue culture plastic dishes at 3 x 106 (2-ml
total volume). IL-4, IL-13, IL-10, and IFN- (all 20 ng/ml, except
for IFN- at 100 U/ml) were added to day 6 postisolation
differentiated macrophages for 72 or 144 h (specified for each
assay) before measurement of endocytic uptake. Subsequent studies with
selected inhibitors (concentrations described in Results)
were performed by titration on cytokine-treated and control
monocyte-derived macrophages (MDMs) for 4 h before measurement of
HRP uptake as described below.
Quantitation of dextran and zymosan uptake
Macrophage cultures were treated with cytokines in triplicate in 48-well plates for 72 h as specified above. Texas Red 70-kDa dextran (TR-70DX) was added at a final concentration of 1 mg/ml for 60 min at 37°C, while fluoresceinated zymosan was added at 50 particles/cell. The cells were then washed four times with cold PBS and lysed in 1% Nonidet P-40 buffer (total volume, 100 µl) by thorough scraping of wells. The amount of fluorescent probe accumulated was calculated by fluorometer plate readings (Fluoroscan II, Labsystems, Chicago, IL) at the following settings for fluoresceinated zymosan and TR-70DX, respectively: 495 and 591 nm for excitation, and 520 and 612 nm for emission. Results from multiple experiments were analyzed by correcting for protein concentration obtained by the bicinchoninic acid assay (Bio-Rad, Richmond, CA).
HRP uptake
Macrophages were cultured in 96-well plates (Becton Dickinson,
Lincoln Park, NJ) at a density of 1 x 105 cells/well.
Cytokines were added as indicated above, with fresh media and cytokines
replaced after 3 days. Following treatment, macrophages were incubated
with HRP (1000 U/mg; Sigma) at a concentration of 1 mg/ml for 10, 20,
30, 45, and 60 min followed by washing three times with 1% FCS in PBS
and three times with PBS alone. Wells were lysed at each indicated time
in 100 µl of 0.05% Triton-X 100. The amount of HRP in the lysate was
quantified by adding substrate (o-dianisidine and
H2O2 in 0.05 M phosphate-citrate buffer)
and measuring the rate at which oxidized o-dianisidine
(absorbing at 460 nm) accumulates with reference to an HRP standard
curve. Kinetic absorbance readings were performed with a Spectra
Rainbow Reader (Salzburg, Austria), and data were analyzed with 
Soft 3 software (Biometallics, Princeton, NJ). Values were expressed as
nanograms of HRP per million MDM.
Electron microscopy
Three pulse-chase experiments were performed in which IL-4-,
IL-10-, IL-13-, or IFN--treated macrophages were cultivated in
30-mm2 tissue culture dishes and treated with cytokines for
72 h in RPMI 1640 and 5% autologous serum at 37°C. Cells were
either incubated with 20-nm colloidal gold particles coupled to
BSA (OD520 of 10) for 30 min at 37°C, washed with PBS,
fixed, and processed in Epon, as described below, or pulsed for 120 min
with 20-nm colloidal gold-BSA at 37°C, after which cells were washed
with warm PBS and cultivated further for 8 h. In the latter
pulse-chase experiments, HRP was incubated with pretreated cells at 10
mg/ml in normal medium for 40 min. Cultures were then washed with
ice-cold PBS and fixed with 0.5% glutaraldehyde in 200 mM sodium
cacodylate, pH 7.2, for 30 min at room temperature as described by
Tooze and Hollinshead (26). To maintain maximum enzyme activity,
samples were immediately reacted with the HRP substrate DAB (1 mg/ml)
for 30 min in the dark. Samples were postfixed for 1 h in 1%
OsO4 plus 1.5% potassium ferricyanide, stained en bloc
with 0.5% magnesium uranyl acetate overnight, dehydrated, and
processed for flat embedding in Epon. Cell monolayers were separated
from the culture dish using liquid nitrogen, and the blocks were
trimmed to a similar area using a Reichert Ultratrim milling device.
Sections were obtained using a Reichert Ultracut E ultramicrotome set
at a section thickness of 100 nm to give a gold interference color and
were collected onto Formvar carbon-coated grids in a serial
section series. Pulse-chase sections were immediately examined in the
electron microscope (EM 912 Omega electron microscope (Zeiss, New York,
NY) at 80 kV and elastic imaging) to avoid noticeable loss of DAB
reaction product upon storage.
Single-cell quantitation of endocytic compartments
DAB product was used to quantify endocytic area, while colloidal gold is naturally electron dense. Samples were analyzed by computer-generated thresholded images from sections of cytoplasm viewed at a constant magnification (x4000). Representative areas were recorded as HRP-early sections by their position relative to the plasma membrane (immediately beneath the plasma membrane with no other organelles or nuclei between the object and the plasma membrane), while representative HRP-gold sections were recorded in perinuclear and Golgi-rich regions. At least 15 random representative sections per analysis were acquired in a double-blind format using a ProScan 1024x1024 CCD camera and the EsiVision proprietary software package (SIS, Munster, Germany). A database was initiated for each treatment, and images were stored on a magneto-optical disk. Each treatment group was then decoded and analyzed using thresholded and density slice functions of the EsiVision analytical software. The software employs a digital version of point counting, a well-established quantitative immunocytochemical technique (27). Computer analysis of the images and quantitation of endocytic area were performed by establishing a threshold of electron density for every image, above which only the HRP and/or HRP-gold compartment were highlighted. The resulting computer thresholded image identified endosomal electron-dense areas by pseudo-color representation. Images were analyzed for the density of pixels, and the endocytic area for the section was calculated. Data for endocytic area were converted to relative image values by dividing pixels occupying the endocytic compartment by total pixels in cell profile per section.
Statistical analysis
Each group of data was analyzed for normal distribution, and all
subsequent comparisons between groups were two tailed. Significance in
the text is used for differences at an 
level of 0.05
(p < 0.05). All descriptive analysis and
statistical tests were performed with JMP 3.2.1 (SAS Institute, Cary,
NC).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The effects of IL-4, IL-13, IL-10, and IFN- on HRP uptake by
MDM (28) were examined in the absence or the presence of mannan, to
block MR-dependent uptake. IL-4 and IL-13 induced both MR-dependent and
independent uptake, whereas IFN- and IL-10 shared suppressive
effects. IL-4 and IL-13 induced a 280% increase in fluid phase HRP
uptake, while corresponding MR-dependent uptake increased sixfold
(n = 3; Fig. 1
). Similar
effects were observed on uptake of Texas Red-labeled dextran
(n = 4; data not shown).
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. Consistent with a sustained increase
in fluid phase and MRM uptake, IL-4 or IL-13 increased the rate of
endosomal uptake to 41.4 and 52.2 ng HRP/106 macrophages/h,
respectively. IFN-- or IL-10-treated macrophages showed similar
decreases in HRP rates of uptake, consistent with previous
observations. Interestingly, IL-10 and IFN- decreases were
associated with the lack of accumulation of HRP over time rather than
with a decrease in total uptake within the first timed samples.
Statistical differences between control and IL-10- or IFN--treated
samples were observed at the 45 min point, whereas IL-4 and IL-13
showed significant differences at the first time point.
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(40%; n = 3; data not shown).
Taken together, the results showed that type 2 cytokines activated
endocytosis differentially (IL-4 and IL-13 vs IL-10), while type 1
cytokine IFN- decreased fluid phase and MRM uptake. Role of PI3-kinase and actin polymerization in induction of endocytosis by IL-4 and IL-13
Wortmannin was used as a PI3-kinase inhibitor (30, 31) and was
studied for its role in HRP uptake in the presence or the absence of
IL-4 or IL-13. Wortmannin at 25 µM significantly reduced IL-4- or
IL-13-mediated uptake compared with that in control cytokine-treated
macrophages (Fig. 3). The sustained
increase in uptake in the presence of 25 µM wortmannin suggested a
contribution by additional PI3-independent mechanisms in IL-13- or
IL-4-induced pinocytosis. While higher concentrations of wortmannin
enhanced the inhibition of uptake in both cytokine-treated and control
cells, cellular functions other than P13-kinase could be affected at
these concentrations (31).
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). Interestingly, the ratio between
control and cytokine-treated uptake levels remained similar at the
highest concentrations of cytochalasin D tested, suggesting the
presence of an enhanced uptake mechanism in cytokine-treated
macrophages that is independent of actin.
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Results from cytokine-treated macrophage cultures pulsed with HRP
served as the basis of single cell ultrastructural analysis to 1)
define the intracellular distribution of HRP-containing endosomes
associated with cytokine regulation and 2) evaluate the relationship of
fluid phase uptake and substrate sorting following uptake over an 8-h
period. Cytokine (IL-4, IL-13, IL-10, or IFN-)-treated macrophages
were analyzed by electron microscopy for changes in HRP endosome
morphology and substrate sorting by incorporating a pulse chase with
colloidal gold (26). HRP was added as a short, additional pulse
following an 8-h previous timed incubation with colloidal gold-BSA to
identify vesicles containing previously sorted colloidal gold from
those taking up HRP within the subsequent shorter period. A schematic
representation of the experimental design and expected results within
untreated MDM is shown in Fig. 5.
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A),
compatible with early endosome ultrastructure (26). Rounded
HRP-containing vesicles were also within Golgi-rich or perinuclear
areas. The presence of colloidal gold aggregates sorted to a common
vesicle distal from the surface plasma membrane was consistent with
sorting of colloidal gold to later lysosome-like vesicles over the
8 h before fixation (Fig. 7A). The presence of HRP in
perinuclear vesicles, both singly and colocalized with colloidal gold,
indicated progression of HRP-only vesicles to these areas as well as a
shared sorting route for HRP and colloidal gold in a subset of
vesicles. Computer-assisted quantification of electron-dense areas
within MDM serial sections showed a greater concentration of substrate
within perinuclear and peri-Golgi areas, indicating active transport
and accumulation of colloidal gold and HRP substrates (Fig. 8).
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Cytokine-treated macrophages showed significant alterations in HRP
and colloidal gold vesicle formation and associated ultrastructure.
IL-4 and IL-13 increased the appearance of tubular HRP-containing
vesicles in areas underneath the plasma membrane (Fig. 6
, D
and F), significantly increasing the ratio in substrate
relative to that in perinuclear/peri-Golgi areas (Fig. 8). Quantitative
analysis of tracer electron-dense areas containing HRP and/or colloidal
gold confirmed that IL-4 and IL-13 significantly increased the
endosomal area underneath the plasma membrane by 297%
(p = 0.0005) and 229%
(p = 0.029), respectively (Fig. 8). Although no
significant change in perinuclear/peri-Golgi area was present in IL-13-
or IL-4-treated macrophages, the morphology of this compartment was
different from that in untreated cells. Specifically, an increased
density of tubular vesicles with minimal amounts of colloidal gold
particles indicated a decrease in lysosome-like vesicles containing
colloidal gold aggregates, as in untreated controls (Fig. 7, D and F). Taken together, both IL-13 and IL-4
showed a similar induction of endosome formation underneath the plasma
membrane, consistent with the increase in total uptake observed in
previous experiments.
Morphological changes in IL-10-treated macrophages indicated a striking
difference compared with those induced by IL-4 and IL-13. IL-10
treatment increased colloidal gold in areas underneath the plasma
membrane, while perinuclear/peri-Golgi areas contained reduced HRP and
colloidal gold compared with untreated controls (Fig. 8). Colloidal
gold-laden vesicles proximal to the plasma membrane varied in size,
with the occasional distinctive observation of single enlarged vesicles
that contained both colloidal gold and HRP substrate (Figs. 6G and 9C). A
decrease in substrate within perinuclear/peri-Golgi areas was
consistent with reduced endocytic uptake as observed in Figs. 1 and 2.
The presence of colloidal gold in vesicles close to the plasma membrane
suggested that the uptake that does take place may reach a common
sorting vesicle that is able to accumulate substrate over time.
In contrast to IL-10, IFN- treatment reduced total substrate within
perinuclear/peri-Golgi areas (Fig. 8), but increased the formation of
lysosome-like vesicles containing distinct aggregates of colloidal gold
(Fig. 10D). In contrast to
untreated controls, a reduced amount of HRP was present at
perinuclear/peri-Golgi areas. The latter finding is relevant to the
observed reduction in uptake observed in IFN--treated macrophages
(Figs. 1 and 2); this may reflect a reduced accumulation of substrates
over time concurrent with an increased capacity to sort contents to
later vesicles with higher efficiency. Overall, cytokine-induced
changes in endosomal morphology and substrate localization establish
the distinct regulation of endosome formation and substrate sorting by
different cytokines.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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as opposed to IL-4 and IL-13 treatments show
for the first time the consequences of type 1 and type 2 cytokine
regulation of MR- and non-MR-mediated uptake in association with
specific ultrastructural and functional changes.
Among T cell-derived cytokines, IFN- is a central type 1 cytokine
involved in macrophage activation due to its induction of microbicidal
mechanisms and Ag presentation, resulting in proteolytic degradation of
internalized proteins or pathogens (16). Although type 2 cytokines are
generally summarized as deactivators of IFN--like effects and thus
are seldom viewed as regulating an activated phenotype in macrophages
(32), IL-4 and IL-13 activate several macrophage functions associated
with enhanced cellular immunity. IL-4 and IL-13 increase expression of
MHC class II (33), costimulatory molecules (34), MR uptake (35, 36),
and signal transduction, leading to increased secretion of
proinflammatory cytokines such as IL-12 and TNF- after stimulation
by LPS (37). In this report we provide further support for the concept
that IL-4 and IL-13 induce an alternative activated state in
macrophages by our observations that both cytokines induce a two- to
threefold increase in non-MR-mediated uptake and a sixfold increase in
MRM uptake (Fig. 1). Activation of pinosome formation and membrane
turnover by both cytokines is consistent with the linear increase in
HRP accumulation in IL-4 or IL-13-treated macrophages over time (Fig. 2). While no additive effects were observed between IL-13 and IL-4 when
used jointly, a reversal of their inductive effects on endocytosis was
observed within 48 h if cytokines were removed (data not shown).
In contrast to previous reports suggesting a predominant role for IL-4-
or IL-13-mediated MRM uptake, we document a greater total, rather than
only relative, increase in non-MRM uptake by both cytokines. Non-MRM
HRP uptake includes micro- and macropinocytosis. The latter has been
associated with activation of PI3-kinase and actin polymerization (20).
Direct involvement of PI3-kinase in IL-13- and IL-4-mediated induction
of both MRM and non-MRM uptake was shown by inhibition of uptake in the
presence of wortmannin (Fig. 3). Involvement of PI3-kinase in the
signal transduction pathway of IL-13 is further supported by its
activation in epithelial cells expressing the IL-13R (23). The role of
PI3-kinase in macropinosome formation in M-CSF-differentiated
macrophages together with its role in the induction of IL-13 and
IL-4-stimulated pinocytosis suggest a common signal transduction
mechanism for endocytic enhancement in macrophages. Experiments with
cytochalasin D showed that the effects of IL-13 and IL-4 were partly
dependent on actin (Fig. 4).
Activation of pinosome formation by IL-4 and IL-13 was also
demonstrated by an increased density of tubular vesicles underneath the
plasma membrane, suggestive of expansion of the early endosomal
compartment (Fig. 6). This conclusion was supported by the localization
of a large density of tubular endosomes at pericentriolar regions that
are associated with trafficking of recycling early endosomes, such as
the mannose and transferrin receptors (6, 38, 39) (Fig. 10). An
increase in transferrin-FITC uptake by IL-4- or IL-13-treated
macrophages is consistent with activation of both fluid phase and
recycling receptor-mediated uptake (L. J. Montaner, unpublished
observations). In addition to endocytosis, IL-13 and IL-4 also increase
gene expression of both the transferrin and mannose receptors (40, 41).
Definitive characterization of cytokine effects on endosomal
trafficking awaits the combined use of endocytic tracers with specific
mAbs against early or late vesicle-associated proteins.
Although the relationship between pinocytosis and enhancement of Ag
presentation capacity is well recognized in dendritic and related cells
(8, 9, 42), our data suggest that T cell secretion of IL-4 or IL-13, in
contrast to that of IFN- or IL-10, is able to induce dendritic
cell-like properties in differentiated macrophages; IL-4/IL-13 could
therefore enhance acquisition of soluble or mannosylated Ag for
continued restimulation of memory T cells.
The selectivity of IL-4 and IL-13 effects among type 2 cytokines
regulating macrophage function was best exemplified by the decrease in
fluid phase and mannose-mediated uptake observed with IL-10 (Figs. 1 and 2). The latter was consistent with the described role of IL-10 as a
general deactivator of immune function, including down-regulation of
MHC class II expression by macrophages (32). The decreased HRP uptake
induced by IL-10 together with its regulation of HRP endosome
ultrastructure suggest a general effect on uptake associated with a
decreased accumulation of substrates within later vesicles.
Surprisingly, this analysis also showed an accumulation of colloidal
gold particles within vesicles underneath the plasma membrane, which
was not observed with other cytokine treatments (Fig. 9). It is of
interest to contrast this latter observation with the recent
characterization of an IL-10-induced decrease in membrane trafficking
of MHC class II, since IL-10 inhibited re-expression of recycling
molecules by promoting their accumulation within distended
intracellular vesicles (12). Further analysis is needed to determine
whether fluid phase substrates internalized in the presence of IL-10
are sorted to high MHC class II-containing vesicles. Taken together,
our data suggest that IL-10 induces a distinct endocytic phenotype,
consistent with a decreased capacity to take up and present Ag.
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increased
compartmentalization and sorting of colloidal gold aggregates (Fig. 10)
consistent with the enhanced formation of late endosomes or lysosomes
(43). The latter is also in accordance with its activation of aspartyl
protease activity, cathepsin D (active at pH 3.5), and late endosomal
Ag processing (13, 14, 44). We show for the first time that this
activity is associated with a relative shut-down of fluid phase and MRM
pinocytosis, further supporting a potential inverse relationship
between the induction of pinocytosis (fluid phase and MR uptake) and
lysosome formation. Additional experiments are needed to determine
whether IL-4 and IL-13 decrease lysosomal maturation in contrast to
IFN-, as predicted by our morphological observations.
Our data support a differential role for IL-4 or IL-13 compared with
IFN- in suppressing colloidal gold aggregate formation; this may
bear on the inability of macrophages to clear intracellular pathogens
in immune environments associated with type 2 responses (45). On the
other hand, the endosomal stimulation by IL-4 or IL-13 may support
increased Ag uptake and presentation of soluble extracellular Ags,
providing a mechanism for T cell-dependent enhancement of Ag uptake by
bystander macrophages. Additional studies will explore whether
differential regulation of endosome ultrastructure and sorting capacity
influences Ag processing (7, 46) and MHC class I-associated
presentation by macrophages (1, 47).
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Luis J. Montaner, The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104. E-mail address:
3 Abbreviations used in this paper: MR, mannose receptor; MRM, mannose receptor-mediated; GM-CSF, granulocyte-macrophage CSF; PI3-kinase, phosphatidylinositol 3-kinase; HRP, horseradish peroxidase; Hr, human recombinant; MDM, monocyte-derived macrophage; DAB, diaminobenzidine.
Received for publication November 16, 1998. Accepted for publication January 28, 1999.
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 G. Tian, D. Wilcockson, V. H. Perry, P. M. Rudd, R. A. Dwek, F. M. Platt, and N. Platt Inhibition of {alpha}-Glucosidases I and II Increases the Cell Surface Expression of Functional Class A Macrophage Scavenger Receptor (SR-A) by Extending Its Half-life J. Biol. Chem., September 17, 2004; 279(38): 39303 - 39309. [Abstract] [Full Text] [PDF]
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 Y. Liu, H. Liu, B. O. Kim, V. H. Gattone, J. Li, A. Nath, J. Blum, and J. J. He CD4-Independent Infection of Astrocytes by Human Immunodeficiency Virus Type 1: Requirement for the Human Mannose Receptor J. Virol., April 15, 2004; 78(8): 4120 - 4133. [Abstract] [Full Text] [PDF]
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 Y. Zhu, X. Li, E. H. Schuchman, R. J. Desnick, and S. H. Cheng Dexamethasone-Mediated Up-Regulation of the Mannose Receptor Improves the Delivery of Recombinant Glucocerebrosidase to Gaucher Macrophages J. Pharmacol. Exp. Ther., February 1, 2004; 308(2): 705 - 711. [Abstract] [Full Text] [PDF]
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J. Chehimi, Q. Luo, L. Azzoni, L. Shawver, N. Ngoubilly, R. June, G. Jerandi, M. Farabaugh, and L. J. Montaner HIV-1 transmission and cytokine-induced expression of DC-SIGN in human monocyte-derived macrophages J. Leukoc. Biol., November 1, 2003; 74(5): 757 - 763. [Abstract] [Full Text] [PDF]
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L. Martinez-Pomares, D. M. Reid, G. D. Brown, P. R. Taylor, R. J. Stillion, S. A. Linehan, S. Zamze, S. Gordon, and S. Y. C. Wong Analysis of mannose receptor regulation by IL-4, IL-10, and proteolytic processing using novel monoclonal antibodies J. Leukoc. Biol., May 1, 2003; 73(5): 604 - 613. [Abstract] [Full Text] [PDF]
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Y. Delneste, P. Charbonnier, N. Herbault, G. Magistrelli, G. Caron, J.-Y. Bonnefoy, and P. Jeannin Interferon-gamma switches monocyte differentiation from dendritic cells to macrophages Blood, January 1, 2003; 101(1): 143 - 150. [Abstract] [Full Text] [PDF]
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M. B. M. Teunissen, G. Piskin, S. d. Nuzzo, R. M. R. Sylva-Steenland, M. A. de Rie, and J. D. Bos Ultraviolet B Radiation Induces a Transient Appearance of IL-4+ Neutrophils, Which Support the Development of Th2 Responses J. Immunol., April 15, 2002; 168(8): 3732 - 3739. [Abstract] [Full Text] [PDF]
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J. Zerrahn, U. E. Schaible, V. Brinkmann, U. Guhlich, and S. H. E. Kaufmann The IFN-Inducible Golgi- and Endoplasmic Reticulum- Associated 47-kDa GTPase IIGP Is Transiently Expressed During Listeriosis J. Immunol., April 1, 2002; 168(7): 3428 - 3436. [Abstract] [Full Text] [PDF]
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P. Ancuta, Y. Bakri, N. Chomont, H. Hocini, D. Gabuzda, and N. Haeffner-Cavaillon Opposite Effects of IL-10 on the Ability of Dendritic Cells and Macrophages to Replicate Primary CXCR4-Dependent HIV-1 Strains J. Immunol., March 15, 2001; 166(6): 4244 - 4253. [Abstract] [Full Text] [PDF]
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M. Groger, W. Holnthoner, D. Maurer, S. Lechleitner, K. Wolff, B. B. Mayr, W. Lubitz, and P. Petzelbauer Dermal Microvascular Endothelial Cells Express the 180-kDa Macrophage Mannose Receptor In Situ and In Vitro J. Immunol., November 15, 2000; 165(10): 5428 - 5434. [Abstract] [Full Text] [PDF]
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A. W. Tsang, K. Oestergaard, J. T. Myers, and J. A. Swanson Altered membrane trafficking in activated bone marrow-derived macrophages J. Leukoc. Biol., October 1, 2000; 68(4): 487 - 494. [Abstract] [Full Text]
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A. Prada-Delgado, E. Carrasco-Marin, G. M. Bokoch, and C. Alvarez-Dominguez Interferon-gamma Listericidal Action Is Mediated by Novel Rab5a Functions at the Phagosomal Environment J. Biol. Chem., May 25, 2001; 276(22): 19059 - 19065. [Abstract] [Full Text] [PDF]
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