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Prepublished online as a Blood First Edition Paper on April 30, 2002; DOI 10.1182/blood-2001-11-0017.
IMMUNOBIOLOGY
From the Research Department and the Oncology
Department, Cantonal Hospital St Gallen, Switzerland, and the
Experimental Surgery and Immunology Section, University
Erlangen-Nürnberg, Erlangen, Germany.
Dendritic cells (DCs) are potent antigen-presenting cells
that are able to initiate and modulate immune responses and are hence
exploited as cellular vaccines for immunotherapy. Their capacity to
migrate from peripheral tissues to the T-cell areas of draining lymph
nodes is crucial for the priming of T lymphocytes. In this study, we
investigated how the maturation of human monocyte-derived DCs (MoDCs)
by several different stimuli under serum-free conditions affected their
T-cell stimulatory function, cytokine secretion, and migratory
behavior. Surprisingly, we found that for all maturation stimuli
tested, the addition of prostaglandin E2 (PGE2) was required for
effective migration of MoDCs toward the lymph node-derived chemokines
CCL19 (EBI1 ligand chemokine/macrophage inflammatory protein--3 Dendritic cells (DCs) are professional
antigen-presenting cells that are uniquely able to stimulate naive T
cells and initiate and control immune responses1 through
the activation of T-helper (TH) cells of the
TH1, TH2, or TH regulatory
phenotype.2-4 They reside in an immature stage in
peripheral tissues, where they capture antigens such as invading
bacteria, viruses, or damaged tissue. Upon encountering antigens, but
also in response to proinflammatory cytokines or T-cell-derived
signals such as CD40 ligand (CD40L), DCs lose their phagocytic capacity
and up-regulate costimulatory proteins, as well as major
histocompatibility complex class I and II molecules presenting
processed antigen.5-7 At the same time, DCs secrete large
amounts of inflammatory cytokines, such as tumor necrosis factor- These unique features of DCs are increasingly exploited for the design
of DC-based vaccines in immunotherapy since sufficient numbers of
monocyte-derived DCs (MoDCs) can be obtained through in vitro
differentiation of monocytes in the presence of granuloctye-macrophage colony-stimulating factor (GM-CSF) and IL-4.17,18
Unfortunately, little is known about migratory capacities of MoDCs
generated under serum-free conditions for use as cellular vaccines in
therapeutic application. It has been shown that immature MoDCs fail to
migrate to lymph nodes,19 most likely owing to a lack of
CCR7 expression, and consequently prime TH regulatory
cells.20,21 Therefore, the use of matured MoDCs is crucial
for the initiation of cytotoxic immune responses. Currently, several
groups use a cocktail of proinflammatory mediators, such as TNF- PGE2 acts through 4 G protein-coupled receptors, designated EP1, EP2,
EP3, and EP4, that display different tissue distribution and deliver
distinct intracellular signals.32,33 The 2 Gs
protein-coupled receptors EP2 and EP4, which both mediate their signal
through elevated cyclic adenosine monophosphate (cAMP), are expressed on monocytoid cells,34,35 but nothing is yet known about
prostaglandin receptors expressed on DCs.
In this study, we have examined the effect of PGE2 on
phenotypical and functional maturation of MoDCs generated under
serum-free conditions with the use of 3 different stimuli. In
particular, we analyzed surface expression of the chemokine receptors
CCR7, CCR1, CCR5, and CXCR4 on immature and mature MoDCs, as well as their migratory capacity in response to CCL19 and CCL21. Our
experiments identified PGE2 as a proinflammatory agent that
generally enhances T-cell stimulatory capacity of MoDCs and, most
importantly, not only supports CCR7 surface expression of MoDCs during
maturation but is also able to strongly promote migration
toward lymph node-derived chemokines.
Generation of MoDCs
T-cell purification and MoDC cocultures
Intracellular staining Expanded T cells were stimulated with 100 nM phorbo myristate acetate and 1 µg/mL Ionomycin (both from Sigma) for 6 hours. During the last 4 hours of culture 10 µg/mL Brefeldin A (Sigma) was added. After fixation with 2% paraformaldehyde, T cells were permeabilized with phosphate-buffered saline containing 0.1% saponin, 2% fetal calf serum (FCS), and 5 mM EDTA; stained with fluorescein isothiocyanate (FITC)-labeled anti-interferon- (anti-IFN-) and phycoerythrin (PE)-labeled anti-IL-4 (Becton Dickinson, Basel, Switzerland); and analyzed by flow cytometry.
Fluorescence-activated cell sorter analysis of MoDCs MoDCs were analyzed on a FACScan flow cytometer (Becton Dickinson) after staining with the following monoclonal antibodies (mAbs): FITC-labeled anti-CD83 (Immunotech, Berlin, Germany), FITC-labeled anti-CD86, PE-labeled anti-CD80, anti-CCR5 (clone 2D7) (Pharmingen, Basel, Switzerland), anti-CCR1 (clone 53504.111), anti-CXCR4 (clone 12G5) (R&D Systems, Wiesbaden-Nordenstadt, Germany), and anti-CCR7.13 As secondary reagents for unlabeled mAbs, FITC-conjugated sheep-antimouse (Silenus, Melbourne, Australia) and FITC-conjugated goat-antirat immunoglobulin-G (Jackson Immunoresearch, La Roche, Switzerland) were used.Cytokine assays Immature MoDCs were stimulated with a cocktail of proinflammatory cytokines (20 ng/mL TNF- ,10 ng/mL IL-1 , and 1000 U/mL IL-6), 500 ng sCD40L (Immunex), or 20 µg/mL polyI:C (Sigma) in the presence or absence of 1 µg/mL PGE2. After 48 hours, culture supernatants were collected and analyzed by enzyme-linked immunosorbent assay (ELISA) by means of commercially available kits to detect IL-12p70 (Endogen, Woburn, MA), TNF-, and IL-10 (Pharmingen) according to the manufacturer's protocols.
RNA isolation and complementary DNA synthesis Total RNA was isolated from immature and mature MoDCs by means of TRIZOL reagent (Invitrogen) according to the protocol provided by the manufacturer. We used 2 µg total RNA for synthesis of first-strand complementary DNA (cDNA) by means of Moloney murine reverse transcriptase (Promega, Wallisellen, Switzerland) following the manufacturer's recommendations. The resulting cDNA was used for real-time reverse-transcription polymerase chain reaction (RT-PCR).Real-time RT-PCR Real-time RT-PCR was performed by means of the LightCycler (Roche) and the LightCycler-DNA Master SYBR Green I kit (Roche) according to the protocol provided by the manufacturer. After initial denaturation for 30 seconds at 95°C, thermal cycling was performed for 40 cycles with steps of 95°C for 5 seconds, 60°C for 10 seconds, and 72°C for 20 seconds, with the fluorescence being read at the end of each cycle. The following oligonucleotides were used as primers for the PCR: for CCR7, 5'-CCTGGGGAAACCAATGAAAAGC-3' and 5'-GAGCATGCCCACTGAAGAAGC-3'; for EP2, 5'-GCAATGCCTCCAATGACTCC-3' and 5'-GCGCCAGTGCCACCAGGG-3'; and for EP4, 5'-CACTCCCGGGGTCAATTCG-3' and 5'-GGCATGGTTGATGGCCAGG-3'. Analysis was performed with Light Cycler Software 3. The obtained values were within the linear range of a standard curve and were normalized to yield the same amount of glyceraldehyde phosphate dehydrogenase (GAPDH) messenger RNA (mRNA). All PCR products were analyzed by determination of melting profiles as well as by agarose gel electrophoresis.Chemotaxis assay Chemotaxis of MoDCs was measured by migration through a polycarbonate filter with 5-µm pore size in 24-well transwell chambers (Corning Costar, Cambridge, MA) with the use of AIM V as assay medium. Added to the lower chamber was 600 µL assay medium containing 300 ng/mL CCL19 (R&D Systems) or 250 ng/mL CCL21 (R&D Systems), or assay medium alone as a control for spontaneous migration. We added 1 × 105 MoDCs unstimulated or stimulated for 48 hours with the indicated reagents to the upper chamber in a total volume of 100 µL and incubated this for 3 hours at 37°C. A 500-µL aliquot of the cells that migrated to the bottom chamber was counted by flow cytometry acquiring events for a fixed time period of 60 seconds with the use of CellQuest software (Becton Dickinson). Each experiment was performed in duplicate. The mean number of spontaneously migrated cells was subtracted from the total number of migrated cells. Values are given as the mean number of migrated cells ± SEM.
Influence of PGE2 on phenotypical maturation and function of MoDCs In the first series of experiments, we investigated the effect of PGE2 on the phenotypic maturation and T-cell stimulatory functions of human MoDCs that were generated under serum-free conditions and stimulated with either sCD40L, polyI:C, or a cocktail of proinflammatory cytokines (TNF-, IL-1, and IL-6).24
Immature MoDCs were treated with each of the stimuli in the presence or absence of PGE2 for 48 hours, and the expression of maturation-related surface markers was analyzed by flow cytometry. Consistent with previous reports,24,26,27 PGE2 induced or up-regulated
surface expression of CD83 and the costimulatory molecule CD80 on
immature MoDCs and on MoDCs stimulated with the proinflammatory
cytokines, but it had no effect on the phenotypic maturation of MoDCs
treated with sCD40L or polyI:C (Figure
1). In contrast to MoDCs differentiated in the presence of FCS, our MoDCs, which were generated under serum-free conditions, displayed relatively high CD86 expression in the
immature stage, and this was barely enhanced upon exposure to
maturation stimuli (Figure 1, and data not shown).
The capability of immature MoDCs to stimulate allogeneic naive
CD4+ T cells was very low and increased when MoDCs
displayed a mature phenotype (Figure 2).
It is known that PGE2 together with TNF-
PGE2 inhibits cytokine production by activated MoDCs As a consequence of maturation, MoDCs usually secrete inflammatory cytokines.37 PGE2 has previously been shown to inhibit the production of bioactive IL-12p70 and TNF-, while enhancing the
production of the immunosuppressive cytokine
IL-10.28,38,39 To test these parameters in our
experimental setup, we analyzed, by ELISA, the amount of IL-12p70,
TNF-, and IL-10 present in the cell culture supernatant of MoDCs
after 48 hours of stimulation with the respective stimuli (Figure
3). Considerable amounts of IL-12p70
could be detected in the supernatant of polyI:C-stimulated MoDCs, but
interestingly, PGE2 down-regulated its expression by more than 50%
(Figure 3A). In contrast, treating cells with 500 ng/mL sCD40L
or the cocktail of proinflammatory cytokines did not alter IL-12p70
secretion. However, when we raised the concentration of sCD40L to 2 to
3 µg/mL for stimulation, MoDCs produced levels of IL-12p70 similar to
what we observed with polyI:C (data not shown). The addition
of PGE2 decreased the secretion of TNF- by MoDCs that were
stimulated with polyI:C or sCD40L, while immature MoDCs did not produce
detectable amounts of TNF- at any time point (Figure 3B). Because
TNF- was present in the cytokine cocktail used for MoDC maturation,
the quantities of secreted TNF- could not be determined in this
case. In agreement with previous reports,39 IL-10
production was significantly increased in immature MoDCs treated with
PGE2 alone. On the contrary, PGE2 did not affect IL-10 production in
MoDCs in combination with sCD40L or proinflammatory cytokines, while it
decreased IL-10 secretion by about 3-fold in MoDCs stimulated with
polyI:C (Figure 3C). Taken together, these data suggest that PGE2
generally suppresses the production of the examined cytokines in mature
MoDCs, but stimulates immature MoDCs to produce IL-10.
T-cell priming and polarization are not affected by PGE2 PolyI:C-matured MoDCs have been shown to be strong inducers of TH1 differentiation,3 which is, at least in part, due to the secretion of bioactive IL-12p70. Since PGE2 suppressed IL-12p70 production in polyI:C-treated MoDCs (Figure 3A), we next asked whether adding PGE2 would affect TH1 polarization. Naive CD4+ T cells were primed with allogeneic MoDCs that had been stimulated with polyI:C in the presence or absence of PGE2. After 7 to 10 days, the pattern of IFN- and IL-4 production by these
T cells was analyzed by flow cytometry after intracellular cytokine
staining. Our data suggest that PGE2 had no effect on the
TH1-type polarizing capacities of MoDCs irrespective of
whether they were matured with polyI:C (Figure
4) or any other stimulus tested that led comparable numbers of CD4+ T cells to express IL-4
(2% to 4%) or IFN- (17% to 25%) (data not shown).
PGE2 modulates chemokine receptor expression on MoDCs Maturation of DCs is also accompanied by down-regulation of inflammatory chemokine receptors and induction of CCR7.10 This change is essential for migration of DCs to lymphoid organs and optimal initiation of an immune response. Hence, we analyzed the effect of PGE2 on surface expression of the chemokine receptors CCR1, CCR5, CXCR4, and CCR7 on MoDCs generated under serum-free conditions (Figure 5). Unexpectedly, CCR1 expression was present only on freshly isolated monocytes, and after 8 days of cultivation, it was detectable neither in medium containing GM-CSF and IL-4 nor in the presence of any maturing agent tested (data not shown). Immature MoDCs expressed relatively high levels of CCR5 but undetectable levels of CXCR4 and CCR7. The addition of sCD40L or polyI:C resulted in slight down-regulation of CCR5, whereas the proinflammatory cytokines did not have such an effect. In the presence of PGE2, however, CCR5 was further down-regulated on both immature and mature MoDCs. An up-regulation of CXCR4 was barely visible on MoDCs matured with sCD40L and polyI:C, and CXCR4 expression was negligible on MoDCs stimulated with the proinflammatory cytokines. In the presence of PGE2, however, CXCR4 expression was increased on immature and mature MoDCs. Even more prominent was the effect of PGE2 on CCR7 expression, when PGE2 was added to untreated immature MoDCs or to MoDCs treated with the cocktail of proinflammatory cytokines (Figure 5). As expected, CCR7 was induced in MoDCs by sCD40L and polyI:C. While PGE2 did not significantly up-regulate CCR7 expression on polyI:C-treated MoDCs, it was able to further enhance CCR7 expression in combination with sCD40L.
Surface expression of CCR7 correlated well with CCR7 mRNA levels in
these cells as determined by real-time RT-PCR (Figure 6). Marginal expression of CCR7 mRNA was
detected in immature and cytokine-stimulated MoDCs. In MoDCs stimulated
with sCD40L and polyI:C, the CCR7 mRNA expression was up-regulated 20- and 45-fold, respectively, as compared with unstimulated cells. With additional stimulation by PGE2, the expression of CCR7 mRNA increased 38-fold in cytokine-stimulated, 49-fold in sCD40L-activated, and 52-fold in polyI:C-treated MoDCs when compared with immature MoDCs.
PGE2 is required for efficient migration of MoDCs toward CCL19 and CCL21 As we could detect up-regulation of CCR7 surface expression on MoDCs by the action of PGE2 during maturation, we next analyzed whether this functionally results in a better migration of MoDCs toward the 2 known ligands for CCR7: CCL19 and CCL21.40,41 Therefore, immature MoDCs and MoDCs stimulated with sCD40L, polyI:C, or the cytokine cocktail, in the absence or presence of PGE2, were examined in a transwell migration assay (Figure 7). In accordance with undetectable CCR7 surface expression, immature MoDCs and MoDCs that were matured in the presence of proinflammatory cytokines did not migrate at all or barely migrated in response to CCL19 and CCL21, respectively. Interestingly, when CCR7 surface expression was up-regulated by PGE2, immature MoDCs also gained a moderate capability to migrate toward CCL19 and CCL21, while the migratory response of MoDCs matured with proinflammatory cytokines was induced about 80-fold for CCL19 and at least 6-fold for CCL21. To our surprise, MoDCs matured by sCD40L and polyI:C exhibited only weak migratory activity in response to both CCR7 ligands, although they expressed comparable levels of CCR7 on their surface. Costimulation with PGE2, however, also substantially amplified the capability of these cells to migrate toward CCL19 as well as CCL21. Taken together, these experiments show that MoDCs require a maturation stimulus and PGE2-provided signals to acquire the potential to migrate effectively in response to the lymph node-derived chemokines CCL19 and CCL21.
PGE2 receptors EP2 and EP4 are expressed in MoDCs and mediate the increased migratory potential of MoDCs Binding of PGE2 to its receptors can trigger quite distinct signals in cells because, while the stimulation of the prostaglandin receptors EP1 and EP3 leads to intracellular mobilization of Ca++ and decreased cAMP levels, the 2 Gs-coupled receptors EP2 and EP4 signal through increased cAMP by stimulation of the adenylate cyclase.33 First, we quantitatively investigated mRNA expression of the 2 prostaglandin receptors reported to be expressed in monocytes and peritoneal macrophages, EP2 and EP4,34,35 in immature or mature MoDCs by real time RT-PCR. As shown in Figure 8A, the expression of EP2 mRNA was not significantly altered by the different maturation stimuli. However, in the presence of PGE2, EP2 mRNA expression was down-regulated in all cases, most prominently in immature and sCD40L-stimulated MoDCs. In contrast, EP4 mRNA was up-regulated by the different maturation stimuli; the up-regulation was most evident for sCD40L, followed by polyI:C, and was least prominent for proinflammatory cytokines (Figure 8B). Treatment with PGE2 likewise resulted in a markedly reduced expression of EP4 mRNA in all samples. To test the expression of EP1 and EP3 mRNA, we performed RT-PCR on the same cells, but no EP1 and EP3 mRNAs were detected, indicating that these 2 types of prostaglandin receptors are not expressed in MoDCs (data not shown).
These data suggest that the effects of PGE2 on MoDCs are probably
mediated by elevating the intracellular second messenger, cAMP, via
signaling through EP2 and EP4. To confirm this notion, we investigated
whether forskolin, a pharmacological activator of adenylate cyclase;
cholera toxin, which activates the G
CCR7 expression on mature DCs is essential for their homing to secondary lymphoid organs where the CCR7 ligands CCL19 and CCL21 are produced.13 Our results show that PGE2 induces CCR7 expression in MoDCs matured with proinflammatory cytokines and enhances CCR7 expression on MoDCs stimulated with sCD40L, but has no additional effect on CCR7 expression of MoDCs matured with polyI:C. However, the migratory capability of MoDCs stimulated with sCD40L and poyI:C in the absence of PGE2 seems to be impaired, since these cells did not effectively migrate in response to the 2 CCR7 ligands CCL19 and CCL21. In our serum-free system, signals provided by PGE2 were absolutely required for an efficient migration of mature MoDCs in response to CCL19 and CCL21. These data, as well as observations made by Luft et al (Eugene Maraskovsky, written communication, September 2001) that PGE2 also positively affects migration of MoDCs toward the CXCR4 ligand CXCL12 (stromal cell derived factor-1), imply that the migratory capacity of MoDCs toward constitutively expressed chemokines in general is selectively promoted by the action of PGE2. D'Amico et al42 have recently shown that IL-10-treated MoDCs and monocytes did not migrate in response to CCL3, CCL4, or CCL5 despite CCR1 and CCR5 surface expression. Moreover, it was demonstrated that in the presence of IL-10, MoDCs had a defective capacity for signaling through chemokine receptors, thus indicating that they were uncoupled through IL-10. Similarly, activation of CCR7 receptors expressed on mature MoDCs might be inhibited by an as-yet-unidentified mechanism in the absence of signals provided by PGE2 during maturation. CCR7 receptor uncoupling was also reported for plasmacytoid DCs isolated from peripheral blood, which express quite high levels of CCR7 on their surface but fail to migrate in response to CCL19 unless they received a maturation stimulus that restored their migratory capacity.43 Although it seems very unlikely, we should point out that as a hypothetical alternative to the coupling of CCR7 to signaling, the effect of PGE2 on MoDC migration toward CCR7 ligands might be due to the induction or activation of an as-yet-unknown chemokine receptor for CCL19 and CCL21. The effect of PGE2 was mediated mainly by the intracellular second messenger, cAMP, because only prostaglandin receptors EP2 and EP4, which signal through increased cAMP, were expressed in MoDCs and were down-regulated after PGE2 treatment. Moreover, the EP2/EP4 agonist 11-deoxy-PGE1, as well as cAMP-elevating agents like forskolin or cholera toxin, could substitute for PGE2 in the activation of MoDC migration toward lymph node-derived chemokines. Signals mediated by intracellular cAMP were shown to be involved in cell polarization and uropod formation induced by chemokines.44 In particular, activation of the cAMP-dependent protein kinase (PKA) seems to be important, as the inhibition of PKA led to an abrogation of the chemokine-mediated uropod formation in T cells.45 Furthermore, upregulation of metalloproteinases, which are involved in migration processes, is mediated by elevated intracellular cAMP.46 One reason why exogenous PGE2 is required to fully restore the
migratory capacity of MoDCs in response to CCL19 and CCL21 could be an
impaired production of PGE2 by MoDCs generated under serum-free
conditions in the presence of GM-CSF and IL-4. At sites of
inflammation, the formation of prostaglandins from its precursor, arachidonic acid, is catalyzed by the prostaglandin synthetase cyclo-oxigenase 2 (COX-2) that is induced in monocytes by inflammatory stimuli, such as bacterial lipopolysaccharide (LPS) or proinflammatory cytokines (TNF- This could also explain why the defective migratory capacity of MoDCs toward lymph node-derived chemokines remained unnoticed in previous studies in which MoDCs were generated in the presence of GM-CSF and IL-13 instead of IL-4 or in cell culture medium supplemented with FCS.8,51 However, Luft et al (Eugene Maraskovsky, written communication, September 2001) showed that MoDCs generated in the presence of FCS display only moderate migratory responses toward CCL19 and CCL21, but that this was significantly enhanced in the presence of PGE2. It has been shown that the chemokine receptors CCR1 and CCR5, which respond to the inflammatory chemokines CCL3, CCL4, and CCL5, are down-regulated on the surface of MoDCs owing to an autocrine mechanism.10 Probably because of different cultivation conditions, we were unable to detect CCR1 surface expression on immature MoDCs generated in a serum-free environment. PGE2 has been previously shown to down-regulate CCR5 on human monocytes, thus inducing resistance to human immunodeficiency virus-1 infection.52,53 Analogously to monocytes, an almost complete down-regulation of CCR5 surface expression on MoDCs could be observed only in the presence of PGE2 (Figure 5). In agreement with previous reports,24,26,27 we demonstrated that PGE2 elevated maturation-related surface markers and enhanced the T-cell stimulatory capacity of MoDCs matured with proinflammatory cytokines. The latter positive effect of PGE2 on MoDCs was not restricted to cytokine-stimulated MoDCs but was also valid for MoDCs activated with sCD40L or polyI:C, thus suggesting that PGE2 is a key promoter of MoDC function. The presence of PGE2 during the maturation of MoDCs decreased the
secretion of bioactive IL-12p70 by MoDCs stimulated with polyI:C, in
accordance with previous reports.26,54 Interestingly, in
LPS-treated macrophages, the EP4 receptor is apparently involved in the
down-regulation of TNF- Kalinski et al56 found that the presence of PGE2 during
maturation yielded MoDCs, which promoted TH2
differentiation. Our results are contradictory to this finding, because
we could not see an effect of PGE2 on TH-cell polarization
by MoDCs in any of our experiments (Figure 4, and data not shown).
Also, Steinbrink et al36 demonstrated that naive
TH cells primed by MoDCs and matured in the presence of
proinflammatory cytokines (TNF- In conclusion, signals provided by the action of PGE2 selectively ameliorate functional maturation of MoDCs generated under serum-free conditions, allowing them to efficiently prime TH cells and migrate in response to CCL19 and CCL21. This is an important new parameter that needs to be considered for the in vitro differentiation of MoDCs as cellular vaccines in cancer immunotherapy.
We thank Immunex Corporation for providing sCD40L and Annalisa Macagno for critical reading of the manuscript and help with ELISA experiments. Wolfhart Seelentag as well as Hans Schiefer, and Markus Arn are acknowledged for the irradiation of cells and Dr Markus Fopp and the personnel of St Gallen blood bank for supplying blood products.
Submitted November 21, 2001; accepted April 1, 2002.
Prepublished online as Blood First Edition Paper, April 30, 2002; DOI 10.1182/blood-2001-11-0017.
Supported by the Cancer League St Gallen-Appenzell, Swiss Cancer League, Foundation Propter Homines Vaduz Liechtenstein, Cancer Research Insitute, CaPCURE Foundation, R&A Dietschweiler Foundation, W & V Spühl-Foundation, and AstraZeneca AG, OSKK.
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: Marcus Groettrup, Kantonsspital St Gallen, Laborforschungsabteilung, Haus 09, CH-9007 St Gallen, Switzerland; e-mail: marcus.groettrup{at}kssg.ch.
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R. B. Mailliard, A. Wankowicz-Kalinska, Q. Cai, A. Wesa, C. M. Hilkens, M. L. Kapsenberg, J. M. Kirkwood, W. J. Storkus, and P. Kalinski {alpha}-Type-1 Polarized Dendritic Cells: A Novel Immunization Tool with Optimized CTL-inducing Activity Cancer Res., September 1, 2004; 64(17): 5934 - 5937. [Abstract] [Full Text] [PDF]
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A. Rivas-Carvalho, M. A. Meraz-Rios, L. Santos-Argumedo, S. Bajana, G. Soldevila, M. E. Moreno-Garcia, and C. Sanchez-Torres CD16+ human monocyte-derived dendritic cells matured with different and unrelated stimuli promote similar allogeneic Th2 responses: regulation by pro- and anti-inflammatory cytokines Int. Immunol., September 1, 2004; 16(9): 1251 - 1263. [Abstract] [Full Text] [PDF]
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A. K. Bengtsson, E. J. Ryan, D. Giordano, D. M. Magaletti, and E. A. Clark 17{beta}-Estradiol (E2) modulates cytokine and chemokine expression in human monocyte-derived dendritic cells Blood, September 1, 2004; 104(5): 1404 - 1410. [Abstract] [Full Text] [PDF]
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T. Luft, E. Maraskovsky, M. Schnurr, K. Knebel, M. Kirsch, M. Gorner, R. Skoda, A. D. Ho, P. Nawroth, and A. Bierhaus Tuning the volume of the immune response: strength and persistence of stimulation determine migration and cytokine secretion of dendritic cells Blood, August 15, 2004; 104(4): 1066 - 1074. [Abstract] [Full Text] [PDF]
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D. Kamei, K. Yamakawa, Y. Takegoshi, M. Mikami-Nakanishi, Y. Nakatani, S. Oh-ishi, H. Yasui, Y. Azuma, N. Hirasawa, K. Ohuchi, et al. Reduced Pain Hypersensitivity and Inflammation in Mice Lacking Microsomal Prostaglandin E Synthase-1 J. Biol. Chem., August 6, 2004; 279(32): 33684 - 33695. [Abstract] [Full Text] [PDF]
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 S. Kubo, H. K. Takahashi, M. Takei, H. Iwagaki, T. Yoshino, N. Tanaka, S. Mori, and M. Nishibori E-Prostanoid (EP)2/EP4 Receptor-Dependent Maturation of Human Monocyte-Derived Dendritic Cells and Induction of Helper T2 Polarization J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 1213 - 1220. [Abstract] [Full Text] [PDF]
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V. Angeli, D. Staumont, A.-S. Charbonnier, H. Hammad, P. Gosset, M. Pichavant, B. N. Lambrecht, M. Capron, D. Dombrowicz, and F. Trottein Activation of the D Prostanoid Receptor 1 Regulates Immune and Skin Allergic Responses J. Immunol., March 15, 2004; 172(6): 3822 - 3829. [Abstract] [Full Text] [PDF]
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E. Scandella, Y. Men, D. F. Legler, S. Gillessen, L. Prikler, B. Ludewig, and M. Groettrup CCL19/CCL21-triggered signal transduction and migration of dendritic cells requires prostaglandin E2 Blood, March 1, 2004; 103(5): 1595 - 1601. [Abstract] [Full Text] [PDF]
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C. C. Bowman and K. L. Bost Cyclooxygenase-2-Mediated Prostaglandin E2 Production in Mesenteric Lymph Nodes and in Cultured Macrophages and Dendritic Cells after Infection with Salmonella J. Immunol., February 15, 2004; 172(4): 2469 - 2475. [Abstract] [Full Text] [PDF]
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T. Chen, J. Guo, M. Yang, C. Han, M. Zhang, W. Chen, Q. Liu, J. Wang, and X. Cao Cyclosporin A impairs dendritic cell migration by regulating chemokine receptor expression and inhibiting cyclooxygenase-2 expression Blood, January 15, 2004; 103(2): 413 - 421. [Abstract] [Full Text] [PDF]
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H. Hammad, H. J. de Heer, T. Soullie, V. Angeli, F. Trottein, H. C. Hoogsteden, and B. N. Lambrecht Activation of Peroxisome Proliferator-Activated Receptor-{gamma} in Dendritic Cells Inhibits the Development of Eosinophilic Airway Inflammation in a Mouse Model of Asthma Am. J. Pathol., January 1, 2004; 164(1): 263 - 271. [Abstract] [Full Text] [PDF]
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 J.A. Keelan, J. Yang, R.J. Romero, T. Chaiworapongsa, K.W. Marvin, T.A. Sato, and M.D. Mitchell Epithelial Cell-Derived Neutrophil-Activating Peptide-78 Is Present in Fetal Membranes and Amniotic Fluid at Increased Concentrations with Intra-amniotic Infection and Preterm Delivery Biol Reprod, January 1, 2004; 70(1): 253 - 259. [Abstract] [Full Text] [PDF]
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D. Giordano, D. M. Magaletti, E. A. Clark, and J. A. Beavo Cyclic Nucleotides Promote Monocyte Differentiation Toward a DC-SIGN+ (CD209) Intermediate Cell and Impair Differentiation into Dendritic Cells J. Immunol., December 15, 2003; 171(12): 6421 - 6430. [Abstract] [Full Text] [PDF]
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H. Jing, E. Vassiliou, and D. Ganea Prostaglandin E2 inhibits production of the inflammatory chemokines CCL3 and CCL4 in dendritic cells J. Leukoc. Biol., November 1, 2003; 74(5): 868 - 879. [Abstract] [Full Text] [PDF]
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 I. J. M. de Vries, W. J. Lesterhuis, N. M. Scharenborg, L. P. H. Engelen, D. J. Ruiter, M.-J. P. Gerritsen, S. Croockewit, C. M. Britten, R. Torensma, G. J. Adema, et al. Maturation of Dendritic Cells Is a Prerequisite for Inducing Immune Responses in Advanced Melanoma Patients Clin. Cancer Res., November 1, 2003; 9(14): 5091 - 5100. [Abstract] [Full Text] [PDF]
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H. Hammad, H. Jan de Heer, T. Soullie, H. C. Hoogsteden, F. Trottein, and B. N. Lambrecht Prostaglandin D2 Inhibits Airway Dendritic Cell Migration and Function in Steady State Conditions by Selective Activation of the D Prostanoid Receptor 1 J. Immunol., October 15, 2003; 171(8): 3936 - 3940. [Abstract] [Full Text] [PDF]
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M. Jefford, M. Schnurr, T. Toy, K.-A. Masterman, A. Shin, T. Beecroft, T. Y. Tai, K. Shortman, M. Shackleton, I. D. Davis, et al. Functional comparison of DCs generated in vivo with Flt3 ligand or in vitro from blood monocytes: differential regulation of function by specific classes of physiologic stimuli Blood, September 1, 2003; 102(5): 1753 - 1763. [Abstract] [Full Text] [PDF]
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A. Martin-Fontecha, S. Sebastiani, U. E. Hopken, M. Uguccioni, M. Lipp, A. Lanzavecchia, and F. Sallusto Regulation of Dendritic Cell Migration to the Draining Lymph Node: Impact on T Lymphocyte Traffic and Priming J. Exp. Med., August 18, 2003; 198(4): 615 - 621. [Abstract] [Full Text] [PDF]
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M. Schnurr, T. Toy, P. Stoitzner, P. Cameron, A. Shin, T. Beecroft, I. D. Davis, J. Cebon, and E. Maraskovsky ATP gradients inhibit the migratory capacity of specific human dendritic cell types: implications for P2Y11 receptor signaling Blood, July 15, 2003; 102(2): 613 - 620. [Abstract] [Full Text] [PDF]
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A. C. Yopp, G. J. Randolph, and J. S. Bromberg Leukotrienes, Sphingolipids, and Leukocyte Trafficking J. Immunol., July 1, 2003; 171(1): 5 - 10. [Full Text] [PDF]
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H. Harizi, C. Grosset, and N. Gualde Prostaglandin E2 modulates dendritic cell function via EP2 and EP4 receptor subtypes J. Leukoc. Biol., June 1, 2003; 73(6): 756 - 763. [Abstract] [Full Text] [PDF]
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V. Angeli, H. Hammad, B. Staels, M. Capron, B. N. Lambrecht, and F. Trottein Peroxisome Proliferator-Activated Receptor {gamma} Inhibits the Migration of Dendritic Cells: Consequences for the Immune Response J. Immunol., May 15, 2003; 170(10): 5295 - 5301. [Abstract] [Full Text] [PDF]
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M. Dauer, B. Obermaier, J. Herten, C. Haerle, K. Pohl, S. Rothenfusser, M. Schnurr, S. Endres, and A. Eigler Mature Dendritic Cells Derived from Human Monocytes Within 48 Hours: A Novel Strategy for Dendritic Cell Differentiation from Blood Precursors J. Immunol., April 15, 2003; 170(8): 4069 - 4076. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
Multi Sort Kit (Miltenyi).
This method yielded purified (exceeding 98%)
CD4+/CD45RA+/CD45RO
PGE2), with polyI:C in combination with
PGE2; or with polyI:C along with forskolin, cholera toxin,
11-deoxy-PGE1, or pertussis toxin in combination with PGE2;
the MoDCs were subsequently analyzed in a transwell migration
assay for their chemotactic response to CCL21. (D) MoDCs stimulated for
48 hours with TNF-