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Divisions of Clinical Pharmacology and Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY 10016
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(100 U/ml) but
markedly attenuated in cells pretreated with IFN-
(100 U/ml).
Similarly, IL-1 and TNF- treatment potentiated the stimulatory
effect of adenosine and CGS-21680 on IL-10 production, whereas IFN-
treatment almost completely abolished this effect. CGS-21680 stimulated
an increase in intracellular cAMP in a time- and dose-dependent manner
in IL-1- and TNF--treated cells but not in control or
IFN--treated cells. Both IL-1 and TNF- increased A2A
receptor mRNA and protein. In parallel with its effect on
A2A receptor function, IFN- down-regulated
A2A receptor message and protein. Because adenosine
mediates many of the antiinflammatory effects of drugs such as
methotrexate, these observations suggest that local changes in the
cytokine milieu may influence the therapeutic response to those drugs
by altering the expression and function of adenosine receptors on
inflammatory cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Monocytes and macrophages synthesize and release into their environment
a variety of cytokines and other proteins that play a central role in
the development of acute and chronic inflammation. There have been some
lines of evidence suggesting a regulatory connection between adenosine
and its receptors and inflammatory cytokines. In human and murine
monocytes/macrophages, the activation of adenosine receptors,
particularly A2A receptors, by adenosine or it
analogues modulates the production of inflammatory cytokines including
TNF-, IL-10, and IL-12 (4, 5, 6, 7, 8). IL-12, a proinflammatory
cytokine and a central inducer of Th1 responses and cell-mediated
immunity, is suppressed by adenosine and its analogues, whereas
secretion of IL-10, a protective cytokine that suppresses IL-12 and
TNF- release, is enhanced by adenosine and A2A
receptor agonists both in vitro and in vivo (6, 7, 8, 9).
In contrast, other lines of evidence have suggested that the expression
and functions of adenosine receptors may be regulated by numerous
endogenous factors involved in inflammation and in cellular growth and
differentiation such as glucocorticoids (10, 11), growth
factors (12, 13), and other cytokines. For example, Xaus
et al. (14) reported that IFN- up-regulates expression
of A2B receptors and promotes macrophage
activation. The effects of IFN- and other prominent inflammatory
cytokines such as IL-1 and TNF- on expression and function of
A2A receptors, however, have not been
documented.
We therefore investigated the effects of IL-1, TNF-, and IFN-,
the most prominent Th1-inflammatory cytokines in rheumatoid arthritis
and other inflammatory diseases, on function and expression of
adenosine A2A receptors. We found, to our
surprise, that IL-1, TNF-, and IFN- all modulate the effects of
A2A receptor occupancy on secretion of IL-10 and
IL-12 as well as cellular accumulation of cAMP in human monocytic THP-1
cells. In accord with their effects on A2A
receptor function, IL-1, TNF-, and IFN- also regulate expression
of A2A receptors in THP-1 cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human rIL-1, TNF-, and IFN- were purchased from R&D
Systems (Minneapolis, MN). The A2A receptor
agonist
2-[p-(2-carnonylethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosine
(CGS-21680)3 was purchased from Sigma (St. Louis,
MO). The A2A receptor antagonist
4-{2-[7-amino-2-(2-furyl)[1,2,4-triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl}phenol
(ZM-241385) was purchased from Tocris Cookson (Ballwin, MO). LPS
(from Escherichia coli, serotype K-235) and adenosine were
obtained from Sigma. The murine mAb (7F6-G5-A2) against human
A2A receptors with a high affinity and
specificity (15) was a gift from Dr. J. Linden (University
of Virginia School of Medicine, Charlottesville, VA).
Cell culture and cytokine treatment
THP-1 cells, a human monocytic leukemia cell line
(16), were maintained in culture with RPMI 1640 medium
supplemented with 10% FBS, penicillin (50 U/ml) and streptomycin (50
µl/ml) at 37°C in a humidified atmosphere consisting of 5%
CO2. At the onset of each experiment the cells
were placed in fresh medium and then cultured in the presence of
IL-1 (10 U/ml), TNF- (100 U/ml), IFN- (100 U/ml), or medium
alone for 3 h or overnight (18 h) followed by further
analyses.
Assays for IL-10 and IL-12
THP-1 cells were pretreated overnight with IL-1, TNF-, or
IFN- and then placed in 24-well tissue culture plates at
106 cell/ml with 1.5 ml medium/well. The cells
were further cultured overnight in the presence or absence of LPS (5
µg/ml). The A2A receptor agonist CGS-21680 or
adenosine with or without the A2A receptor
antagonist ZM-241385 was added to cultures 20 min before the addition
of LPS. Culture supernatants were collected and subjected to assays for
human IL-12 p70 (the heterodimer form), IL-12 p40 subunit, and IL-10
using ELISA Quantikine kits purchased from R&D Systems.
cAMP assay
THP-1 cells were pretreated overnight with the cytokines. On the day of the cAMP assay, the cells were placed in fresh medium and incubated with CGS-21680 at different concentrations (0.01–100 µM) or 1 µM CGS-21680 for varying periods of time (0–25 min). Cells were then harvested, lysed, and assayed for cellular cAMP accumulation using the cAMP enzyme immunoassay system kit (Amersham Pharmacia Biotech, Piscataway, NJ) following the manufacturer’s instructions.
Isolation of mRNA and semiquantitative RT-PCR
mRNA was isolated from THP-1 cells using a MicroFastTrack kit (Invitrogen, Carlsbad, CA) and transcribed into cDNA (RT). Aliquots of RT, after serial dilutions, were subject to PCR using an RNA-PCR Core kit (PerkinElmer, Branchburg, NJ). The PCRs were performed using primers specific for adenosine A2A receptors and GAPDH, a housekeeping gene. The cycle number was adjusted to allow the PCR to proceed in a linear range. Briefly, PCR conditions for A2A receptors were 32–35 cycles of 45 s at 94oC, 45 s at 62oC, and 1 min at 72oC with 1x and 2x diluted RT as templates. PCR for GAPDH was run for 22–25 cycles with RT of 100x and 200x dilutions as templates. The primer sequences were 5'-ACCTGCAGAACGTCACCAAC-3' (forward) and 5'-TCTGCTTCAGCTGTCGTCGC-3' (reverse) for A2A receptor and 5'-ACCATCATCCCTGCCTCTAC-3' (forward) and 5'-CCTGTTGCTGTAGCCAAAT-3' (reverse) for GAPDH. All primers were designed to amplify cDNA that crossed an intron in the genomic DNA, and the amplicon was sequenced to confirm the identity of the cDNA amplified. Aliquots of PCR product were loaded onto ethidium bromide-stained agarose gel, visualized with an ultraviolet transilluminator, and digitally photographed. The amplicon was quantitated densitometrically using Kodak Digital Science software and all values were normalized to the GAPDH amplicon.
Membrane protein extraction and Western blot analysis
All Western blots were done on cell membrane preparations after
overnight cytokine treatment. Crude membrane protein was isolated after
sonication of the cells in a modification of a previously described
technique (13, 17). Proteins (10 µg/lane) were
separated by 10% SDS-PAGE and electrophoretically transferred to
nitrocellulose membranes. Nonspecific Ab binding to the membrane was
blocked with 3% nonfat milk in Tris-buffered saline containing 0.3%
Tween 20. The membranes were then incubated for 1–2 h with a mAb
against adenosine A2A receptors
(15). After three washes of 5 min each in 0.3% Tween
20-TBS, the blots were incubated with an alkaline
phosphatase-conjugated secondary Ab for 1 h. After extensive
washes, the blots were exposed to a fluorescent enhanced
chemifluorescence (diethanolamine) substrate (Amersham Pharmacia
Biotech, Sunnyvale, CA) and scanned using the Storm PhosphorImager
system (Molecular Dynamics, Sunnyvale, CA). The band density was
then directly quantitated using Image Quant software (Molecular
Dynamics).
Data analysis
Data are presented as mean ± SEM. One-way and two-way ANOVAs were used to determine statistical significance between means or curves. Differences with a p value of <0.05 were considered significant. All statistical analysis was performed using the SigmaStat program (SPSS, Chicago, IL).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Without LPS stimulation, production of IL-12 in monocytic THP-1
cells (either cytokine-treated or control) was undetectable (data not
shown). In control LPS-activated THP-1 cells (without cytokine
pretreatment), CGS-21680, a selective A2A
agonist, suppressed production of IL-12 p70 and p40 in a dose-dependent
manner (IC50 
100 and 60 nM, respectively) as
previously reported (7, 8). CGS-21680 itself, at
concentrations up to 10 µM, inhibited LPS-induced IL-12 production by
up to 40% (for IL-12p70) and 60% (for IL-12p40). In the cells
pretreated with IFN-, LPS stimulated greater IL-12 p70 and p40
secretion than control, IL-1-treated, and TNF--treated cells, and
the inhibitory effect of CGS-21680 on secretion of IL-12, especially
IL-12 p40, was markedly attenuated (p < 0.05,
IFN- vs control, for both IL-12 p70 and IL-12 p40). In contrast,
pretreatment of the cells with either IL-1 or TNF- significantly
enhanced the effect of CGS-21680 on suppression of both active
heterodimer IL-12 p70 (p < 0.05 and
p < 0.01 vs control, respectively;
IC50 50 nM) and IL-12 p40 subunit
(p < 0.01 for both vs control,
IC50 10 nM). Under all treatment conditions,
the changes in levels of p40 subunit were more marked than those of p70
heterodimer (Fig. 1
, A and
B). The inhibitory effect of CGS-21680 on IL-12 production
was reversed by the specific A2A receptor
antagonist ZM-241385 (10 µM; Fig. 1C), further supporting
the role of A2A receptors in modulation of IL-12
release.
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-treated cells but not in IFN--treated cells, although it
seemed that adenosine was less potent than CGS-21680 at the same
concentration, probably due, in part, to prompt uptake and metabolism
of adenosine by THP-1 cells (Fig. 2A). Moreover, the effect of
adenosine was abrogated by ZM-241385 (Fig. 2B), providing
further evidence that the A2A receptor is
primarily involved in regulation of IL-12 production.
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Like IL-12, no detectable IL-10 was produced by THP-1 cells
without LPS stimulation (not shown). The concentrations of IL-10 in
supernatants of control LPS-activated THP-1 cells remained low but were
increased in a dose-dependent manner by CGS-21680
(EC50 100 nM). The stimulatory effect of
CGS-21680 on IL-10 production was significantly greater in THP-1 cells
pretreated with IL-1 or TNF- (p < 0.05 and
p < 0.01 vs control, respectively;
EC50 50 nM for both) and reached increases of
160 and 170%, respectively, in IL-10 secretion in response to 10 µM
CGS-21680, compared with an increase of 141% in controls. In contrast,
CGS-21680 did not increase IL-10 production in THP-1 cells that had
been pretreated with IFN- (p = 0.01 vs
control; Fig. 3A). ZM-241385
reversed the effect of CGS-21680 on IL-10 production by untreated THP-1
cells and THP-1 cells pretreated with IL-1 or TNF- (Fig. 3B).
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, and IFN- on IL-10 secretion were very similar to
those observed with CGS-21680 (Fig. 4A). The enhancement in IL-10
levels by adenosine in control, IL-1-treated, and TNF--treated cells
was completely abolished in the presence of ZM-241385 (Fig. 4B). These results indicate that, as with IL-12, the
A2A receptor is the adenosine receptor primarily
responsible for modulation of IL-10 production.
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Both A2A and A2B
receptors signal via Gsa protein-cAMP pathways.
To further determine whether inflammatory cytokines modulate
A2A receptor function, we studied the cAMP
response of cytokine-treated THP-1 cells after agonist ligation.
Surprisingly, the basal levels of cAMP in IL-1- and TNF--treated
cells were higher than those in either control or IFN--treated cells
(p < 0.05 vs control for TNF-; Fig. 5).
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A). Moreover, there was only
a slight increase of cAMP production in control cells with a very high
concentration (100 µM) of CGS-21680 (Fig. 5B). The
CGS-21680-induced cAMP response of IFN--treated cells was very
similar to that of controls. Although the cAMP levels induced by high
doses (>1 µM) of CGS-21680 in IFN--treated cells were slightly
lower than in control cells, the overall responses to CGS-21680
stimulation by IFN--treated and control cells were not significantly
different (p > 0.05, two-way ANOVA; Fig. 3).
In contrast, CGS-21680 induced striking cAMP generation by IL-1- and
TNF--treated cells, as much as 3- to 4-fold higher than basal
levels, and this increment differed significantly from the response of
control cells (two-way ANOVA, p < 0.001). The peak
levels of cAMP generation in IL-1- and TNF--treated cells occurred
as early as 2–5 min after CGS-21680 stimulation (Fig. 5A)
and in a dose-dependent manner (EC50 40 and 30
nM, respectively; Fig. 5B). These observations together with
those on IL-10 and IL-12 production are consistent with the hypothesis
that IL-1, TNF-, and IFN- regulate A2A
receptor levels and/or function. Inflammatory cytokines regulate A2A receptor expression
To gain greater insight into the mechanism by which the Th1
cytokines IL-1, TNF-, or IFN- modulate A2A
receptor sensitivity and function, we examined the effects of those
cytokines on the expression of A2A receptors in
THP-1 cells. As shown in Fig. 6, the
message for A2A receptors was significantly
altered on treatment of the cells with each of the cytokines studied. A
3-h incubation with IL-1 or TNF- led to an increase in expression of
A2A message to 149 ± 16 and 159 ±
22% of control, respectively (n = 9, p
< 0.01 vs control for both). In contrast, a 3-h treatment with IFN-
decreased the A2A message to 69 ± 5% of
control (n = 9, p < 0.01). The effects
of the cytokines on A2A message remained
consistent after overnight incubation; the message levels for
A2A receptors were 144 ± 12, 167 ±
16, and 65 ± 8% of control in IL-1-, TNF--, and
IFN--treated cells, respectively (n = 9,
p < 0.01 vs control for IL-1 and IFN-, and
p < 0.001 for TNF-).
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A). Compared with controls,
protein levels of A2A receptors were increased by
IL-1 and TNF- to 127 ± 9 and 136 ± 9%
(n = 5, p < 0.05 vs control for IL-1,
and p < 0.01 for TNF-) and decreased by IFN- to
73 ± 4% of control (n = 5, p <
0.05; Fig. 7B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and IFN-, the most prominent cytokines secreted
by monocyte/macrophages and Th1 cells, modulated the capacity of
A2A receptor occupancy to regulate secretion of
IL-10 and IL-12 in LPS-activated THP-1 cells. Whereas IL-1 and TNF-
clearly potentiate the A2A receptor function,
IFN- attenuates it. These data also extend the previous observation
that the suppressive effect of adenosine on IL-12 production by murine
macrophages was much less pronounced in cells activated with both LPS
and IFN- than in those activated with LPS alone (7). It
is well recognized that cytokines stimulate or inhibit the production
of other cytokines in an autocrine and paracrine manner, and our
findings suggest that adenosine receptors may play a role in mediating
this mutual interaction among cytokines. The functional modulation of
adenosine receptors is likely a key factor in the regulation of
inflammatory conditions involving numerous cytokines. It has been shown previously that adenosine suppresses IL-12 production in murine macrophages by A2A-dependent and A3-dependent mechanisms (7). However, our finding that adenosine and CGS-21680 regulate cytokine secretion by THP-1 cells, both untreated and cytokine treated, and that the effects of both agents were blocked by ZM-241385 is most consistent with regulation via the A2A receptor alone. Absence of a role for A3 receptor in regulating cytokine production by human monocytes is consistent with the previous findings of Link et al. (8).
The A2A receptor-mediated increase in
intracellular cAMP accumulation provides further evidence for the
regulatory effects of inflammatory cytokines on
A2A receptor function and
A2A-mediated signaling. Although some cell types
respond to A2A receptor occupancy with a brisk
cAMP response (18), we observed a minimal cAMP response of
resting THP-1 cells to CGS-21680, consistent with previous findings in
the same cell line by Munro et al. (19). The minimal
accumulation of cAMP in resting and IFN--treated THP-1 cells
reported here may have resulted from a reduction in functional
A2A receptor expression, desensitization of
A2A receptors on THP-1 cells, or diminished
signal transduction machinery. The in vitro up-regulation of
A2A receptor function by IL-1 and TNF-
treatment parallels the observation that in vivo cAMP production is
enhanced in ciliary epithelial bilayers from IL-1 or TNF--inflamed
eyes (20). Our observation that there was an increased
cAMP response after treatment with an A2A
receptor agonist in IL-1- and TNF--treated THP-1 cells suggests that
the elevated cAMP production in these models may have resulted, at
least in part, from the activation of an increased number and/or
sensitivity of A2A receptors. Because elevated
intracellular levels of cAMP are generally associated with suppression
of inflammatory responses, it is likely that the up-regulation of
A2A receptors along with endogenous adenosine
release at inflamed sites constitutes a feedback loop to diminish or
terminate the inflammatory response.
In parallel with the observed functional changes, expression of
A2A receptor message and protein was found to be
regulated on cytokine treatment. The Th1 cytokines IL-1, TNF-, and
IFN- play a critical role in the pathogenesis of many severe
inflammatory conditions such as rheumatoid arthritis (see review in
Refs. 21 and 22). Although they are all
regarded as proinflammatory cytokines, the differences in their actions
on adenosine A2A receptor expression may reflect
a complex mechanism of receptor regulation, especially at inflamed
sites (e.g., inflamed synovium) at which numerous cytokines are
secreted. It has been reported that IFN- up-regulates
A2B receptor expression in murine bone
marrow-derived macrophages (14). Our data indicate that
IFN- has an opposing effect on A2A receptors.
This difference in the regulatory action of IFN- on the two
receptors may be significant in modulating adenosine-mediated functions
in cells and tissues where subtypes of adenosine receptors have
different patterns of expression and distribution.
It is still not clear how the inflammatory cytokines studied here
regulate adenosine A2A receptor expression.
Direct regulation of transcription or altered mRNA stability after
cytokine stimulation may explain our observations. Computerized
analysis of upstream regions of the A2A gene
obtained from chromosome sequence databases demonstrates numerous
potential regulatory elements including several NF-
B-binding sites.
The presence of NF-B-binding sites likely explains, at least in
part, the effect of IL-1 and TNF- on increased receptor expression,
although which of these binding sites is involved is not yet known.
Nevertheless, the effect of inflammatory cytokines on expression of
A2A receptors cannot entirely explain the
observed changes in receptor function with respect to either cAMP
generation or regulation of cytokine secretion. It has been reported
that elevated cAMP inhibits NF-B-mediated transcription of numerous
genes (23). Thus, the increase in cAMP levels, although it
seems transient, in IL-1- and TNF--treated cells observed here may
have a feedback control on the increased expression of
A2A receptors by those cytokines. We were
surprised to find that, in contrast to IL-1- or TNF--treated cells,
A2A occupancy did not alter intracellular cAMP
concentration in untreated cells. Although an increase in the
intracellular levels of cAMP itself can further influence the synthesis
and release of IL-10 and IL-12 (24), our results suggest
that, at least in control cells, cAMP is not the primary intracellular
regulator of IL-10 and IL-12 production. In other words, the absence of
a detectable increase in cAMP in these cells suggests that
A2A occupancy modulates cytokine production by a
cAMP-independent mechanism which may be further enhanced by increased
intracellular cAMP. Indeed, our results suggest that enhanced cAMP
response adds to the regulatory effect in IL-1- and TNF--stimulated
cells. In contrast, it has also previously been reported that the
mechanism of action of adenosine and its analogues on IL-12 and IL-10
production was not associated with alterations in the activation of the
p38 and p42/p44 mitogen-activated protein (MAP) kinases
(7). However, other evidence suggests that in human
endothelial cells stimulation of A2A receptors by
its agonists activates MAP kinases (25). In short, it
cannot be ruled out that IL-1, TNF-, or IFN- may also regulate
the activation of MAP kinases or other A2A
receptor downstream transduction signals including a cAMP/protein
kinase A pathway (8) leading to significant changes of
A2A receptor functions.
We and others have demonstrated that adenosine, acting at one or more
of its receptors, mediates the anti-inflammatory effects of drugs
such as methotrexate and sulfasalazine, commonly used and effective
disease-modifying antirheumatic agents, in in vitro and in vivo models
of acute inflammation and chronic arthritis (26, 27, 28, 29, 30, 31).
Despite its proven efficacy in the treatment of rheumatoid arthritis,
many patients do not respond or only partially respond to methotrexate
therapy. Higher levels of or greater sensitivity to IFN- in
methotrexate-resistant patients may be an explanation for the
diminished therapeutic response.
Our study demonstrates that function and expression of adenosine
A2A receptors are differentially regulated by the
inflammatory cytokines IL-1, TNF-, and IFN-. This finding
suggests that the effects of adenosine and its analogues at inflamed
sites may be modified in the short and long term by inflammatory
mediators. We speculate that the activation or inhibition of adenosine
receptors by inflammatory cytokines may partly account for the
variability in response to adenosine-mediated anti-inflammatory
agents used in the treatment of inflammatory diseases such as
rheumatoid arthritis.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Bruce N. Cronstein, Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016. E-mail address: cronsb01{at}med.nyu.edu
3 Abbreviations used in this paper: CGS-21680, 2-[p-(2-carnonylethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosine; ZM-241385, 4-{2-[7-amino-2-(2-furyl)[1,2,4-triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl}phenol; MAP, mitogen-activated protein.
Received for publication April 17, 2001. Accepted for publication August 8, 2001.
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B. Csoka, Z. H. Nemeth, L. Virag, P. Gergely, S. J. Leibovich, P. Pacher, C.-X. Sun, M. R. Blackburn, E. S. Vizi, E. A. Deitch, et al. A2A adenosine receptors and C/EBP{beta} are crucially required for IL-10 production by macrophages exposed to Escherichia coli Blood, October 1, 2007; 110(7): 2685 - 2695. [Abstract] [Full Text] [PDF]
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A. Haschemi, O. Wagner, R. Marculescu, B. Wegiel, S. C. Robson, N. Gagliani, D. Gallo, J.-F. Chen, F. H. Bach, and L. E. Otterbein Cross-Regulation of Carbon Monoxide and the Adenosine A2a Receptor in Macrophages J. Immunol., May 1, 2007; 178(9): 5921 - 5929. [Abstract] [Full Text] [PDF]
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J. J. Kobie, P. R. Shah, L. Yang, J. A. Rebhahn, D. J. Fowell, and T. R. Mosmann T Regulatory and Primed Uncommitted CD4 T Cells Express CD73, Which Suppresses Effector CD4 T Cells by Converting 5'-Adenosine Monophosphate to Adenosine J. Immunol., November 15, 2006; 177(10): 6780 - 6786. [Abstract] [Full Text] [PDF]
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S. Morello, K. Ito, S. Yamamura, K.-Y. Lee, E. Jazrawi, P. DeSouza, P. Barnes, C. Cicala, and I. M. Adcock IL-1beta and TNF-{alpha} Regulation of the Adenosine Receptor (A2A) Expression: Differential Requirement for NF-{kappa}B Binding to the Proximal Promoter J. Immunol., November 15, 2006; 177(10): 7173 - 7183. [Abstract] [Full Text] [PDF]
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H. Zhong, Y. Wu, L. Belardinelli, and D. Zeng A2B Adenosine Receptors Induce IL-19 from Bronchial Epithelial Cells, Resulting in TNF-{alpha} Increase Am. J. Respir. Cell Mol. Biol., November 1, 2006; 35(5): 587 - 592. [Abstract] [Full Text] [PDF]
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Z. H. Nemeth, B. Csoka, J. Wilmanski, D. Xu, Q. Lu, C. Ledent, E. A. Deitch, P. Pacher, Z. Spolarics, and G. Hasko Adenosine A2A Receptor Inactivation Increases Survival in Polymicrobial Sepsis J. Immunol., May 1, 2006; 176(9): 5616 - 5626. [Abstract] [Full Text] [PDF]
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N. D. Khoa, M. Postow, J. Danielsson, and B. N. Cronstein Tumor Necrosis Factor-{alpha} Prevents Desensitization of G{alpha}s-Coupled Receptors by Regulating GRK2 Association with the Plasma Membrane Mol. Pharmacol., April 1, 2006; 69(4): 1311 - 1319. [Abstract] [Full Text] [PDF]
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A. Fortin, D. Harbour, M. Fernandes, P. Borgeat, and S. Bourgoin Differential expression of adenosine receptors in human neutrophils: up-regulation by specific Th1 cytokines and lipopolysaccharide J. Leukoc. Biol., March 1, 2006; 79(3): 574 - 585. [Abstract] [Full Text] [PDF]
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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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 A. Kaufmann, B. Musset, S. H. Limberg, V. Renigunta, R. Sus, A. H. Dalpke, K. M. Heeg, B. Robaye, and P. J. Hanley "Host Tissue Damage" Signal ATP Promotes Non-directional Migration and Negatively Regulates Toll-like Receptor Signaling in Human Monocytes J. Biol. Chem., September 16, 2005; 280(37): 32459 - 32467. [Abstract] [Full Text] [PDF]
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J. L. Chunn, J. G. Molina, T. Mi, Y. Xia, R. E. Kellems, and M. R. Blackburn Adenosine-Dependent Pulmonary Fibrosis in Adenosine Deaminase-Deficient Mice J. Immunol., August 1, 2005; 175(3): 1937 - 1946. [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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W. A. Sands, A. F. Martin, E. W. Strong, and T. M. Palmer Specific Inhibition of Nuclear Factor-{kappa}B-Dependent Inflammatory Responses by Cell Type-Specific Mechanisms upon A2A Adenosine Receptor Gene Transfer Mol. Pharmacol., November 1, 2004; 66(5): 1147 - 1159. [Abstract] [Full Text] [PDF]
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A. B. Reiss, M. M. Rahman, E. S. L. Chan, M. C. Montesinos, N. W. Awadallah, and B. N. Cronstein Adenosine A2A receptor occupancy stimulates expression of proteins involved in reverse cholesterol transport and inhibits foam cell formation in macrophages J. Leukoc. Biol., September 1, 2004; 76(3): 727 - 734. [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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S. Grenier, N. Flamand, J. Pelletier, P. H. Naccache, P. Borgeat, and S. G. Bourgoin Arachidonic acid activates phospholipase D in human neutrophils; essential role of endogenous leukotriene B4 and inhibition by adenosine A2A receptor engagement J. Leukoc. Biol., April 1, 2003; 73(4): 530 - 539. [Abstract] [Full Text] [PDF]
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 K. Gounaris Nucleotidase Cascades Are Catalyzed by Secreted Proteins of the Parasitic Nematode Trichinella spiralis Infect. Immun., September 1, 2002; 70(9): 4917 - 4924. [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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