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,
*
Institute of Interdisciplinary Research, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, Gosselies, Belgium; and
Institute of Interdisciplinary Research, School of Medicine and
Departement of Medical Chemistry, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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synergize in the
activation and maturation of human dendritic cells (DC); the effect of
ATP was reproduced by hydrolysis-resistant derivatives of ATP and was
blocked by suramin, suggesting the involvement of a P2 receptor, but
the particular subtype involved was not identified. In this report we
confirm that ATP and various derivatives synergize with TNF- and LPS
to induce the maturation of human monocyte-derived DC, as revealed by
up-regulation of the CD83 marker and the secretion of IL-12. The rank
order of potency of various analogs (AR-C67085 > adenosine
5'-O-(3-thiotriphosphate) = 2'- and
3'-O-(4-benzoyl-benzoyl) ATP > ATP >
2-methylthio-ATP) was close to that of the recombinant human
P2Y11 receptor. Furthermore, these compounds activated cAMP
production in DC, in a xanthine-insensitive way, consistent with the
involvement of the P2Y11 receptor, which among P2Y subtypes
has the unique feature of being dually coupled to phospholipase C and
adenylyl cyclase activation. The involvement of the
P2Y11/cAMP/protein kinase A signaling pathway in the
nucleotide-induced maturation of DC is supported by the inhibitory
effect of H89, a protein kinase A inhibitor. Taken together, our
results demonstrate that ATP activates DC through stimulation of the
P2Y11 receptor and subsequent increase in intracellular
cAMP. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Other inflammatory mediators such as PGE2
participate in the maturation of DC. On its own,
PGE2 has little capacity to induce maturation of
DC, but it acts synergistically with TNF-, via an increase in the
cAMP level (4). Vasoactive intestinal peptide, a
well-known stimulus of cAMP accumulation, also synergizes with TNF-
in inducing DC maturation and IL-12 release (5).
Extracellular nucleotides, which are released from damaged cells
(6), could also be involved in DC biology
(7). On the one hand, ATP triggers apoptosis of DC
(8). On the other hand, it has been shown
recently by different laboratories that extracellular ATP synergizes
with TNF- in the activation and maturation of monocyte-derived human
DC. Indeed, ATP transiently enhanced endocytosis, which was followed by
the up-regulation of DC surface markers (CD54, CD80, CD86, CD83), but
also of MHC II molecules, IL-12 secretion, and an increased T cell
stimulatory capacity (9, 10). ATP also induces the release
of cytokines such as TNF- by LPS-matured DC (7). From
these data, it can be postulated that ATP might be a potent stimulus
for the initiation of immune responses and that ATP derivatives could
be considered as new agents, potentially interesting in vaccination
strategies. In this context, it is crucial to identify the subtype of
the receptor mediating this ATP effect, which is the aim of this work.
ATP activates cells through the purinergic P2X or P2Y receptors; the
former are ligand-gated ion channels, while the latter are protein
G-coupled receptors (6, 11). Berchtold et al.
(9) have recently shown by RT-PCR that human DC express
all members of the P2Y subfamily (P2Y1,
P2Y2, P2Y4,
P2Y6, and P2Y11)
and at least five P2X receptors (P2X1,
P2X2, P2X4,
P2X5, and P2X7). Using
single-cell Ca2+ imaging, Liu et al.
(12) suggested that human DC express functional
P2Y1, P2Y2, and/or
P2Y4 as well as a 2-methylthio-ATP (2-MeSATP)-
and UTP-insensitive receptors. Recently, Schnurr et al.
(10) showed that the effect of ATP on activation and
maturation of DC was reproduced by hydrolysis-resistant derivatives of
ATP and was blocked by suramin, suggesting the involvement of a P2
receptor.
In this report, we show that nucleotides induce maturation of DC, in
synergy with TNF- and LPS, through activation of the
P2Y11 receptors coupled to cAMP accumulation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The culture medium used in this study was RPMI 1640 supplemented with 10% heat-inactivated FBS (HyClone, Logan, UT), 25 mM HEPES buffer, 2 mM L-glutamine, 1 mM sodium pyruvate, 50 µg/ml gentamicin (all purchased from Life Technologies, Merelbeke, Belgium), and 5 x 10-5 M 2-ME (Merck, Darmstadt, Germany). Recombinant human GM-CSF or Leucomax was supplied by Novartis (Basel, Switzerland), and recombinant human IL-4 was supplied by R&D Systems (Abingdon, U.K.).
ATP, ADP, adenosine, adenosine 5'-O-(3-thiotriphosphate)
(ATP
S), 2'- and 3'-O-(4-benzoyl-benzoyl) ATP (BzATP),
dATP, UTP, UDP, dibutyryl cAMP (db-cAMP), and LPS were obtained from
Sigma (St. Louis, MO). 2-MeSATP and
8-(p-sulfophenyl)theophyline (8-p-SPT) were
purchased from Research Biochemicals International (Natick, MA). H-89
was obtained from Biomol Research Laboratories (Plymouth Meeting, PA).
Rolipram was a gift from the Laboratoires Jacques Logeais (Trappes,
France). AR-C67085 was a gift from Drs. Turner and Leff (Astrazeneca
R&D Charnwood, Loughborough, U.K.). TNF- was a gift from Dr.
Adolf (Roche, Mannheim, Germany).
DC generation and maturation
Immature human DC were derived from adherent peripheral blood monocytes of normal donors as described by Romani et al. (13). In brief, PBMCs were isolated from leukocyte-enriched buffy coats by standard density gradient centrifugation on Lymphoprep solution from Nycomed (Oslo, Norway) and resuspended in complete medium, and 2 x 108 PBMCs were allowed to adhere for 2 h at 37°C at 5% CO2 in air in 75-cm2 cell culture flasks. Nonadherent cells were removed and rinsed adherent cells were cultured in 15 ml of complete medium supplemented with 800 U/ml of GM-CSF and 1000 U/ml of IL-4. GM-CSF and IL-4 were added twice a week. After 6 days of incubation, cells were replated at 3–4 x 105 cells/ml in 24-multiwell plates in complete medium with GM-CSF and IL-4. Nucleotides or other tested agents were added the next day for 48 h. The purity of each cell preparation has been evaluated by determining the expression of CD1a, HLA-DR, CD14, and CD3; 90–95% of cells were CD1a and HLA-DR positive.
Flow cytometric analysis
Cells staining was performed using FITC-conjugated
anti-human CD83 (IgG1,
, HB15e) supplied by BD PharMingen (San
Diego, CA) on 2 x 105 cells in 100 µl of
PBS with 0.1% sodium azide for 30 min in the dark at 4°C.
After washing with 2 ml of PBS, samples were analyzed on a FACSort
(Becton Dickinson, Franklin Lakes, NJ). Data were analyzed and
presented using WinMDI (version 2.6) software (J. Trotter, The Scripps
Research Institute, San Diego, CA); the number of gated events
were at least 5000. EC50 values were obtained by
curve fitting (Sigma Plot, version 2.0).
Quantitation of IL-12
Human IL-12 was quantified by ELISA using a commercially available kit (BioSource International, Camarillo, CA) that recognizes both bioactive p70 heterodimer and free p40 subunit.
cAMP measurements
Cells were preincubated for 20 min in RPMI 1640 supplemented with 25 mM HEPES buffer and 25 µM rolipram and incubated in the same medium for 10 min in the presence of the agonists. The incubation was stopped by the addition of 0.1 M HCl. The incubation medium was dried up, resuspended in water, and diluted as required. cAMP was quantified by RIA after acetylation as previously described (14).
Quantitative RT-PCR assay of P2Y11 mRNA
Total RNA was isolated using the Tripur isolation reagent from Roche Diagnostics (Basel, Switzerland). To avoid DNA contamination, 1 µg of total RNA was treated with DNA-free from Ambion (Austin, TX). RT was performed with 500 ng of RNA using the Superscript II preamplification system with random hexamers (Life Technologies). The primers and TaqMan fluorogenic probe for P2Y11 (GenBank accession no. AF030335) were obtained from Eurogentec (Seraing, Belgium): forward (nt 19–39), 5'-CTG CCC TGC CAA CTT CTT G-3'; reverse P2Y11 (nt 76–96), 5'-CAG TAT GGG CCA CAG GAA GTC-3'; and probe (nt 45–69), 5'-(Fam)-TGC CGA CGA CAA ACT CAG TGG GTT-(Tamra)-3'. TaqMan PCR assays were performed in duplicate on cDNA samples or RNA in 96-well optical plates on an Applied Biosystems Prism 7700 Sequence Detection system (PE Applied Biosystems, Foster City, CA). For each 25-µl reaction, 1/20 RT product was mixed with 12.5 µl of 2x TaqMan Universal PCR Master Mix (PE Applied Biosystems), primers (300 nM each), and fluorogenic probe (200 nM). PCR parameters were 50°C for 2 min, 95°C for 10 min, 40 cycles of 95°C for 15 s, and 60°C for 1 min. Results for P2Y11 were normalized to GAPDH (Eurogentec). Data were analyzed with Sequence Detector software (SDS version 1.6; PE Applied Biosystems).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(1 ng/ml)
modestly expressed the CD83 protein at their surfaces (Fig. 1
). The TNF- effect involved only a
portion of the population (
20%) due to the low concentration of the
cytokine. When DC were stimulated with ATP alone (1 mM), we also
detected a small portion of the cell population (30%) that was
weakly CD83 positive (Fig. 1). TNF- and ATP acted synergistically,
so that 90% of the cell population was CD83 positive, and the synergy
was also apparent on the level of expression, as judged by the increase
in the mean fluorescence intensity (Fig. 1). Because DC exhibit a
strong ecto-nucleotidase activity (9), the ATP effect
could be due to its degradation into ADP, AMP, and adenosine. Indeed,
in some preparations of DC (five of seven), adenosine and ADP
synergized with TNF- to differentiate DC. This effect was lower than
that of ATP at the same concentration and was inhibited by 8-p-SPT, an
A2 receptor antagonist (data not shown).
Moreover, we tested the effect of ATPS, a hydrolysis-resistant
analog of ATP. At 100 µM, ATPS reproduced the effect of ATP 1 mM
(Fig. 1), and its effect was insensitive to 8-p-SPT (data not shown),
suggesting the involvement of a P2 receptor.
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(Fig. 2A). The rank
order of agonist potency was AR-C67085 > ATPS =
BzATP > ATP. In the presence of TNF-, the
EC50 values were 4.0 ± 1.3 µM for
AR-C67085 and 27 ± 4.0 µM for ATPS (mean of three
independent experiments). The EC50 for AR-C67085
alone was 36.2 ± 4.6 µM (data not shown). Similar
concentration-action curves were observed for IL-12 release (Fig. 2B).
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, A and
B, UTP and UDP did not enhance the expression of CD83 or
IL-12 production, while 2-MeSATP had a very small effect. In the same
experiment, we measured the production of cAMP in DC (Fig. 3C). ATP, ATPS, BzATP, and AR-C67085 stimulated the
production of cAMP, while UTP and UDP were inactive, and 2-MeSATP had a
very modest effect. This increase in cAMP was insensitive to 8-p-SPT,
an A2 receptor antagonist (data not shown). We
have confirmed the observation by Schnurr et al. (10) that
,
-methylene-ATP and ,-methylene-ATP are active on DC, as
evaluated by CD83 expression and IL-12 release, and found that this
activity was associated with an increase in cAMP as it was in CHO-K1
cells expressing the human recombinant P2Y11
(data not shown).
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(Table I).
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to mature DC. The production of IL-12 induced
by db-cAMP (100 µM) was comparable to that obtained in response to
ATPS (data not shown). In the same manner, CD83 expression was
induced by forskolin (10 µM; data not shown). Due to the high
toxicity of H-89 after 24 and 48 h of treatment, we modified the
protocol of stimulation to test the effect of this compound. The DC
were pretreated with H-89 for 90 min and then stimulated by ATPS
alone or with TNF- for 2 h (in the presence of H-89);
thereafter, they were cultured overnight with or without TNF-.
Treatment of the cells with H-89 inhibited the up-regulation of CD83
expression by ATPS (100% inhibition with ATPS alone and 70%
inhibition with ATPS in the presence of TNF-), while the effect
of TNF- alone was unchanged (Fig. 4A). H-89 also inhibited the
release of IL-12 induced by ATPS alone or in combination with
TNF- (Fig. 4B).
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S (100 µM) was also able to act in synergy with
LPS (1 ng/ml), another inflammatory mediator, on CD83 expression (Fig. 5, A and C). When
the production of IL-12 was studied, we also observed a synergy between
ATP or ATPS and LPS (Fig. 5, B and D).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-treated DC express functional P2Y1,
P2Y2, and/or P2Y4 and a
2-MeSATP- and UTP-insensitive P2Y receptor (12). Some
biological functions mediated by these receptors have been suggested.
Coutinho-Silva et al. (8) showed that ATP at millimolar
concentrations induces rapid apoptotic cell death through activation of
the P2X7 receptor in both human and murine DC.
Recently, it has been suggested that the P2X7
receptor is involved in the increase in intracellular
Ca2+, the membrane depolarization, and the
secretion of inflammatory cytokines by human DC in response to ATP
(7). The same P2X7 could be involved
in Ag presentation by murine DC (18). In the same cells
UTP and UDP, but not ATP, mobilized intracellular calcium and
stimulated cytokine production, presumably via activation of the
P2Y6 receptor (19).
In the present study, we have demonstrated that ATP and the ATP
derivatives, ATPS, BzATP, and AR-C67085, synergized with TNF- to
induce de novo expression of CD83 Ag and production of high levels of
IL-12 in human monocyte-derived DC. This is consistent with previous
reports that demonstrated additive or synergistic effects of ATP and
TNF- on up-regulation of the cell surface markers, CD80, CD83, and
CD86, during the maturation of DC (9). Since these authors
have tested only ATP and shown that DC express an important
ecto-nucleotidase activity, the effect of ATP might have resulted from
its degradation into adenosine and activation of adenosine rather than
P2 receptors. Schnurr et al. (10) have shown that ATP
induces CD86 expression, increases IL-12 production, and enhances the T
cell stimulatory capacity in human DC. The lack of adenosine action,
the reproduction of the ATP effect by hydrolysis-resistant analogs, and
the inhibition by suramin supported the involvement of P2 receptors,
but the particular P2 subtype involved was not identified.
Knowing that PGE2, forskolin, or db-cAMP enhances
the maturation of human DC at least with TNF- as maturation factor
(4), we made the hypothesis that the
P2Y11 receptor might be involved in DC
maturation. Indeed, among P2 receptors, the P2Y11
receptor has the unique feature of being dually coupled to
phospholipase C and adenylyl cyclase stimulation. The presence of
P2Y11 mRNA in DC, either immature or mature, as
well as in the monocyte precursors, was indeed demonstrated by
quantitative RT-PCR. Expression of functional
P2Y11 receptors on human DC was confirmed by the
observation that known agonists of the human recombinant
P2Y11 receptor, AR-C67085, ATPS, BzATP, and
ATP (16), increased cAMP in DC in a xanthine-insensitive
way, thus excluding the role of adenosine receptors. The rank order of
potency with which nucleotides enhanced the effect of TNF- on CD83
expression and IL-12 production was similar to that characterizing the
recombinant human P2Y11 receptor: AR-C67085
> ATPS = BzATP > ATP > 2-MeSATP (16).
On the other hand, Schnurr et al. (10) have shown that the
activating effect of nucleotides on DC was abolished by suramin, which
is a potent competitive antagonist of the recombinant
P2Y11 receptor (16). The involvement
of other P2Y receptors can be excluded. Indeed, the lack of a UTP
effect is inconsistent with a role of either P2Y2
or P2Y4 receptor, the inactivity of UDP excludes
the P2Y6 receptor, and the low potency of
2-MeSATP as well as the variable effect of ADP and its sensitivity to
8-p-SPT are incompatible with a role for the P2Y1
receptor (6, 11). On the other hand, AR-C67085, the most
potent activator of DC found in this study, behaves as a weak partial
agonist in tissues containing P2X receptors (20).
Rieser et al. (4) have shown that db-cAMP as well as
agents increasing the endogenous cAMP level, such as forskolin and
PGE2, enhance the maturation of human DC. Our
results with P2Y11 agonists are consistent with
the concept that the cAMP and TNF- signal transduction pathways
cooperate in the maturation of DC. Similarly, in human monocytes,
elevation of cAMP synergized with TNF- to up-regulate the synthesis
of IL-1 (21). In contrast to the synergism between
PGE2 and TNF-, Rieser et al. (4)
have reported that PGE2 inhibited the LPS-induced
synthesis of IL-12 by human DC. In contrast with these results, we have
observed a synergism between ATPS and LPS. This discrepancy could be
due to concentration of LPS, as we did not observe such synergism when
10 ng/ml LPS was used (data not shown).
In conclusion, our results suggest that the P2Y11 receptor plays an immunomodulatory role by activating DC.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Françoise Wilkin, Institute of Interdisciplinary Research, Institut de Biologie et de Médecine Moléculaires, 10 rue A. Bolland, 6041 Gosselies, Belgium. E-mail address: fwilkin{at}hotmail.com
3 Abbreviations used in this paper: DC, dendritic cell; ATPS, adenosine 5'-O-(3-thiotriphosphate); AR-C67085, 2-propylthio-, -dichloromethylene-D-ATP; BzATP, 2'- and 3'-O-(4-benzoyl-benzoyl) ATP; H-89, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide H-89 · 2HCl; 2-MeSATP, 2-methylthio-ATP; 8-p-SPT, 8-(p-sulfophenyl)theophyline; db-cAMP, dibutyryl cAMP.
Received for publication January 4, 2001. Accepted for publication April 6, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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cooperate to activate human dendritic cells: synergistic activation of interleukin 12 production. J. Exp. Med. 186:1603. in inducing human dendritic cell maturation. J. Immunol. 163:3071. synergize in the activation and maturation of human dendritic cells. J. Immunol. 165:4704. by TNF- in human monocytes. J. Immunol. 155:836.[Abstract]
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