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Up-Regulates the A2B Adenosine Receptor Expression in Macrophages: A Mechanism of Macrophage Deactivation1
*
Departament de Fisiologia (Group of Macrophage), Facultat de Biologia, and Fundació August Pi i Sunyer, Campus Bellvitge, Barcelona, Spain; and
Departament de Bioquímica i Biologia Molecular, Facultat de Química, Universitat de Barcelona, Barcelona, Spain
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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up-regulates the surface protein and gene expression of the
A2B adenosine receptor by induction of de novo synthesis.
The up-regulation of A2B receptors correlates with an
increase in cAMP production in macrophages treated with adenosine
receptor agonist. The stimulation of A2B receptors by
adenosine or its analogues inhibits the IFN--induced expression of
MHC class II genes and also the IFN--induced expression of nitric
oxide synthase and of proinflammatory cytokines. Therefore, the
up-regulation of the A2B adenosine receptor expression
induced by IFN- could be a feedback mechanism for macrophage
deactivation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production 5, 8, 9, 10 , the increase in IL-6 or IL-10 production
5, 10, 11 , and the inhibition of proliferation induced by
macrophage-CSF, IL-3, or PMA 12 .
The intra- and extracellular pools of adenosine are regulated by
nucleoside transporters 13, 14 and by the activity of enzymes
responsible for the metabolism of adenosine expressed either inside the
cells or associated with the cell surface 15, 16 . To induce the
synthesis of molecules such as nitric oxide or to inhibit the induction
of TNF- by LPS, adenosine must be transported into the cell. In
contrast, for other functions, adenosine interacts with specific cell
surface receptors that are coupled to G proteins. Several adenosine
receptors have been described and named A1,
A2A, A2B, and A3 according to their
functional ability to modulate adenylate cyclase activity
17, 18 . The number and type of receptors are characteristic of each
cell type. Over the past years, all four adenosine receptor subtypes
have been cloned in many organisms 19, 20, 21, 22 .
We have analyzed the expression of adenosine receptors in
macrophages using murine bone marrow-derived macrophages
(BMDM),3 which are
homogeneous populations of nontransformed primary cells. Our results
suggest that BMDM mainly express A2B and A3
adenosine receptors. The interaction of the A2B receptors
with adenosine induces the production of cAMP. The A2B
adenosine receptor expression is up-regulated by IFN-. The
stimulation of A2B adenosine receptor inhibits the MHC
class II expression induced by IFN- and also inhibits the
IFN--induced expression of iNOS and modulates the expression of
IFN--induced cytokines, such as TNF- and IL-1ß. Therefore, the
up-regulation of A2B adenosine receptors by IFN- could
be a negative feedback mechanism to regulate macrophage activation at
the inflammatory foci.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Adenosine, 5'-N-ethyl-carboxamidoadenosine (NECA),
N6-(R)-phenylisopropyl-adenosine
(R-PIA), and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) were all
obtained from Sigma (St. Louis, MO).
2-[p-(2-Carbonyl-ethyl)-phenylethylamino]-5'-N-ethylcarboxamido-adenosine
(CGS 21680) and
N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide
(IB-MECA) were purchased from Research Biochemicals International
(Natick, MA). [3H]NECA, [3H]R-PIA, and
[3H]CGS21680 were obtained from New England Nuclear
(Boston, MA). Recombinant murine IFN- was a gift from Genentech (San
Francisco, CA). All other products were of the best grade available and
were purchased from Sigma (St. Louis, MO). Deionized water further
purified with a Millipore Milli-Q system (Bedford, MA) was used
throughout.
Cell culture
BMDM were isolated as previously described 23 . Six-week-old BALB/c mice (Charles River Laboratories, Wilmington, MA) were killed by cervical dislocation, and both femurs were dissected free of adherent tissue. The ends of the bones were cut off, and the marrow tissue was eluted by irrigation with medium. The marrow plugs were dispersed by passing through a 25-gauge needle, and the cells were suspended by vigorous pipetting and washed by centrifugation. The cells were cultured in plastic tissue culture dishes (150 mm) in 40 ml of DMEM containing 20% FBS and 30% L cell-conditioned medium as a source of macrophage-CSF. After 7 days of culture the macrophages are a homogeneous population of adherent cells. The cells were incubated at 37°C in a humidified 5% CO2 atmosphere.
Antibodies
The surface expression of adenosine receptor was analyzed using affinity-purified Abs anti-A1 and anti-A2B against human molecules developed by our group 24, 53 . These Abs were developed against peptides of human adenosine receptors, which are highly conserved in murine cells. The peptide used for immunization corresponds to the deduced amino acid sequence from the putative third extracellular loop (FQPAQGKNKPKWA) of the cloned human A2B adenosine receptor 25, 53 . The specificity of these receptors has been assessed using CHO cells transfected with the cDNA encoding each of the adenosine receptors 24, 53 . FITC-labeled rat anti-rabbit IgG Ab fluorescein-conjugated from Sigma was used as secondary Ab. For surface staining of MHC class II molecules we used Ab 34-5-3 (anti-I-Ad; PharMingen, San Diego, CA). FITC-labeled sheep anti-mouse IgG (Cappel, Turnhout, Belgium) was used as secondary Ab. To block Fc receptors we used anti-CD16/CD32 Ab (PharMingen). For Western blot analysis, we used rabbit anti-mouse iNOS Abs (Calbiochem, San Diego, CA) and, as a control, mouse anti-mouse ß-actin Abs (Sigma). Peroxidase-conjugated rat anti-rabbit IgG or anti-mouse IgG were used as secondary Abs, respectively (Cappel).
Binding experiments
The experiments were performed in 24-well plates (2 x 105 cells/well) at 4°C in serum-free DMEM buffered with 20 mM HEPES and containing 2 U/ml adenosine deaminase (Boehringer Mannheim, Indianapolis, IN). Ligand binding was measured by incubation of the cells with the radiolabeled agonist in the presence or the absence of different displacers for 2 h at 4°C. Then, the cells were washed with ice-cold PBS (10 mM; pH 7.4) and disrupted with 0.2% SDS. Aliquots of the suspension were transferred to scintillation vials containing 10 ml of formula 989 scintillation mixture (New England Nuclear), and radioactivity was measured using a Packard 1600 Tri-Carb scintillation counter (Downers Grove, IL) with 50% efficiency. The amount of protein was determined by the bicinchonimic acid method as described previously 26 .
Determination of Ag cell surface expression
Cell surface staining was conducted using specific Abs and cytofluorometric analysis as described previously 27 . Cells (106) were harvested and washed in cold PBS. After fixation with 2% paraformaldehyde during 30 min at 4°C, the cells were resuspended in 50 µl of PBS containing 5% FBS. They were then incubated at 4°C with 1 µg/106 cells of anti-CD16/CD32 mAb to block the Fc receptors. After 15 min, the primary Ab was added, and the cells were further incubated for 1 h. The A2B-specific Ab (MPE1) was used at 5 µg/106 cells, and the anti-I-Ad Ab was used at 1 µg/106 cells. Then, the cells were washed by centrifugation through an FBS cushion. Finally, they were incubated with FITC-conjugated secondary Ab for another hour at 4°C. Stained cell suspensions were analyzed using an EPICS XL flow cytometer (Coulter, Hialeah, FL). FITC excitation was obtained by a 488-nm argon laser lamp, and its fluorescence was collected using a 525-nm band-pass filter. The parameters used to select cell populations for analysis were forward and side light scatter. As a control, we used an unrelated Ab.
To analyze the level of expression induced by IFN-, 106
cells were cultured in plastic dishes (60 mm) and activated with 300
U/ml of IFN- for the indicated times; then, A2B
expression was measured as described.
To permeabilize macrophages, 106 cells were resuspended in 100 µl of PBS containing 0.5% saponin (Sigma) for 20 min at room temperature 28 . Then, the cells were washed by centrifugation through an FBS cushion and resuspended in 50 µl of PBS containing 5% FBS to incubate with the appropriate Abs.
Determination of cAMP
Production of cAMP was evaluated using a standard procedure (cAMP EIA system, Amersham, Aylesbury, U.K.). Briefly, 106 macrophages were cultured in 24-well plates in normal medium. The cells were stimulated with the indicated adenosine agonists and antagonists for 15 min. The cAMP from the cells was extracted using a liquid phase extraction method. Ice-cold ethanol was added to the cell suspension to a final concentration of 65% (v/v) ethanol. After allowing the cells to settle, the supernatants were transferred to test tubes and centrifuged at 2000 x g for 15 min at 4°C. The supernatants were transferred to fresh tubes and dried using a Speed-Vac (Bio-Rad, Hercules, CA). The dried extracts were dissolved in assay buffer, and the amount of cAMP was analyzed using a nonacetylation cAMP EIA system (Amersham). Each sample was made in triplicate, and the results are presented as the mean ± SEM.
Northern blot analysis
Total cellular RNA (20 µg), extracted by the acid guanidinium
thiocyanate-phenol-chloroform method 29 , was run in 1% agarose with
5 mM 3-[N-morpholino]propanesulfonic acid (MOPS) (pH 7.0)
and 1 M formaldehyde buffer. The RNA was transferred to a GeneScreen
(Life Science Products, Boston, MA) nitrocellulose membrane overnight
and fixed with 150 mJ UV. As a probe, we used either a randomly primed
human A2B adenosine receptor cDNA fragment 25 or the
18S ribosomal RNA probe 30 as a control for the amount of loaded RNA.
To detect the A2B receptor mRNA and to ensure the
recognition of the mouse mRNA by the human probe, hybridization was
performed at low stringency in a rotating incubator at 42°C and 10%
formamide for 18 h. For the analysis of I-Aß RNA, a fragment of
I-Aßk cDNA ranging from positions 1–230 of the open
reading frame was used. For I-A we used a fragment of the
IAk cDNA covering positions 1–489 of the open reading
frame. Both fragments were subcloned into the pGEM3 vector (Promega,
Madison, WI) 27 . The IFN--induced cytokine expression was analyzed
using cDNA probes for TNF- and IL-1ß, which were provided by Dr.
M. Nabholz (Institut Suisse de Recherches Experimentales sur le
Cancer, Epalinges, Switzerland) and Dr. R. Wilson (Glaxo,
Greenford, U.K.), respectively. The blots were sequentially washed in
1x SSC/0.2% SDS twice at room temperature and once at 65°C, exposed
for 12–72 h at -80°C to Kodak film (Eastman Kodak, Rochester, NY)
and analyzed using a Molecular Analyst (Bio-Rad).
Protein extraction and Western blot analysis
The cells were washed twice in ice-cold PBS and lysed on ice with lysis solution (1% Triton X-100, 10% glycerol, 50 mM HEPES (pH 7.5), 150 mM NaCl, and protease inhibitors). The protein concentration of the samples was determined by the Bio-Rad protein assay. One hundred micrograms of the cell lysates were boiled at 95°C in Laemmli SDS loading buffer, separated by 7.5% SDS-PAGE, and electrotransferred to nitrocellulose membranes (Hybond-ECL, Amersham, Arlington Heights, IL). The membranes were blocked for at least 1 h at room temperature in Tris-buffered saline/0.1% Tween-20 (TBS-T) containing 5% nonfat dry milk and then incubated with TBS-T containing the primary Ab. For iNOS and ß-actin immunoblotting, incubation was performed for 1 h at room temperature. After three washes of 15 min each in TBS-T, the membranes were incubated with peroxidase-conjugated anti-rabbit or anti-mouse IgG Abs, respectively (Cappel), for 1 h. After three washes of 15 min with TBS-T, enhanced chemiluminescence detection was performed (Amersham), and the membranes were exposed to x-ray films (Amersham). The blots were quantified by densitometric analysis.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To characterize adenosine receptors in BMDM we measured the binding of
adenosine analogues specific to each type of receptor. BMDM were
incubated with NECA, a nonselective adenosine receptor agonist 31 ;
CGS 21680, a specific A2A adenosine receptor agonist 32 ;
R-PIA, a specific A1 adenosine receptor agonist 33 ; and
IB-MECA, a specific A3 adenosine receptor agonist 34 . The
competition experiments between radiolabeled and cold ligands showed
that macrophages bound [3H]NECA, a synthetic adenosine
analogue recognized by all four subtypes of adenosine receptors. Due to
the low affinity of the A2B receptors for any of the
adenosine analogues, there was a considerable amount of nonspecific
[3H]NECA binding. For this reason the binding competition
analysis with 750 µM cold NECA only showed a competition of 45%. The
specific binding of either [3H]R-PIA at low
concentrations (3 nM) or [3H]CGS21680 was negligible,
thus suggesting the absence of A1 or A2A
receptors (Fig. 1
). The binding of
[3H]NECA was competed by high amounts (750 µM) of R-PIA
and IB-MECA. At high concentrations, R-PIA bound to the A2B
receptors, and IB-MECA bound to the A3 receptors. The
displacement of [3H]NECA binding induced by high
concentrations of R-PIA indicated that NECA binding was not due to
adetonine-like molecules 35 . Therefore, these results suggest the
presence of both A2B and A3 receptors in
macrophages.
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). BMDM stained with the
MPE-1 Ab contained two cell populations, one lacking and the other
(76.4 ± 4.8%) expressing the A2B adenosine
receptors. As a control we used an Ab against the A1
adenosine receptor 24 , which did not result in cell surface staining
(Fig. 2).
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A). The treatment of
macrophages with 10-5 M CGS 21680 did not increase cAMP
production. Similar results were obtained when we used
10-6 M R-PIA or 10-5 M IB-MECA. As selective
agonists for A1, A2A, and A3
adenosine receptors did not induce cAMP production, the increase in
cAMP production obtained with adenosine or NECA may be mediated through
interaction with the A2B adenosine receptor. Furthermore,
DPCPX at a concentration (10-6 M) that blocked
A2B receptor 38 inhibited completely the increase in cAMP
induced by 10-5 M NECA. Although we could not exclude the
presence of A3 adenosine receptors, the cAMP-mediated
responses in macrophages seemed to be mediated through A2B
receptors.
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B) with an ED50 of 5 µM, which is
similar to that reported for other model systems 17 . The induction of
cAMP by NECA showed biphasic kinetics (Fig. 3C); it
increased quickly during the first 30 min of stimulation and then it
decreased, reaching basal levels 5 h later.
Macrophage activation has been defined as a series of functional and
biochemical modifications in macrophage populations that are induced by
several lymphokines. IFN- can activate macrophages and may be the
major macrophage activator produced by T cells 41 . The treatment of
macrophages with saturating amounts of IFN- (300 U/ml) induced an
up-regulation of the expression of A2B adenosine receptors
at the cell surface (Fig. 4A).
This increase was a late event and was not measurable until 24–48 h
after the treatment. The permeabilization of the macrophages with 0.5%
saponin also allowed measurement of the intracellular receptors. We
observed that in these conditions the up-regulation of the
A2B adenosine receptors took place not only at the cell
surface but also inside the cell (Fig. 4A). This suggested
that the up-regulation of the A2B adenosine receptors was
not caused by the expression of an internal pool of receptors, but
probably by de novo synthesis of receptors. This was confirmed by
Northern blotting; BMDM initially expressed little A2B
receptor mRNA, which suggested that the half-life of the
A2B receptor protein is very high in resting macrophages
(Fig. 4B). After treatment with IFN-, an increase in the
mRNA levels of A2B adenosine receptor became evident after
24 h and especially after 48 h. This demonstrated that the
up-regulation of A2B adenosine receptors both inside and at
the cell surface was due to the induction of de novo synthesis by
IFN-. This is the first time that a heterologous regulation of
adenosine receptors by a cytokine has been demonstrated, and it is
crucial to understand the relationship between the
anti-inflammatory effect of adenosine on the different components
of the immune system and the resolution of the immune response.
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, we measured the
production of cAMP induced by agonists. The IFN--induced increase in
A2B receptor expression is time-dependent (Fig. 5A). After the addition of
adenosine or NECA to IFN--activated macrophages, we observed that
production of cAMP increased in a time-dependent manner (Fig. 5B). The increase in cAMP correlated with the up-regulation
by IFN- of the A2B adenosine receptors. This suggested
that up-regulation of A2B adenosine receptors in activated
macrophages is physiologically relevant.
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, and these proteins are expressed at the macrophage cell
surface only 24–72 h after stimulation 27 . cAMP represses at the
transcriptional level the expression of MHC class II induced by IFN-
on macrophages 42, 43, 44 . The activation of the A2B
adenosine receptor by NECA produced enough cAMP to inhibit by 66% the
expression of class II molecules at the surface of macrophages (Fig. 6). The inhibition was higher when the
macrophages were treated for a long time with IFN-, i.e., when the
up-regulation of A2B adenosine receptors was higher.
Therefore, it seems that the up-regulation of adenosine receptors is a
mechanism of deactivation of macrophages. The inhibitory effect of NECA
was receptor mediated, since it was blocked by the antagonist DPCPX.
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induced the expression of IA
and IAß mRNA (Fig. 6C). The addition of the adenosine
agonist NECA inhibited almost completely the expression of IA and
IAß mRNA induced by IFN- (Fig. 6C). As IA and IAß
mRNAs are very stable 45 , this suggested that inhibition by cAMP of
MHC class II production takes place at the transcriptional level. The
inhibition by adenosine analogues of class II mRNA expression induced
by IFN- took place through the production of cAMP, since only NECA,
forskolin, or 8-bromo-cAMP, but not the control drug R-PIA,
repressed the induction of mRNA (Fig. 7A). Finally, only drugs that
activate A2B receptors inhibited the induction of IA or
IAß mRNA by IFN- (Fig. 7B). Therefore, the inhibition
of class II expression is mediated through the production of cAMP by
the interaction of adenosine and its analogues with the A2B
receptors. Thus, the activation of up-regulated A2B
receptors would lead to an inhibition of the IFN- induction of MHC
class II molecules.
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-induced expression of
class II MHC genes, we wanted to analyze the effects of adenosine
analogues on other aspects of IFN--induced macrophage activation.
IFN- induces the expression of NOS, regulates the production of
nitric oxide in macrophages 4 , and modulates the expression of
several proinflammatory cytokines, such as TNF- and IL-1ß 41 .
The treatment of macrophages with NECA inhibited the IFN--induced
expression of iNOS (Fig. 8A).
Moreover, NECA also inhibits the expression of TNF- and IL-1ß
induced by IFN- (Fig. 8B). Thus, the inhibitory effect of
adenosine and its analogues is not specific for IFN--induced class
II MHC expression, but is also present for several aspects of
macrophage activation induced by IFN-.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The role of the adenosine A2B receptors was demonstrated using BMDM, which are primarily quiescent nontransformed cells 23 , and was supported by several observations. First, the low affinity binding of radiolabeled NECA, an agonist of the four types of adenosine receptors that is not displaced by low concentrations of agonists specific for either A1 or A2A adenosine receptors; this is consistent with the presence of the A2B adenosine receptor. Second, a specific Ab against A2B receptors, but not against A1 receptors, stained a high percentage of the macrophages; this is the first time that specific Abs against the A2B receptors have been used. Third, the effects of NECA on cAMP levels are probably mediated by A2B receptors, since CGS 21680, which is a selective agonist for A2A receptors, was ineffective. The activation of A3 receptors does not seem to be involved in cAMP production, since A3 receptors are negatively coupled to the adenylate cyclase, and DPCPX, which does not interact with A3 receptors, blocks the NECA-induced response. These results are consistent with the presence of the A2B and A3 subtypes, but not A1 or A2A receptors, in macrophages. The presence of A3 receptors in cells of the monocyte/macrophage lineage has been previously reported 8, 9 . In contrast, this is the first report demonstrating the presence of A2B receptors in macrophages.
IFN- is the major activator of macrophages, and over 200 genes are
now known to be regulated by this cytokine 46, 47 . IFN- modulates
the expression of many receptors. In some cases, IFN- induces the
expression of receptors such as the high affinity IgG receptor
(Fc-RI) 48 and also down-regulates the expression of other
receptors, such as the CSF-1 receptor (c-fms) 49 . A
time-course analysis showed that IFN- induced an increase in the
number of A2B adenosine receptors on the cell surface. This
is the first time that a modulation of the adenosine receptors by a
cytokine has been described. This progressive increase was due to de
novo synthesis of the receptor, and it correlated with the higher
capacity of adenosine to induce an increase in cAMP levels, thus
suggesting that the newly synthesized receptors were functional.
It has been shown that the expression of MHC class II molecules induced
by IFN- is down-regulated by several mediators, such as LPS, PGs,
and glucocorticoids 42 . The mechanism of repression by which some of
these agents operate has been described recently. Dexamethasone
decreases MHC class II expression in macrophages at the level of
transcription by inhibiting the transcription factors that bind to the
X box of the promoter 50 . The addition of cAMP to the culture medium
reduces the expression of MHC class II. It was originally found that
the effect of cAMP was mediated at the transcriptional level by
conserved promoter elements 43, 44 . More recently, it has also been
described that an increase in intracellular cAMP levels inhibits STAT1
activity in mononuclear cells 51 , which is necessary for MHC class II
gene expression 52 . Our results show that adenosine, interacting
through the A2B receptor and probably through the
production of cAMP, inhibits the IFN- induction of MHC class II
molecules. The mechanism of inhibition probably acts at the
transcriptional level.
Adenosine and its analogues inhibited the MHC class II expression
induced by IFN- as well as other activities induced by IFN- such
as the induction of iNOS and the regulation of the expression of
proinflammatory cytokines such as TNF- or IL-1ß. Moreover,
adenosine inhibits some LPS-induced functions in macrophage
activation 3, 5, 9 .
The induction of adenosine receptors by IFN- could be
clinically relevant. The expression of adenosine receptors is very
slow, requiring the synthesis of new receptors that seem to be very
stable. This period of time correlates with the time course
of expression of MHC class II molecules, which begins 12 h after
IFN- treatment, reaches a maximum after 48 h, and then begins
to decrease 27 . The release of adenosine during the inflammatory
process would lead to the activation of A2B receptors and
the production of cAMP. It is likely that the IFN--activated
macrophages at the inflammation sites express more A2B
receptors, and then activation by adenosine would lead to the
cAMP-mediated down-regulation of MHC class II molecules and other
macrophage activities. This may constitute an important mechanism of
macrophage deactivation.
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Acknowledgments |
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and IL-1ß cDNA. We also thank
Martin Cullell-Young for revision of the manuscript. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. A. Celada, Departament de Fisiologia, Facultat de Biologia, Av. Diagonal 645, 08028 Barcelona, Spain. E-mail address:
3 Abbreviations used in this paper: BMDM, bone marrow-derived macrophages; iNOS, inducible nitric oxide synthase; NECA, adenosine 5'-N-ethyl-carboxamidoadenosine; R-PIA, N6-(R)-phenylisopropyl-adenosine; DPCPX, 1,3-dipropyl-8-cyclopentylxanthine; CGS 21680 2-[p-(2-carbonyl-ethyl)-phenyl-ethylamino]-5'-N-ethylcarboxamido-adenosine; IB-MECA, N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide; EIA, enzyme immunoassay.
Received for publication June 12, 1998. Accepted for publication December 7, 1998.
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Z. H. Nemeth, C. S. Lutz, B. Csoka, E. A. Deitch, S. J. Leibovich, W. C. Gause, M. Tone, P. Pacher, E. S. Vizi, and G. Hasko Adenosine Augments IL-10 Production by Macrophages through an A2B Receptor-Mediated Posttranscriptional Mechanism J. Immunol., December 15, 2005; 175(12): 8260 - 8270. [Abstract] [Full Text] [PDF]
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C. M. Lappas, J. M. Rieger, and J. Linden A2A Adenosine Receptor Induction Inhibits IFN-{gamma} Production in Murine CD4+ T Cells J. Immunol., January 15, 2005; 174(2): 1073 - 1080. [Abstract] [Full Text] [PDF]
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 A. HAILU, T. VAN DER POLL, N. BERHE, and P. A. KAGER ELEVATED PLASMA LEVELS OF INTERFERON (IFN)-{gamma}, IFN-{gamma} INDUCING CYTOKINES, AND IFN-{gamma} INDUCIBLE CXC CHEMOKINES IN VISCERAL LEISHMANIASIS Am J Trop Med Hyg, November 1, 2004; 71(5): 561 - 567. [Abstract] [Full Text] [PDF]
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L. Marques, M. Brucet, J. Lloberas, and A. Celada STAT1 Regulates Lipopolysaccharide- and TNF-{alpha}-Dependent Expression of Transporter Associated with Antigen Processing 1 and Low Molecular Mass Polypeptide 2 Genes in Macrophages by Distinct Mechanisms J. Immunol., July 15, 2004; 173(2): 1103 - 1110. [Abstract] [Full Text] [PDF]
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M. Schnurr, T. Toy, A. Shin, G. Hartmann, S. Rothenfusser, J. Soellner, I. D. Davis, J. Cebon, and E. Maraskovsky Role of adenosine receptors in regulating chemotaxis and cytokine production of plasmacytoid dendritic cells Blood, February 15, 2004; 103(4): 1391 - 1397. [Abstract] [Full Text] [PDF]
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 J. P. Headrick, B. Hack, and K. J. Ashton Acute adenosinergic cardioprotection in ischemic-reperfused hearts Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H1797 - H1818. [Abstract] [Full Text] [PDF]
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N. D. Khoa, M. C. Montesinos, A. J. Williams, M. Kelly, and B. N. Cronstein Th1 Cytokines Regulate Adenosine Receptors and Their Downstream Signaling Elements in Human Microvascular Endothelial Cells J. Immunol., October 15, 2003; 171(8): 3991 - 3998. [Abstract] [Full Text] [PDF]
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 Z. H. Neemeth, S. J. Leibovich, E. A. Deitch, E. S. Vizi, C. Szabo, and G. Hasko cDNA Microarray Analysis Reveals a Nuclear Factor-{kappa}B-Independent Regulation of Macrophage Function by Adenosine J. Pharmacol. Exp. Ther., September 1, 2003; 306(3): 1042 - 1049. [Abstract] [Full Text] [PDF]
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M. Comalada, M. Cardo, J. Xaus, A. F. Valledor, J. Lloberas, F. Ventura, and A. Celada Decorin Reverses the Repressive Effect of Autocrine-Produced TGF-{beta} on Mouse Macrophage Activation J. Immunol., May 1, 2003; 170(9): 4450 - 4456. [Abstract] [Full Text] [PDF]
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 D. A. Rees, M. D. Lewis, B. M. Lewis, P. J. Smith, M. F. Scanlon, and J. Ham Adenosine-Regulated Cell Proliferation in Pituitary Folliculostellate and Endocrine Cells: Differential Roles for the A1 and A2B Adenosine Receptors Endocrinology, June 1, 2002; 143(6): 2427 - 2436. [Abstract] [Full Text] [PDF]
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 S. J. Leibovich, J.-F. Chen, G. Pinhal-Enfield, P. C. Belem, G. Elson, A. Rosania, M. Ramanathan, C. Montesinos, M. Jacobson, M. A. Schwarzschild, et al. Synergistic Up-Regulation of Vascular Endothelial Growth Factor Expression in Murine Macrophages by Adenosine A2A Receptor Agonists and Endotoxin Am. J. Pathol., June 1, 2002; 160(6): 2231 - 2244. [Abstract] [Full Text] [PDF]
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N. D. Khoa, M. C. Montesinos, A. B. Reiss, D. Delano, N. Awadallah, and B. N. Cronstein Inflammatory Cytokines Regulate Function and Expression of Adenosine A2A Receptors in Human Monocytic THP-1 Cells J. Immunol., October 1, 2001; 167(7): 4026 - 4032. [Abstract] [Full Text] [PDF]
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 M CUTOLO, A SULLI, C PIZZORNI, B SERIOLO, and R H STRAUB Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis Ann Rheum Dis, August 1, 2001; 60(8): 729 - 735. [Full Text] [PDF]
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N. Boechat, F. Bouchonnet, M. Bonay, A. Grodet, V. Pelicic, B. Gicquel, and A. J. Hance Culture at High Density Improves the Ability of Human Macrophages to Control Mycobacterial Growth J. Immunol., May 15, 2001; 166(10): 6203 - 6211. [Abstract] [Full Text] [PDF]
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 C. Herrera, V. Casadó, F. Ciruela, P. Schofield, J. Mallol, C. Lluis, and R. Franco Adenosine A2B Receptors Behave as an Alternative Anchoring Protein for Cell Surface Adenosine Deaminase in Lymphocytes and Cultured Cells Mol. Pharmacol., January 1, 2001; 59(1): 127 - 134. [Abstract] [Full Text]
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J. Xaus, M. Comalada, M. Barrachina, C. Herrero, E. Gonalons, C. Soler, J. Lloberas, and A. Celada The Expression of MHC Class II Genes in Macrophages Is Cell Cycle Dependent J. Immunol., December 1, 2000; 165(11): 6364 - 6371. [Abstract] [Full Text] [PDF]
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G. HASKÓ, D. G. KUHEL, J.-F. CHEN, M. A. SCHWARZSCHILD, E. A. DEITCH, J. G. MABLEY, A. MARTON, and C. SZABÓ Adenosine inhibits IL-12 and TNF-{alpha} production via adenosine A2a receptor-dependent and independent mechanisms FASEB J, October 1, 2000; 14(13): 2065 - 2074. [Abstract] [Full Text]
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J. Xaus, A. F. Valledor, M. Cardo, L. Marques, J. Beleta, J. M. Palacios, and A. Celada Adenosine Inhibits Macrophage Colony-Stimulating Factor-Dependent Proliferation of Macrophages Through the Induction of p27kip-1 Expression J. Immunol., October 15, 1999; 163(8): 4140 - 4149. [Abstract] [Full Text] [PDF]
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 C. Soler, R. Valdes, J. Garcia-Manteiga, J. Xaus, M. Comalada, F. J. Casado, M. Modolell, B. Nicholson, C. MacLeod, A. Felipe, et al. Lipopolysaccharide-induced Apoptosis of Macrophages Determines the Up-regulation of Concentrative Nucleoside Transporters Cnt1 and Cnt2 through Tumor Necrosis Factor-alpha -dependent and -independent Mechanisms J. Biol. Chem., August 3, 2001; 276(32): 30043 - 30049. [Abstract] [Full Text] [PDF]
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