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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 1039-1046
IMMUNOBIOLOGY
The PI3 kinase, p38 SAP kinase, and NF- B signal transduction
pathways are involved in the survival and maturation of
lipopolysaccharide-stimulated human monocyte-derived
dendritic cells
Kirit M. Ardeshna,
Arnold R. Pizzey,
Stephen Devereux, and
Asim Khwaja
From the Department of Haematology, Royal Free and University
College Medical School, London, United Kingdom.
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Abstract |
As a dendritic cell (DC) matures, it becomes more potent as an
antigen-presenting cell. This functional change is accompanied by a
change in DC immunophenotype. The signal transduction events underlying
this process are poorly characterized. In this study, we have
investigated the signal transduction pathways involved in the
lipopolysaccharide (LPS)-induced maturation of human monocyte-derived DCs (MoDCs) in vitro. We show that exposure of immature MoDCs to LPS
activates the p38 stress-activated protein kinase (p38SAPK), extracellular signal-regulated protein kinase (ERK), phosphoinositide 3-OH kinase (PI3 kinase)/Akt, and nuclear factor (NF)- B pathways. Studies using inhibitors demonstrate that PI3 kinase/Akt but not the
other pathways are important in maintaining survival of LPS-stimulated MoDCs. Inhibiting p38SAPK prevented activation of the transcription factors ATF-2 and CREB and significantly reduced the
LPS-induced up-regulation of CD80, CD83, and CD86, but did not have any
significant effect on the LPS-induced changes in macropinocytosis or
HLA-DR, CD40, and CD1a expression. Inhibiting the NF-B pathway
significantly reduced the LPS-induced up-regulation of HLA-DR as well
as CD80, CD83, and CD86. Inhibiting the p38SAPK and NF-B pathways
simultaneously had variable effects depending on the cell surface
marker studied. It thus appears that different aspects of LPS-induced
MoDC maturation are regulated by different and sometimes overlapping pathways.
(Blood. 2000;96:1039-1046)
© 2000 by The American Society of Hematology.
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Introduction |
Dendritic cells (DCs) are the most potent of all
antigen-presenting cells and are unique in their ability to stimulate
naive T cells.1 DCs are found in almost all tissues where,
in their immature state, they take up antigens from their environment
with high efficiency. Upon encounter with foreign antigen, DCs undergo a complex maturation process and become specialized in antigen presentation. This is achieved by up-regulation of cell surface major
histocompatibility complex (MHC) class I and II and the costimulatory
molecules CD80, CD86, and CD40. Concomitantly, the DC down-regulates
its antigen-capture mechanisms.2 In addition, DCs migrate
from the tissues via the afferent lymphatics to the paracortical areas
of regional lymph nodes. This is achieved by a change in the cell
surface expression of receptors, which alter their responsiveness to
various chemokines.3 The constant traffic of T cells
through the paracortical areas of lymph nodes makes this a prime site
for antigen-laden DCs to encounter the low-frequency antigen-specific
naive or memory T cells, which recognize the MHC-peptide complexes
displayed on the surface of the DCs. In this way, a
specific immune response can be initiated.
The maturation process is central to the function of the DC and enables
one cell to perform different, highly specialized functions
sequentially. There are many stimuli that can initiate this maturation
process in vitro. These include the proinflammatory cytokines tumor
necrosis factor (TNF)- and interleukin (IL)-1 , and bacterial
products such as lipopolysaccharide (LPS).4,5 Ligation of
CD40 by CD40L and the engagement of Fc receptor by immune complexes
have also been shown to stimulate maturation, as have CpG DNA motifs
found in prokaryotic DNA and viral double-stranded RNA.6-9
LPS has also been shown to lead to the maturation of DCs in
vivo.10
Signal transduction via mitogen-activated protein (MAP) kinases plays
an important role in cellular responses including growth factor-induced cell proliferation, differentiation, and survival. Three groups of MAP kinases have been identified in mammals: the extracellular signal-regulated protein kinases
(ERKs),11,12 the c-Jun N-terminal kinases
(JNKs),13,14 and the p38 stress-activated protein kinases
(p38SAPKs).15,16 These kinases are activated by
phosphorylation of both threonine and tyrosine residues in a regulatory
TXY motif present in all MAP kinases. This phosphorylation is carried
out by upstream MAP kinase kinases. Activated MAP kinases subsequently
phosphorylate their respective substrates on serine or threonine
residues. The ERK pathway appears mainly to respond to mitogens and
growth factors that regulate cell proliferation and differentiation.
The JNK and p38SAPK pathways are predominantly activated by stress,
such as osmotic changes and heat shock, but also by inflammatory
cytokines such as IL-1 and TNF-.
In addition to MAP kinases, other signal transduction pathways may
mediate cellular responses to external stimuli. These include the
phosphoinositide-3-OH kinase (PI3 kinase) pathway, a downstream target
of which is the Akt kinase known to be important in cell survival,17 and the NF-B transcription factor, which is
stimulated by proinflammatory cytokines and growth
factors.18 It is becoming increasingly clear that there is
cooperation between different signaling pathways and, with the
development of specific inhibitors, it has become possible to dissect
out further the roles of each component in important cellular processes.
Despite their pivotal role in DC function, little is known regarding
the signal transduction events involved in DC maturation. In this
study, we have looked at the activation of several signaling pathways
in LPS-stimulated DCs. Using specific inhibitors, we have found that
the PI3 kinase/Akt pathway is important in the survival of
LPS-stimulated human monocyte-derived DCs (MoDCs) and that the p38SAPK
and NF-B pathways play important and sometimes overlapping roles in
regulating some, but not all, aspects of LPS-induced MoDC maturation.
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Materials and methods |
Cytokines and inhibitors
Recombinant human granulocyte-macrophage colony-stimulating factor
(rhGM-CSF) (Hoechst, Marburg, Germany) and IL-4 (Schering Plough,
England) were used at a final concentration of 100 ng/mL. SB203580
(Calbiochem-Novabiochem UK, Nottingham, UK) was used at a final
concentration of 40 µmol/L. This concentration was used because it
was required to be present in some cultures for up to 48 hours in some
instances. PD98059 (Biomol Research Labs Inc., Plymouth
Meeting, PA) was used at a final concentration of 50 µmol/L. LY294002
(Biomol Research Labs, Plymouth Meeting, PA) was used at a final
concentration of 25 µmol/L. SN50 peptide and a control peptide
(Calbiochem-Novabiochem UK) were used at a final concentration of 50 µg/mL. SB203580, PD98059, and LY294002 were all dissolved in
dimethylsulfoxide (DMSO), whereas SN50 peptide was made as an aqueous solution.
Cell selection
Peripheral blood was collected from normal volunteers in EDTA. Red
cells were largely removed by dextran sedimentation using 1% w/v
dextran (Pharmacia Biotech, Uppsala, Sweden); the supernatant was then
layered on Ficoll-Paque (Pharmacia Biotech, Uppsala, Sweden) and
centrifuged at 800g for 15 minutes at 20°C. Interface cells
were removed, diluted with phosphate-buffered saline (PBS; Gibco BRL,
Paisley, Scotland), and centrifuged at 725g. The resulting cell
pellet was resuspended in 200 µL of PBS, and monocytes were positively selected using a murine anti-human CD14 antibody (Dako A/S,
Glostrup, Denmark) with which the cells were incubated for 30 minutes
at 4°C. After this, the cells were washed and further incubated
with goat anti-mouse microbeads (Miltenyi Biotec, Bergisch Gladbach,
Germany) for 30 minutes. The monocytes were then magnetically selected
using a VS+ column (Miltenyi Biotec). The resulting samples were
greater than 90% pure monocytes by morphology. The manufacturer (Miltenyi Biotec) has shown that cells that have been selected using
their antibodies have shed 25% of their microbeads (50 nm diameter)
after 4 hours in culture at 37°C, and that by 24 hours almost
nothing remains on the cells (personal communication, E. Schultz).
Cell culture and flow cytometric analysis of cell surface
antigens
Monocyte-enriched cells were cultured at a starting concentration of
between 5 × 105 and 1 × 106
cells/mL in RPMI 1640 (Gibco BRL) supplemented with 10% fetal calf
serum (FCS; Gibco BRL) containing GM-CSF and IL-4 for 7 days in 6-well
plates (Costar, Cambridge, MA). On days 3 and 5, half of the original
medium was removed and replaced by fresh medium containing growth
factors. On day 7, the resulting immature DCs were split as
appropriate, and LPS (100 ng/mL; Sigma Chemical Co., St. Louis, MO)
and/or inhibitors were added. The resulting cells were analyzed at
varying time points afterward.
Cells at 2.5 × 105 were pelleted and resuspended in
100 µL of 50:50 PBS and human AB serum. These cells were stained for
60 minutes on ice using an antibody to which a fluorochrome was
directly conjugated. Cells were then washed once in ice-cold PBS.
Appropriate isotype controls were used at the same protein
concentration as the test antibody. Samples were analyzed using the
Beckman-Coulter EPICS Elite flow cytometer. Fluorochrome-conjugated
murine antibodies directed against the following antigens were used:
CD1a, CD40, CD80, and CD86 (Serotec, Oxford, UK); HLA-DR (Dako A/S);
and CD83 (Immunotech, Marseille, France). In preliminary studies, we
were able to show that DMSO (at the same concentrations as diluent for
SB203580) did not inhibit the LPS-induced changes in expression of
these cell surface antigens (ratio of LPS [%
positive × MCF]:LPS/DMSO [%
positive × MCF) = 1.00:1.05 [n = 7]).
Endocytosis assay with fluoroisothiocyanate (FITC)-dextran
The method described by Sallusto et al5 was used. In
brief, FITC-dextran (Molecular Probes, Eugene, OR) was added to the DCs or mononuclear cells, resuspended in RPMI/10% FCS, at a final concentration of 1 mg/mL. After incubation for varying time intervals of up to 1 hour at 37°C, the cells were removed and washed 4 times with ice-cold PBS and analyzed on a Beckman-Coulter EPICS Elite flow
cytometer. Dead cells were excluded by propidium iodide staining.
Quantification of cell survival
At indicated time points, cells were washed in annexin V binding
buffer (140 mmol/L NaCl, 5 mmol/L CaCl2, 10 mmol/L HEPES, pH 7.4) and resuspended in buffer containing annexin V-FITC
(Boehringer Mannheim, Lewes, UK) and propidium iodide, according to the
manufacturer's instructions. After 10 minutes of incubation at room
temperature, samples were placed on ice and directly analyzed by flow
cytometry. Cells negative for annexin V and propidium iodide staining
were considered viable.
Sodium dodecyl sulfate/polyacrylamide gel
electrophoresis (SDS/PAGE) and Western blotting
Immature MoDCs were washed twice and incubated in RPMI 1640 alone
for 2 hours at 37°C. Cells were stimulated with LPS (100 ng/mL)
and, at indicated time points, 1 × 106 cells were
removed and washed once with cold PBS, and the pellet was resuspended
in 2× SDS sample buffer and boiled for 5 minutes. When inhibitors
were used, cells were incubated for 30 minutes before the addition of
LPS. Proteins were separated by SDS/PAGE and blotted onto
nitrocellulose membranes (Hybond C-Extra; Amersham, Amersham, UK).
Membranes were blocked with 5% (w/v) nonfat dry milk (Marvel, Premier
Brands, Wirral, UK)/0.1% (v/v) Tween 20 in PBS for 1 hour at room
temperature and incubated overnight with primary antibody at 4°C.
Antibodies to phospho- and total p38, phospho- and total Akt, phospho-
and total ERK, phospho- and total ATF2, and phospho- and total CREB
were all from New England Biolabs (Hitchin, UK). Anti-IB was from
Santa Cruz Biotechnology (Santa Cruz, CA) and anti-tubulin was from
Boehringer Mannheim. Detection was by enhanced chemiluminescence
(ECL) or ECL Plus (Pharmacia Biotech, Amersham)
Nuclear NF-B pull-down assay
Day-7 MoDCs (5 × 106 per point) were stimulated
with LPS after preincubation with SN50 or control SN50M peptide
(concentration 50 µg/mL), and nuclear extracts were prepared. Cells
were pelleted and resuspended in 0.4 mL hypotonic lysis buffer (20 mmol/L HEPES, pH 7.9, 10 mmol/L KCl, 1 mmol/L EDTA, 0.2% Triton X-100,
1 mmol/L sodium orthovanadate plus protease inhibitors) and kept on ice for 20 minutes. After centrifugation at 14 000g for 5 minutes at 4°C, the nuclear pellet was extracted with 0.1 mL hypertonic lysis buffer (20 mmol/L HEPES, pH 7.9, 0.4 mol/L NaCl, 1 mmol/L EDTA, 1 mmol/L sodium orthovanadate plus protease inhibitors) on ice for a
further 20 minutes. After centrifugation at 14 000g for 5 minutes at 4°C, the supernatant was diluted to 100 mmol/L NaCl and
incubated with 25 µL of agarose beads conjugated to a consensus
NF-B binding oligonucleotide (Santa Cruz) for 1 hour at 4°C.
After 3 washes, 25 µL of 2× sample buffer was added and boiled
for 5 minutes. The result was analyzed by SDS/PAGE and immunoblotting
using a polyclonal anti-p65 NF-B antibody (Santa Cruz).
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Results |
LPS induces phenotypic maturation of MoDCs
Peripheral blood monocytes were cultured with GM-CSF and
IL-4 for 7 days to generate immature MoDCs. We have previously shown that these cells have the functional attributes of DCs, being able to
present both primary and secondary antigens to CD4+ T cells
and being potent stimulators of a mixed lymphocyte
reaction.19 Incubation of these cells with LPS at a
concentration of 100 ng/mL for a further 48 hours led to significant
up-regulation of cell surface CD80, CD86, HLA-DR, CD83, and CD40 (Table
1). Incubation of immature MoDCs with LPS
has been shown to result in the down-regulation of CD1a; in our series
of experiments, although there was a decrease in CD1a expression, this
was not statistically significant (Table 1). The uptake of
FITC-dextran is known to be maximal in the immature MoDC and occurs by
a combination of macropinocytosis and binding to the mannose receptor.
Accordingly, we were able to demonstrate a reduction in FITC-dextran
uptake over 1 hour by 70% ± 10% (n = 4) when the MoDCs were
matured with LPS.
LPS activates p38SAPK, ERK, and Akt in immature MoDCs
LPS has been shown to activate multiple signaling pathways
in macrophages, including ERK, JNK, and p38SAPK.15,20,21
The classic MAP kinase pathway (MEK/ERK), the PI3 kinase/Akt pathway, and the p38SAPK pathway are known to be important in many cell types as
regulators of cell survival, proliferation, and differentiation. We
therefore looked for activation of these pathways in MoDCs treated with
LPS. Activation of ERK, Akt, and p38SAPK results in their
phosphorylation, and this can be detected by Western blotting using
phosphorylation-specific antibodies. We found that within 15 to 30 minutes of the addition of LPS to immature MoDCs, p38SAPK, Akt, and ERK
were activated (Figure 1).
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| Fig 1.
LPS induces the phosphorylation of p38SAPK, ERK, and Akt
kinase.
Peripheral blood monocytes cultured with GM-CSF and IL-4 for 7 days
(immature MoDCs) were exposed to LPS (100 ng/mL) and, after variable
lengths of time, samples were removed and analyzed by probing Western
blots and with phosphorylation-specific antibodies. In some cases, the
day-7 MoDCs were preincubated with signal transduction pathway
inhibitors for 30 minutes before exposure to LPS. (A) The
phosphorylation (and hence activation) of p38SAPK induced by LPS occurs
within 15 minutes and persists for at least 60 minutes. The lower part
shows the same blot probed for total p38SAPK to demonstrate equal
loading of samples. (B) The phosphorylation (and hence activation) of
Akt and ERK induced by LPS occurs within 30 minutes after exposure of
MoDCs to LPS. The phosphorylation of Akt is inhibited if MoDCs are
preincubated with the PI3 kinase inhibitor LY294002. Similarly, the
phosphorylation of ERK is inhibited if MoDCs are preincubated with the
MKK1/MEK inhibitor PD98059. PD98059 and LY294002 were both dissolved in
DMSO; therefore, MoDCs that had been incubated with DMSO alone were
used as controls (d). The lower part shows the same blot probed for
total Akt to demonstrate equal loading of samples. Similar results were
obtained in 4 separate experiments.
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Inhibition of PI3 kinase leads to decreased survival of
LPS-stimulated MoDCs
To evaluate the role of these pathways in MoDC survival and
maturation, we used specific inhibitors of these pathways. PD98059 suppresses the activation of MAPK/ERK by inhibiting the upstream MAPK
kinase-1 (MKK1/MEK).22 LY294002 is a specific inhibitor of
PI3 kinase and prevents activation of the Akt kinase and other targets
of PI3 kinase.23 SB203580 binds to the ATP-binding pocket of p38SAPK, inhibiting its activity but not its own
phosphorylation.24 Figure 1B shows that incubation of MoDCs
with LY294002 or PD98059 effectively blocked the LPS-induced activation
of the PI3 kinase/Akt and MEK/ERK pathways, respectively. Inhibition of
PI3 kinase with LY294002 led to reduced viability as a result of
increased apoptosis (Figure 2), with only a
quarter of MoDCs remaining viable at 48 hours. Inhibition of either the
MEK/ERK or p38SAPK pathways did not affect MoDC survival (Figure 2).
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| Fig 2.
Viability of LPS-stimulated MoDCs exposed to inhibitors.
Peripheral blood monocytes cultured with GM-CSF and IL-4 for 7 days
were incubated with LPS with or without inhibitors for 24 or 48 hours.
The percentage of cells surviving at the end of this incubation was
measured by flow cytometry. Only cells that did not bind
FITC-conjugated annexin V and did not take up propidium iodide were
classified as viable. PD indicates PD98059 (MKK1/MEK inhibitor); LY,
LY294002 (PI3 kinase inhibitor); SB, SB203580 (p38SAPK inhibitor).
Blocking the PI3 kinase pathway has a marked effect on MoDC survival,
whereas blocking the MAPK or p38SAPK pathway does not affect MoDC
survival even after 48 hours. Results are the mean ± SEM of 4 experiments.
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Inhibition of p38SAPK prevents some, but not all, of the maturation
changes induced by LPS
Because inhibition of PI3 kinase resulted in apoptosis, the effect
of blocking this pathway on MoDC maturation could not be reliably
assessed. Inhibition of MEK with PD98059 had no effect on any measure
of MoDC maturation (data not shown). Blocking the p38SAPK pathway with
SB203580 significantly inhibited the LPS-induced up-regulation of CD83,
CD86, and, to a lesser extent, CD80 (Figure 3; Table 2).
Inhibition of p38SAPK did not, however, affect the LPS-induced
up-regulation of CD40 and HLA-DR. The reduced uptake of FITC-dextran
seen in LPS-matured MoDCs was also unaffected. The effects of SB203580
were not likely to be due to nonspecific toxicity because there was no
increase in apoptosis. In addition, washout experiments showed that the
effects of SB203580 once removed from the culture system did not
prevent the subsequent phenotypic changes normally induced by LPS (data
not shown). These results show that certain features of MoDC maturation
are regulated by signaling via p38SAPK and imply that different aspects
of the maturation process induced by LPS may be regulated by distinct signal transduction pathways.
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| Fig 3.
Inhibition of LPS-induced up-regulation of CD80, CD83,
and CD86.
Bar charts showing the expression of various cell surface markers on
MoDCs. Immature MoDCs were split on day 7 of culture and exposed to
either diluent control, LPS (100 ng/mL), SB203580 (40 µmol/L), or
SB203580 together with LPS for 48 hours, before incubation with
fluorochrome-conjugated antibodies directed against cell surface
antigens and analysis using a flow cytometer. The data shown are the
product of the percentage of cells expressing various cell surface
antigens and the mean cell fluorescence of the whole population of
cells under scrutiny. The value obtained for cells exposed to LPS alone
has been normalized to 1. Error bars indicate the SEM. (A) The
LPS-induced up-regulation of CD80, CD83, and CD86 is inhibited by the
p38SAPK inhibitor SB203580. Representative single-parameter histograms
show the expression of CD80, CD83, and CD86 by day-7 MoDCs 48 hours
after the addition of LPS (shaded gray), SB203580 plus LPS (shaded
black), or nothing (unshaded). (B) Inhibiting p38SAPK has little or no
effect on the LPS-induced changes with regard to CD1a, CD40, HLA-DR,
and macropinocytosis.
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The addition of LPS results in the phosphorylation of CREB and
ATF-2 transcription factors in a p38SAPK-dependent manner
It is likely that activation of p38SAPK influences the transcription
of various genes involved in the maturation process of MoDCs.
Therefore, we studied changes in the phosphorylation of CREB and ATF-2,
which are known downstream transcription factors in the p38SAPK
pathway. Figure 4 shows that these
transcription factors are activated by phosphorylation within 30 minutes of the addition of LPS to immature MoDCs. Inhibiting the
p38SAPK pathway with SB203580 before the addition of LPS resulted in
inhibition of the activation of CREB and ATF-2.
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| Fig 4.
LPS induces phosphorylation of the transcription factors
ATF-2 and CREB in a p38SAPK-dependent manner.
Peripheral blood monocytes cultured with GM-CSF and IL-4 for 7 days
(immature MoDCs) were exposed to LPS (100 ng/mL), and after variable
lengths of time, samples were removed, separated by SDS/PAGE, and then
probed with phosphorylation-specific antibodies to the transcription
factors CREB and ATF-2. In some cases, the day-7 MoDCs were
preincubated with the p38SAPK inhibitor SB203580 for 30 minutes before
exposure to LPS. Because SB203580 was dissolved in DMSO, MoDCs that had
been incubated with DMSO alone were used as controls (d). The Western
blots show that phosphorylation (and hence activation) of the
transcription factors ATF-2 and CREB is induced by the addition of LPS
within 30 minutes. This appears to be mediated via the p38SAPK pathway
because blocking this prevents the LPS-induced phosphorylation of these
transcription factors. The faint bands that appear below the
phospho-CREB bands in the middle panel are due to cross-reactivity of
the anti-phospho-ATF-2 antibody with ATF-1, which runs in this
position. The lowest panel shows the blot probed for total ATF-2 and
CREB to demonstrate loading of samples. Similar results were obtained
in 3 separate experiments.
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Inhibition of NF-B signaling prevents MoDC maturation in response
to LPS
NF-B knockout mice are known to have defective DCs.25
In addition, NF-B plays a significant role in LPS-induced signaling in macrophages, and there is growing evidence that p38SAPK can interact
with signaling by the NF-B pathway.26,27 Therefore, we
investigated the role of NF-B in LPS-induced maturation in MoDCs.
The transcription factor NF-B is bound to IB- in the cytoplasm
and retained there in an inactive form. Various stimuli result in the
phosphorylation and subsequent ubiquitination of IB-, leading to
its being targeted to the proteasome for destruction. Free NF-B is
able to translocate to the nucleus and activate the transcription of
various genes. Western blotting revealed that IB- is rapidly
degraded upon addition of LPS to immature MoDCs (Figure
5A), allowing NF-B to translocate to the
nucleus and become active as a transcription factor.
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| Fig 5.
Role of the NF-B pathway in MoDC maturation.
(A) LPS induces the degradation of I-B in MoDCs.
Day-7 immature MoDCs were exposed to LPS (100 ng/mL) for variable
lengths of time (as shown), after which samples were removed and
analyzed by Western blotting with an antibody directed against
I-B. The blot shows the degradation of I-B induced in MoDCs
by the addition of LPS. The lower panel shows the blot probed for
tubulin to demonstrate equal loading of samples. Similar results were
obtained in 3 separate experiments. (B) SN50 peptide inhibits the
LPS-induced nuclear translocation of NF-B. Day-7 immature MoDCs were
stimulated with LPS (100 ng/mL) after preincubation with SN50 or
control SN50M peptide (50 µg/mL), after which nuclear extracts were
prepared. Oligonucleotides (containing the consensus binding sequence
for NF-B) bound to agarose beads were used to pull down nuclear
NF-B. The resulting samples were analyzed by SDS/PAGE and
immunoblotting using a polyclonal anti-p65 NF-B antibody. LPS can be
seen to induce the nuclear translocation of NF-B within 30 minutes
of its addition to MoDCs. This is prevented by the addition of the SN50
peptide. The control peptide had no such effect.
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To assess the role of the NF-B pathway in MoDC maturation, we used
the cell-permeable SN50 peptide, which inhibits the nuclear translocation of NF-B.28 We initially demonstrated the
efficacy of this peptide using agarose-bound oligonucleotides that
contained the consensus binding motifs for NF-B. Appropriate mutant
controls were also used. Nuclear extracts were made from unstimulated
MoDCs and MoDCs that were stimulated with LPS, either in the presence of the SN50 peptide or not. These nuclear extracts were incubated with
the oligonucleotide-agarose conjugate. Any NF-B that had translocated to the nucleus would bind to the oligonucleotide-agarose conjugate and would be detected by probing a Western blot with an
antibody directed against NF-B p65. We were able to demonstrate that
the addition of LPS to MoDCs resulted in the nuclear translocation of
NF-B and that this was prevented by the SN50 peptide (Figure 5B).
Addition of SN50, but not a control peptide, resulted in partial
inhibition of the LPS-induced up-regulation of CD80, CD83, CD86, and
HLA-DR (Figure 6). To assess any potential
interactions between p38SAPK and NF-B, we investigated the effect of
inhibiting both pathways simultaneously. This appeared to have varying
effects depending on the phenotypic marker examined. For example,
blocking both pathways virtually abolished the LPS-induced
up-regulation of CD80, which did not occur when either pathway was
blocked in isolation, suggesting an additive effect and thus
independent but overlapping signaling pathways. In the case of CD86,
inhibiting both pathways did not appear to be additive, nor was the
up-regulation of this molecule entirely abolished. In contrast to the
minimal effect seen with blocking p38SAPK signaling, inhibiting NF-B significantly reduced the LPS-induced up-regulation of HLA-DR (Figure
6).
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| Fig 6.
The effect of inhibiting the NF-B and/or p38SAPK
pathways on the LPS-induced up-regulation of CD80, CD83, CD86, and
HLA-DR.
Day-7 immature MoDCs were pretreated with either nothing, a
cell-permeable peptide that inhibits NF-B nuclear translocation
(SN50 peptide; 50 µg/mL), the p38SAPK inhibitor SB203580 (40 µmol/L), or both for 2 hours before the addition of LPS (100 ng/mL)
for 24 hours. Control cells were pretreated with a control peptide plus
or minus LPS. The cell surface expression of CD80, CD83, CD86, and
HLA-DR was then measured using the flow cytometer. Figures obtained are
the product of the percentage of cells expressing the various cell
surface antigens and the mean cell fluorescence of the whole population
of cells under scrutiny. The value obtained for cells exposed to LPS
alone has been normalized to 1. Mean ± SEM of 3 to 4 experiments is
shown.
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| |
Discussion |
Fundamental to the specialized function of the DC is the maturation
process, during which the cell changes from being highly efficient in
taking up exogenous antigen to being specialized in antigen
presentation.2 This maturation process is multifaceted: (1)
Antigen-uptake mechanisms are down-regulated (mannose receptor and
Fc receptor-mediated uptake, macropinocytosis, and phagocytosis); (2) there is up-regulation of cell surface MHC molecules, which in the
case of both MHC I and II is due to increased biosynthesis, and in the
case of MHC II is due to a prolongation of the half-life of
MHC-peptide complexes; and (3) the costimulatory molecules CD80, CD86,
and CD40 are up-regulated, as is the DC-specific molecule CD83, to
which no function has currently been assigned.29 Clearly, any antigen that is encountered in the peripheral tissues must be
presented to T cells in the lymph nodes; thus, the maturation process
also must encompass the migration of DCs from the peripheral tissues to
the paracortical area of lymph nodes, through which large numbers of T
cells circulate. This occurs by a rapid and coordinated switch in
chemokine receptor expression after DCs receive a maturation
stimulus.3
Consistent with the findings of others, we found that exposing MoDCs to
LPS for 48 hours led to a change to a mature phenotype. FITC-dextran
uptake, which occurs by macropinocytosis and via the mannose receptor,
was reduced by 70% ± 10%, and there was an increase in cell
surface MHC class II molecules and the costimulatory molecules CD80,
CD86, and CD40. The marker for mature DCs, CD83, was also
increased.2,4,5,10,30,31
Little is known about the signal transduction pathways involved in the
maturation of MoDCs. We have shown that the classic MAP kinase pathway
(MEK/ERK), the PI3 kinase/Akt pathway, and the p38 SAP kinase pathway
were all activated when immature MoDCs were exposed to LPS, suggesting
a role of these pathways in the maturation process. To our knowledge,
this is the first demonstration of Akt activation in DCs triggered with
a maturation stimulus, and we show that PI3 kinase activity is
important for MoDC survival. The Akt kinase, which is regulated by PI3
kinase, has been shown to control survival in many cell types,
including fibroblasts,32 hemopoietic cells,33
epithelial cells,34 and neuronal cells,35 and
is likely to be involved in MoDC survival.
Inhibiting the MAPK/ERK pathway with PD98059 did not have any effect on
MoDC survival. This is in contrast to the findings of Rescigno et
al.36 Using a growth factor-dependent murine DC cell line
(D1 cells) that maintains its immature phenotype in vitro, they showed
that LPS promoted the survival of D1 cells after growth factor
withdrawal. LPS was shown to activate ERK in these cells, and
inhibiting this pathway using PD98059 abrogated the survival effect of
the LPS. These differences may reflect the different biology of primary
human cells compared with murine cell lines. In addition, in our
experiments, we found that inhibiting the MAPK/ERK pathway with PD98059
did not affect any of the parameters of MoDC maturation that we measured.
Inhibiting the p38SAPK pathway with SB203580 was found to significantly
reduce the LPS-induced up-regulation of CD80, CD83, and CD86, but did
not significantly affect the up-regulation of CD40 or HLA-DR or the
down-regulation of CD1a or endocytotic capacity. Thus, it appears that
some, but not all, aspects of DC maturation are regulated via the
p38SAPK pathway. There are many known targets of p38SAPK. These include
transcription factors such as ATF-2, CHOP/GADD153, Elk-1, and MEF-2C;
and other kinases such as MAPKAP kinase 2 and 3, Mnk 1 and 2, and
Msk-1. MAPKAP kinase 2 and Msk-1 in turn activate the
transcription factors ATF-1 and CREB.
We were able to detect phosphorylation, and hence activation, of the
transcription factors ATF-2 and CREB soon after the MoDCs were exposed
to LPS. This was shown to occur in a p38SAPK-dependent manner. Using
the MatInspector V2.2 database,37,38 we were able to
identify at least 1 binding site for ATF and CREB in the promoter
sequence of CD86. The human CD80 promoter sequence also has 1 binding
site for CREB.38 Thus, one possible mechanism by which LPS
causes up-regulation of the costimulatory molecules is at the
transcriptional level mediated by the actions of CREB or ATF.
The p38SAPK pathway is involved in many aspects of immune cell
function, being important in the innate immune response15 as well as in the adaptive immune response. In addition, p38SAPK may
play an important role in T-cell development because it is found to be
activated in T cells in the thymus.39 The cytokines IL-2
and IL-7 also activate p38SAPK in T cells.40 In B cells, it
is activated during CD40-induced B-cell proliferation.41 In
macrophage cell lines, p38SAPK has been shown to be phosphorylated in
response to LPS.15 Cytokine release by various cell types, including IL-12 by DCs and macrophages42 and interferon
(IFN)- by TH1 cells,43 is mediated via the
p38SAPK pathway. CpG DNA-specific activation of murine
DCs is also mediated by p38SAPK,9 as is the IL-10-mediated
selective repression of TNF--induced MoDC maturation.44
Hence, the finding that the p38SAPK pathway is important in MoDC
maturation is in keeping with its central role in immune cell signal transduction.
The activation of macrophages by LPS occurs via a Toll-like receptor
and CD14.45 This, in turn, results in activation of NF-B. Because of this and in view of findings that RelB, a member of
the NF-B/Rel family, is highly expressed in DCs46 and
that RelB knockout mice have greatly decreased numbers of DCs, we
investigated the role of the NF-B pathway in LPS-induced DC maturation.
We have shown that LPS results in activation of the NF-B
pathway. Inhibiting NF-B translocation to the nucleus with an
inhibitory peptide decreases the up-regulation of HLA-DR, as well as
that of CD80, CD83, and CD86. Rescigno et al36 have also
shown that LPS activates NF-B in DCs and that blocking nuclear
translocation using the serine protease inhibitor TPCK
(N-tosyl-L-phenylalanine chloromethyl ketone), which prevents IB-
degradation, reduces LPS-induced up-regulation of HLA-DR and CD86. We
found that blocking NF-B had no effect on MoDC survival, whereas in
other cell types, this pathway can regulate apoptosis.47-49
It thus appears that the up-regulation of CD80, CD83, and CD86 by LPS
is controlled by at least 2 signal transduction pathways. The
up-regulation of HLA-DR, however, is NF-B dependent but not p38SAPK
dependent. Interestingly, blocking the NF-B and p38SAPK pathways was
additive for CD80, whereas for CD83, maximal inhibition was achieved by
blocking p38SAPK alone. For CD86, blocking both NF-B and p38SAPK did
not completely abolish the effect of LPS, suggesting the existence of
an unrelated regulatory pathway. The LPS-induced up-regulation of CD40
and down-regulation of CD1a and endocytosis did not appear to be
mediated by the p38SAPK or NF-B pathways, and further work will be
needed to dissect out the pathways involved in these processes. It will
also be of interest to see whether other stimuli that result in MoDC
maturation (such as TNF-, IL-1, or monocyte-conditioned medium)
also use the same pathways. In keeping with this possibility, Sato et
al44 have shown that TNF- can activate the ERK2, JNK,
and p38SAPK pathways in MoDCs.
It thus appears that different aspects of DC maturation are regulated
by different signal transduction pathways. It may be possible in the
future to selectively block these pathways and thus manipulate the
immune response toward anergy or activity, which could be useful in the
treatment of autoimmune disease, malignancy, or chronic infection.
| |
Footnotes |
Submitted November 10, 1999; accepted April 4, 2000.
Supported by grants from the Leukaemia Research Fund and the Medical
Research Council (U.K.).
Reprints: Kirit M. Ardeshna, Department of Haematology,
University College Medical School, 98 Chenies Mews, London WC1E 6HX
United Kingdom; e-mail: k.ardeshna{at}ucl.ac.uk.
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.
| |
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Top
Abstract
Introduction