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Departments of
* Experimental Dermatology and
Psychiatry, University of Freiburg, Germany; and
Department of Dermatology, University of Kiel, Germany
2Correspondence: PD Dr. Johannes Norgauer, Department of Experimental Dermatology, Hauptstraße 7, D-79104 Freiburg i. Br., Germany. E-mail: Norgauer{at}haut.ukl.uni-freiburg.de
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: DCs • calcium • chemotaxis • cytokine release
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2
3)
. DCs originate from hemopoietic stem
cells and migrate into peripheral tissues. DCs reside in an immature
form in unperturbed tissue, where they are capable of taking up
antigens but weak at stimulating T cells. Under the influence of a
variety of so-called danger signals—including pathogens; dying cells;
soluble CD40 ligand; cytokines such as tumor necrosis factor 
,
interleukin 1 (IL-1), and interleukin 6 (IL-6); or bacterial products
such as lipopolysaccharide (LPS)—DCs undergo a process of
differentiation known as maturation (1)
. Thereafter, they
migrate to the T-cell areas of secondary lymphoid organs. This
maturation process is associated with reduced phagocytic and endocytic
activity, increased membrane expression of major histocompatibility
complex and costimulatory molecules, production of cytokines such as
interleukin 12 (IL-12), and acquisition of potent T-cell-stimulating
functions (1)
. Depending on the conditions, DCs can
stimulate growth of a variety of T-cell subsets. In the presence of
IL-12, they support the growth of Th1 cells, whereas with IL-4 DCs
induce Th2-cell differentiation (1)
. Recent reports
suggest that recruitment of immature DCs to the skin and of mature DCs
to secondary lymphoid organs is regulated by differential expression of
chemotaxin receptors in a "weigh anchor/hoist the sail manner":
e.g., immature DCs express chemokine receptor types 1 and 5 (CCR-1 and
CCR-5) and platelet-activating factor (PAF) receptor, whereas chemokine
receptor type 7 (CCR-7) is found only in mature DCs (4)
.
Thus, macrophage/monocyte chemoattractant protein (MCP) 1–4,
macrophage/monocyte inflammatory protein 3ß (MIP-3ß), and
phosphatidylcholine-derived PAF act as chemotaxins in immature DCs,
whereas MIP-3ß, the ligand of CCR-7, stimulates migration in mature
DCs (5)
.
Nucleosides and nucleotides such as adenosine and ATP are important
modulators in the nervous and cardiovascular systems
(6
7
8
9
10)
. Nucleotides are released in either physiological
or pathological conditions via nonlytic pathways by many cells, such as
macrophages, platelets, neurons, T cells, and epithelial and
endothelial cells. Although the mechanisms of adenosine release are not
well understood, there is evidence of nonlytic secretion of adenosine
during hypoxic conditions. In addition, in tissues significant amounts
of adenosine can be generated extracellularly by membrane-bound
ecto-apyrase and 5'-nucleotidase, which degrade ATP, ADP, and AMP.
Consequently, high concentrations of extracellular adenosine can be
reached in ischemic and inflamed tissues (11
, 12)
. Apart
from effects of adenosine on the cardiovascular and nervous systems,
effects on immune cells have been reported. Adenosine inhibited
lymphocyte-mediated cytolysis and displayed chemotactic activity for
neutrophils (12
13
14)
.
Cellular responses to adenosine are evoked through activation of
G-protein-coupled purinoceptors type 1. To date, four adenosine
receptor subtypes—A1, A2a,
A2b, and A3—have been identified.
Receptors A1 and A3 are coupled to
Gi-, G0-, and Gq-proteins and
mediate inhibition of adenylate cyclase and activation of phospholipase
C (15)
. Phospholipase C cleaves phosphoinositide into
diacylglycerol and inositol 1,4,5-trisphosphate, the latter mobilizing
Ca2 + from intracellular stores. Studies with
various leukocytes revealed that activation of pertussis
toxin-sensitive Gi proteins followed by
intracellular Ca2+ transients and actin
reorganization is a prerequisite for the migration response
(16
17
18)
. Adenosine A2a receptors
interact with Gs- proteins, which activate adenylate
cyclase, thus generating the second messenger cAMP (12
13
14
, 19)
. Adenylate cyclase is a common effector, which is negatively
coupled to adenosine A1 and
A3 receptors and positively coupled to
A2 receptors, enabling reciprocal control and
fine tuning of this signaling pathway. In mature DCs, the increase in
cAMP results in inhibition of IL-12 production (20
21
22
23)
.
Recent publications in which cholera toxin, forskolin, and
ß2-agonists had been used provided evidence
that the inhibition of IL-12 is regulated via cAMP
(20
21
22
23)
. In addition, inhibition of IL-12 production in
macrophages by adenosine has been reported (24)
. Because
IL-12 has an important regulatory influence on Th1 and Th2 functions
(1
, 20)
, our results may represent a mechanism by which
adenosine skews the Th1/Th2 cytokine balance toward Th2-type dominance
(20)
. The present study characterizes the biological
activity of adenosine as related to human DCs and the involvement of
adenosine receptors in intracellular signaling events and cell
responses.
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MATERIALS AND METHODS |
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Preparation of human DCs
Peripheral blood cells were isolated from buffy coats by using
Ficoll separation (25)
. After centrifugation, the
leukocyte-containing pellet was resuspended in 2 ml of PBS containing
0.15% EDTA and 0.5% bovine serum albumin. The cells were separated by
using CD14 antibody-coated MicroBeads with Macs single-use separation
columns. The CD14-positive cells were suspended in RPMI 1640 medium
containing 10% FCS, 1% glutamine, 50 IU/ml penicillin, 50 µg/ml
streptomycin, 1000 U/ml IL-4, and 10,000 U/ml GM-CSF and were cultured
at 37°C in a humidified atmosphere with 5%
CO2. After 6 days, cells were harvested for
experiments. To ensure differentiation of monocytes into DCs, the
surface markers CD1a and CD14 (antibodies and respective isotype
controls; Coulter-Immunotech, Krefeld, Germany) were routinely measured
by flow cytometry. To initiate further differentiation of DCs, 3
µg/ml LPS was added at day 4 to the cells suspended in the RPMI 1640
medium supplemented with FCS, GM-CSF, and IL-4 . Forty-eight hours
later, at day 6, LPS-differentiated DCs were again harvested for
experiments. Maturation was controlled cytometrically by measurement of
CD54, CD83, and CD115 and functionally by stimulation with MIP-3ß.
Actin polymerization
The content of filamentous actin was analyzed by flow cytometry
with NBD-phallacidin staining (26)
. Briefly, aliquots (50
µl) of stimulated cell suspensions (5 x
105 DCs/ml) were collected at the indicated time
intervals and fixed in a 7.4% formaldehyde buffer. After 1 h,
cells were mixed with the staining mixture containing 7.4%
formaldehyde, 0.33 µM NBD-phallacidin, and 1 mg/ml
lysophosphatidylcholine. Fluorescence intensities were measured by flow
cytometry. The relative F-actin content (compared with the medium
control) was calculated.
Intracellular Ca2+ measurements
Intracellular free Ca2+ was measured in
fura-2-labeled DCs with the digital fluorescence microscope unit
Attofluor (Zeiss, Oberkochem, Germany) (25)
. Briefly, DCs
were incubated with 2 µmol fura-2 for 30 min at 37°C in
Ca2+- and Mg2+-free buffer.
Cells were washed twice and resuspended in the same buffer containing
1.5 mM CaCl2 and MgCl2. The
fluorescence traces after stimulation were followed
fluorospectrometrically, and the ratio between absorption at 340 nm and
that at 380 nm was calculated. The intracellular
Ca2+ concentration was calibrated with ionomycin
by using following equation:
[Ca2+]i =
Kd(F -
Fmin)/(Fmax - F).
Migration assay
The experiments were performed with 48-well chambers (Nuclepore,
Tübingen, Germany) (25)
. Buffer or stimuli filled
the wells of the lower compartment. Then a polycarbonate membrane 10
µm thick with a pore size of 5 µm was placed over the wells. DCs
(105 cells/well) were added to the upper
compartment and incubated at 37°C for 90 min in a humidified
atmosphere. Cells from the upper side of the membrane were removed by
wiping over a profiled rubber, and migrated DCs on the lower side of
the membrane were fixed in methanol and stained with hematoxylin. For
each sample, DCs in five randomly chosen high-power fields
(magnification: 400 x) were counted, and a mean value for each sample
was calculated. The chemotactic index was calculated as the ratio
between stimulated cells and the medium control.
Detection of mRNA by reverse transcriptase and polymerase
chain reaction
mRNA was isolated by using QIAshredder and RNeasy kits (Qiagen).
mRNA, M-MLV reverse transcriptase, and pd(N)6
primers were used to obtain cDNA. All oligonucleotides used as primers
in polymerase chain reaction (PCR) were designed to recognize sequences
specific for each target cDNA. Primer sequences are as follows:
A1 (278 bp) forward, 5'-TCCCCCTCGCCATCCTCATCAACA-3', and 5'-GGCCCGCTCCACCGCACTCAG-3' reverse primers. A2a (631 bp) forward, 5'-CTGGTCCTCACGCAGAGCT-3', and 5'-ACTCGCGGATACGGTAGGC-3' reverse primers. A2b (385 bp) forward, 5'-GCCATGCCCGGCGGGTCTCACG-3', and 5'-ACTGCCACGGCCAGAAGGCTGAAGATGGA-3' reverse primers. A3 (509 bp) forward, 5'-GCTTACCGTCAGATACAAG-3', and 5'-GCATAGACGATAGGGTTCA-3' reverse primers. ß2-Microglobulin (259 bp) forward, 5'-CCTTGAGGCTATCCAGCGTA-3', and 5'-GTTCACACGGCAGGCATACT-3' reverse primers.
Thirty-five PCR cycles were run at 94°C (denaturation, 1 min), 62°C (annealing, 1 min), and 72°C (extension, 1 min). PCR products were subjected to electrophoresis on a 2% agarose gel and were visualized by ethidium bromide staining. Identity of the PCR products was confirmed by sequencing after cloning with pCRII vectors.
Measurement of intracellular cAMP
Intracellular cAMP was measured by cAMP EIA according to the
manufacturer’s instructions.
Measurement of IL-12
IL-12 release was analyzed by the IL-12 immunoassay (R&D
Systems) according to the manufacturer’s instructions.
Statistical analysis
Unless stated otherwise, data are expressed as means ±
SE. ANOVA was used to compare experimental groups with
control values. When the global test of differences was significant at
the 5% level, pairwise tests of differences between groups were
applied (Turkey’s comparison test). Statistical analysis of PCR bands
was performed by the Dunnet comparison test (ANOVA).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, lanes 2–5). In LPS-differentiated DCs, only mRNA expression of the
A2a receptor was seen (Fig. 1
, lanes 7–10).
After reverse transcriptase was omitted in the RT reaction, no
amplification products were observed in immature and LPS-differentiated
DCs (data not shown).
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Mobilization of intracellular Ca2 + by adenosine
Next, intracellular Ca2 + transients after
stimulation with adenosine were analyzed in fura-2-labeled immature DCs
by use of digital fluorescence microscopy. Adenosine induced a rapid
and concentration-dependent intracellular response (Fig. 2
). Maximal and half-maximal responses were seen at
10-4 M and 10-6 M
adenosine, respectively. To characterize the influence of cell
differentiation on this response, experiments were conducted at day 6
after addition of 3 µg/ml LPS for 2 days. Adenosine was no longer
able to elicit intracellular calcium transients (Table 1
).
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Actin response and chemotaxis
Actin reorganization is a prerequisite for migration of different
types of leukocytes (16
, 17)
. In our study, we analyzed
the influence of adenosine on the actin network in immature and
LPS-differentiated DCs by flow cytometry. This nucleoside caused a
rapid polymerization of actin molecules (Fig. 3
). There was an increase of the F-actin content of about 50% within
25 s. Maximal and half-maximal effects were observed at
10-4 M and 10-7 M
adenosine, respectively. After addition of LPS, DCs lost their ability
to respond to adenosine stimulation with actin polymerization (Table 1)
.
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Migration of DCs along different concentration gradients of adenosine
was analyzed and compared with migration in response to the
well-characterized chemotaxin complement fragment C5a. The nucleoside
adenosine elicited a typical dose-dependent bell-shaped chemotactic
response for immature DCs, which results from the requirements for this
response such as continuous interaction of ligands with free cell
surface receptors (27)
. Half-maximal and maximal effects
were seen at 10-5 M and
10-8 M adenosine, respectively (Fig. 4
). Again, adenosine had no effect on LPS-differentiated DCs (Table 1)
.
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Effects of adenosine on intracellular cAMP levels and IL-12
production
It is known that adenosine can induce an increase of cAMP via
A2a-receptors. To characterize the function of
A2a receptors in DCs, intracellular cAMP levels
after stimulation with adenosine were analyzed. Adenosine did not
elicit an increase of intracellular cAMP levels in immature DCs (Table 1)
. However, adenosine stimulated adenylate cyclase activity in
LPS-differentiated DCs. Maximal and half-maximal effects were seen with
10-4 M and 10-6 M
adenosine, respectively (Fig. 5
).
|
As shown elsewhere, stimulation of adenylate cyclase activity inhibits
IL-12 production in LPS-differentiated DCs (20)
. Here, we
found that adenosine inhibited IL-12 production in a
concentration-dependent manner. Maximal and half-maximal effects were
seen with 10-4 M and 10-5
M adenosine, respectively (Fig. 6
).
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Characterization of the involved adenosine receptors by using
selective agonists
To characterize the involved adenosine receptors in DC responses,
studies with optimal concentrations of the A1
agonist CHA, the A2 agonist DPMA, and the
A3 agonist IB-MECA were performed (Table 2
). We could show that CHA and IB-MECA induced a rapid intracellular
Ca2+ release, actin polymerization, and
chemotaxis in immature DCs. It is worth noting here that the
A1-agonist CHA induced stronger biological
activity than the A3 agonist IB-MECA. In
contrast, DPMA did not induce these responses in immature DCs. However,
this agonist stimulated adenylate cyclase activity and modulated IL-12
production in LPS-differentiated DCs. The A1
agonist CHA and the A3 agonist IB-MECA had no
influence on these responses.
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To corroborate these findings, experiments with isotype-specific
receptor antagonists and pertussis toxin were also performed. The
adenosine-induced Ca2+ response, actin
polymerization, and migration could be inhibited with the
A1 antagonist DPCPX, the A3
antagonist MRS-1220 (Table 3
), and pertussis toxin (Fig. 7
), but not with the A2 antagonist CSC. The effects
on cAMP and IL-12 production in LPS-differentiated DCs was blocked by
the A2 antagonist CSC.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 28)
. It can be assumed that these agents are
involved at different stages during the recirculation process of DCs
from the bone marrow via the bloodstream and target sites in the skin
to secondary lymphoid organs (29)
. Recent findings
indicate that adenosine, a well-known modulator in the nervous and
cardiovascular systems, also has immunomodulatory effects on
lymphocytes, neutrophils, and eosinophils (11
, 30)
.
Adenosine inhibits lymphocyte-mediated cytolysis (13)
and
enhances chemotaxis in neutrophils (12)
. Although the
mechanism for adenosine release is not well understood, it is well
established that this mediator is released from biological tissues
during hypoxia and ischemic conditions. Significant amounts of
adenosine can also be generated extracellularly by hydrolysis of
nucleotides (11)
. To improve our understanding of the
biological effects of adenosine on human DCs, we analyzed intracellular
calcium transients, chemotaxis, migration-associated actin
polymerization, activation of adenylate cyclase, and IL-12 production
as well as mRNA expression of adenosine receptors in immature and
LPS-differentiated DCs.
Adenosine interacts with a family of G-protein-coupled P1 purinoceptors
including the four adenosine subtypes A1,
A2a, A2b, and
A3 receptors (19)
. The present
RT-PCR experiments clearly show mRNA expression of
A1, A2a, and
A3 receptors in immature DCs. No mRNA expression
of A2b receptors could be detected. LPS-triggered
maturation of DCs was accompanied by down-regulation of the mRNA
expression of A1 and A3
receptors. These differentiated cells expressed only
A2a receptor mRNA. Adenosine
A1 and A3 receptors couple
to Gi-, G0-, or
Gq-proteins and mediate activation of
phospholipase C (15)
. Phospholipase C cleaves
phosphoinositide into diacylglycerol and inositol 1,4,5-trisphosphate,
the latter mobilizing Ca2+ from intracellular
stores (16
17
18)
. The A2a receptor
typically couples to Gs proteins, which stimulate
adenylate cyclase activation, thus enhancing cAMP levels. To
demonstrate functional adenosine receptor expression at the cell
surface of DCs, we showed here that adenosine, adenosine
A1 receptor agonist CHA, and
A3 receptor agonist IB-MECA elicited
Ca2+ transients. This effect could also be
reversed by pretreatment with A1 and
A3 receptor antagonists. In contrast, we were
unable to detect any Ca2+ response by specific
activation of A2a receptors. These findings agree
with results from Kohno et al. (31)
, who showed that the
A3 receptor agonist IB-MECA elicited
Ca2+ transients in eosinophils, whereas the
selective A2a receptor agonist CGS 21680 did not
increase intracellular Ca2+.
In leukocytes, Gi-protein-coupled receptors
regulate the reorganization of the actin cytoskeleton, which is a
prerequisite of cell motility (18)
. In addition to
demonstrating the calcium response, we showed here that adenosine
induced actin polymerization and migration in immature human DCs
involving A1 and A3
receptors, but not A2a receptors. DCs originating
from hemopoietic cells are recruited at target sites in the skin to
capture antigens and migrate thereafter to secondary lymphoid organs to
prime T cells (1
2
3)
. This trafficking is regulated by
specific expression of chemokine receptors during different maturation
states of the cell, e.g., immature DCs express receptors for CCR-1,
CCR-5, and PAF, which are down-regulated during maturation (4
, 21)
. Chemotaxis in mature DCs is regulated by MIP-3ß; mature,
but not immature, DCs express the receptor for this ligand. Analogous
to the situation for PAF and MCP 1–4, differentiated DCs also did not
respond to adenosine with intracellular Ca2+
transients, actin polymerization, and a chemotactic response. The
present data agree with the model proposed by Sozzani et al. that DCs
change their chemokine receptors during maturation (4)
.
Our studies suggest that adenosine is involved in accumulation of DCs
in primary inflammatory sites, and down-regulation of its receptors
might be a prerequisite for departure from these sites on the way to
secondary lymphoid organs (4)
. In contrast to other
well-characterized chemokine receptors, which couple only to
Gi-proteins, adenosine receptors interact with
various G-protein subsets including Gi-,
G0-, Gq-, and
Gs-proteins. Experiments with pertussis toxin
revealed that the effects in immature DCs are mediated via
Gi- or G0-proteins.
However, our data also suggest that adenosine, via activation of
A2a receptors, induced an increase of
intracellular cAMP levels in LPS-differentiated DCs, involving
Gs-protein. Surprisingly, despite the
demonstration of mRNA expression of A2a receptors
in immature DCs we could not detect an enhancement of cAMP levels in
immature DCs. This finding could support either that the
A2a receptor in immature DCs is not expressed as
protein on the cell surface or that this receptor is not able to couple
to adenylate cyclase via Gs-protein at this
differentiation stage. DCs are believed to be critical in both
initiating and modulating immune responses. After DCs capture, process,
and transport antigens to secondary lymphoid organs, they prime T cells
(1
2
3)
. Depending on the microenvironment, DCs can
regulate the outgrowth of a variety of T-cell subsets. In the presence
of IL-12 they produce Th1 cells, whereas with IL-4 they induce Th2-cell
subsets (1)
. In this context it is of interest that
previous publications reported that cAMP inhibits IL-12 production in
DCs and regulates the outgrowth of Th2-cell differentiation,
suppressing Th1 priming (20
21
22
23)
. Here we report that
activation of A2a receptors also results in the
inhibition of IL-12 production. This finding agrees well with a
publication by Hasko et al., which showed inhibition of IL-12
production by adenosine in macrophages (24)
. Therefore,
adenosine not only regulates the circulatory pathway in a weigh
anchor/hoist the sail manner but may also influence the local
microenvironment and the outcome of T-cell differentiation.
The present results indicate that adenosine, the A1 agonist CHA, and the A3 agonist IB-MECA induced Ca2+ transients as well as actin polymerization and chemotaxis only in immature DCs. These findings suggest that adenosine may control proinflammatory activities of DCs and regulate their accumulation at target sites. Maturation of DCs is accompanied by a loss of the adenosine responses such as Ca2+ transients, actin polymerization, and migration. However, adenosine increased the intracellular cAMP levels in mature DCs via A2a- receptors and reduced IL-12 production. At this stage adenosine may have functions as a regulator of T-cell priming.
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FOOTNOTES |
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Received for publication March 14, 2001.
Revision received May 30, 2001.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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production via adenosine A2a receptor-dependent and independent mechanisms. FASEB J 14,2065-2074This article has been cited by other articles:
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E. Panther, S. Corinti, M. Idzko, Y. Herouy, M. Napp, A. la Sala, G. Girolomoni, and J. Norgauer Adenosine affects expression of membrane molecules, cytokine and chemokine release, and the T-cell stimulatory capacity of human dendritic cells Blood, May 15, 2003; 101(10): 3985 - 3990. [Abstract] [Full Text] [PDF]
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J. Fossetta, J. Jackson, G. Deno, X. Fan, X. K. Du, L. Bober, A. Soude-Bermejo, O. de Bouteiller, C. Caux, C. Lunn, et al. Pharmacological Analysis of Calcium Responses Mediated by the Human A3 Adenosine Receptor in Monocyte-Derived Dendritic Cells and Recombinant Cells Mol. Pharmacol., February 1, 2003; 63(2): 342 - 350. [Abstract] [Full Text] [PDF]
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E. Panther, M. Idzko, S. Corinti, D. Ferrari, Y. Herouy, M. Mockenhaupt, S. Dichmann, P. Gebicke-Haerter, F. Di Virgilio, G. Girolomoni, et al. The Influence of Lysophosphatidic Acid on the Functions of Human Dendritic Cells J. Immunol., October 15, 2002; 169(8): 4129 - 4135. [Abstract] [Full Text] [PDF]
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