| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, and
Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, IL-2, and TNF-ß, which promote cellular immunity, whereas
Th2 cells secrete a different set of cytokines, primarily IL-4, IL-10,
and IL-13, which promote humoral immunity (1, 2).
IL-12 is a 75-kDa heterodimeric cytokine composed of p35 and p40
chains; p35 is constitutively expressed in most cells, whereas p40 is
up-regulated in monocytes and macrophages in response to infection or
appropriate activating substances such as LPS (3). IL-12
is a central inducer of Th1 responses and cell-mediated immunity.
First, it induces IFN- production from NK and T cells, which
contributes to phagocytic cell activation and inflammation. Second, it
favors Th1 cell differentiation and proliferation (3).
IL-12 is essential for the clearance of certain intracellular pathogens
such as Mycobacterium tuberculosis (4).
However, excessive production of IL-12 may be responsible for the
proinflammatory activities and the tissue damage typical of
organ-specific autoimmunity, as seen in insulin-dependent diabetes
mellitus in nonobese diabetic mice (5) and in type II
collagen-induced arthritis in DBA/1 mice (6). In addition,
stimulation of IL-12 secretion by microbial products was shown to be
the crucial factor for the proliferation and differentiation of
pathogenic autoreactive Th1 effector cells in experimental allergic
encephalomyelitis (7).
Adenosine (ADO),2 together with ADP and ATP, belongs to a class of endogenous purine nucleosides produced by many cells during normal metabolic activity (8, 9, 10). These ubiquitous molecules are utilized in selective extracellular signaling (8, 9, 10). For example, ADO appears to be an important endogenous regulator of coronary blood flow (8). Postganglionic sympathetic nerve terminals also release ATP that is rapidly degraded to ADO, which induces vasodilatation mediated by A2 receptors (10). Local extracellular ADO levels increase dramatically during ischemia and hypoxia, possibly providing cytoprotection and increased blood flow to ischemic tissues (11). Inflammation and tissue injury represent pathologic states that are also associated with enhanced extracelluar ADO concentrations.
One of the first clinical observations linking ADO to the immune system was made in patients with SCID. These patients lack the enzyme adenosine deaminase, i.e., they are unable to catabolize ADO (12). This abnormality results in highly elevated plasma levels of ADO and consequent impairment of cellular immunity, marked by recurrent infections. The immunosuppression observed in SCID is explained by the direct lymphotoxicity of ADO catabolites and by the strong extracellular ADO-induced inhibition of the TCR-triggered proliferation and T cell effector functions mediated by A2a receptor signaling (13, 14). More recently, it has been demonstrated that ADO also exerts diverse anti-inflammatory effects, mediated mainly by A2 receptors, including diminished leukocyte accumulation, inhibition of C2 production, and reduction of the superoxide anion generation (15, 16, 17). Therefore, the regulation of ADO receptors is recognized as having significant therapeutic potential (9).
Recent evidence suggests that the anti-inflammatory effects of
methotrexate and sulfasalzine, currently the most commonly prescribed
and effective second-line agents for the treatment of rheumatoid
arthritis (RA), are mediated in part by increases in the extracellular
concentrations of ADO (15, 18). Because excessive
production of IL-12 appears to play an important role in RA, the
question arises: does ADO suppress IL-12 production? This may explain,
at least in part, the beneficial effects of these drugs in RA. This
hypothesis arose from previous studies showing that ADO inhibits the
production of TNF-
(19, 20, 21, 22), another proinflammatory
cytokine implicated in the pathogenesis of RA, while it increases the
secretion of the anti-inflammatory cytokine IL-10 (23, 24), which suppresses IL-12 and TNF- release. In this paper,
we demonstrate that ADO analogues, via activation of A2a receptors on
monocytes, cause substantial inhibition of human IL-12 production and
simultaneous stimulation of IL-10 production. Through these mechanisms,
increased concentrations of ADO may polarize the Th1/Th2 balance toward
Th2 dominance and may contribute to the immunomodulatory properties
of ADO.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
LPS from Escherichia coli, serotype K-235 (Sigma, St. Louis, MO), was dissolved in distilled water. The mixture was sonicated for at least 3 min in a sonicating bath, and aliquots were stored at -20°C until they were used. After thawing, appropriate dilutions were made in RPMI 1640 medium. Stapholococcus aureus Cowan strain 1 (SAC) was purchased from Calbiochem (La Jolla, CA). 5'-N-ethylcarboxamidoadenosine (NECA), N6-Benzyl-5'-N-ethylcarboxamidoadenosine (N6-Benzyl-NECA), 2-[p-(2-carbonyl-ethyl)-phenyl-ethylamino]-5'-N-ethylcarboxamido-adenosine (CGS-21680) HCL, 2-Chloro-N6-cyclopentyladenosine (CCPA), N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA), 8-(3-Chlorostyryl)caffeine (CSC), Rp-cAMPS triethylamine, 8-(chlorophenylthio)-cAMP, and Ro 20-1724 were obtained from Research Biochemicals (Natick, MA). TRIZOL reagent was purchased from Life Technologies (Gaithersburg, MD). TaqMan cytokine gene expression plate I was obtained from Applied Biosystems (Foster City, CA). Anti-human IL-10 Abs were purchased from R&D Systems (Minneapolis, MN).
Blood donors
Twenty healthy female and male volunteers participated in this study, which was approved by an institutional review board of the National Institutes of Health. Volunteers refrained from using any drugs, including cyclooxygenase inhibitors, or hormones for 1 wk before the study.
Whole blood cultures
Blood was drawn into sodium heparin-containing sterile blood collecting tubes (Vacutainer, Becton Dickinson, Lincoln Park, NJ) and diluted 1:5 with RPMI 1640 (supplemented with 1% glutamine and 50 µg/ml gentamicin) with no added exogenous serum. The blood (1 ml) was aliquoted in 24-well culture plates (Costar, Cambridge, MA). Bacterial LPS was added to allow a final concentration of 1 µg/ml for the induction of cytokines, and the samples were incubated in 5% CO2 at 37°C for 18 h. ADO analogues and receptor agonists were added to the wells 10 min before LPS or SAC stimulation. CSC, Rp-cAMPS triethylamine, and the phosphodiesterase inhibitor Ro 20-1724 were added 10 min before the ADO receptor agonists. After incubation, the blood was centrifuged, and the supernatant plasma was collected and stored in polypropylene tubes at -70°C until the samples were measured.
Monocyte elutriation and culture
Human monocytes were obtained from healthy volunteers of the National Institutes of Health, Department of Transfusion Medicine, Cell Processing Section. Mononuclear cells were isolated on lymphocyte separation medium and the monocytes were purified by counterflow centrifugal elutriation as previously described (25). The monocytes were cultured at 5 x 105 cells/ml. All cultures were set up in RPMI 1640 medium supplemented with 15% FCS, 1% glutamine, and 50 µg/ml gentamicin to yield a final volume of 1.5 ml. Cytokine production was induced by LPS (1 µg/ml), and all cultures were incubated in 5% CO2 at 37°C for 18 h. In several experiments, anti-IL-10 Abs were added at a concentration of 10 µg/ml. According to the manufacturer’s instruction, this concentration gives a 50% neutralizing dose in the presence of 5 ng/ml of rhIL-10.
Cytokine assays
IL-12 (p40 and p70) and IL-10 were measured using ELISAs employing the multiple-Ab sandwich principle (Quantikine, R&D Systems). These assays specifically detect human IL-12 p70 (the biologically active heterodimer), p40, and human IL-10, respectively. The IL-12 p70 ELISA specifically recognizes the IL-12 heterodimer without cross-reactivity with the individual subunits of the dimer. The detection limits of the IL-12 p40 and IL-12 p70 high-sensitivity ELISA were 15.0 and 0.5 pg/ml, whereas the IL-10 ELISA detection limit was 2 pg/ml. Plates were read by a microplate reader (model 550, Bio-Rad, Richmond, CA) and absorbency was transformed to cytokine concentration (in pg/ml) using a standard curve computed by Microplate Manager III Macintosh data analysis software (Bio-Rad).
Detection of IL-12 p35 and p40 mRNA
Human monocytes were cultured at 1.5 x 107 cells, with or without LPS (1 µg/ml), in the presence or absence of 10-5 or 10-6 M concentrations of the A2a agonist CGS-21680 at 37°C for 18 h. Total RNA was isolated by using TRIZOL reagent according to the manufacturer’s instructions. cDNAs were reverse transcribed with TaqMan reverse transcription reagents (Applied Biosystems). cDNA solution (5 µl) was used to quantitate mRNA levels using TaqMan cytokine gene expression plate I (Applied Biosystems)with 65 PCR cycles on the ABI PRISM 7700 sequence detection system (Applied Biosystems). Results were analyzed with the sequence detection system software.
Statistical analysis
All data are presented as mean ± SE. Statistical analysis was performed by one-way ANOVA.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Because ADO has an extremely short half-life and is rapidly
metabolized, in our experiments we used nonhydrolyzable ADO analogues
or more metabolically stable analogues that are able to mimic the
effects of extracellular ADO (8, 9). The addition of
increasing concentrations of the ADO analogue NECA to the
LPS-stimulated whole blood cultures resulted in a dose-dependent
inhibition of IL-12 p70 production (Fig. 1
A). NECA at a concentration
of 10-5 M suppressed IL-12 production by 95%.
However, increasing doses of NECA resulted in a dose-dependent increase
of LPS-induced IL-10 production (Fig. 1B), showing a
substantial increase at a concentration of 10-6
M (a 240% increase).
|
To determine whether the effects of NECA on IL-12 and IL-10
production were limited to LPS stimulation, whole blood cultures were
stimulated with SAC in the presence of increasing doses of NECA. As
shown in Fig. 2A, NECA
strongly inhibited SAC-induced production of IL-12 p70 in a
dose-dependent manner, while it simultaneously enhanced the production
of IL-10 (Fig. 2B).
|
The ADO analogue NECA is a nonselective agonist of A1, A2, and A3
receptors. To investigate whether the modulation of cytokine production
is related to the stimulation of specific ADO receptors, the order of
effectiveness of specific ADO receptor agonists was compared in
LPS-stimulated whole blood. As evident from Fig. 3A, the A2a receptor agonist
CGS-21680 also exhibited strong dose-dependent inhibitory activity,
whereas the A1 receptor agonist CCPA and the A3 receptor agonist
N6-Benzyl-NECA were effective only at high
concentrations. The median effective concentration for the A2a receptor
agonist CGS-21680 (5 x 10-8 M) was
approximately two orders of magnitude less than that for the A1 and A3
receptor agonists (10-6 and 5 x
10-6 M, respectively). The same order of
effectiveness of ADO agonists was observed in their enhancing effect of
IL-10 production (Fig. 3B). These data suggest that the
modulation of LPS-induced IL-12 and IL-10 production by ADO analogues
in human whole blood is primarily mediated through A2a receptors.
|
Monocytes are the major cellular source of IL-12 and IL-10
production in human whole blood (26, 27). To verify that
peripheral blood monocytes were directly affected by ADO analogues, we
stimulated enriched human monocytes with LPS in the presence of
different concentrations of A1, A2, and A3 agonists. Although ADO
receptor agonists had an inhibitory effect on the IL-12 p40 production,
they potentiated IL-10 production in monocytes (Fig. 4, A and B).
Similar to the findings in whole blood, the A2a receptor agonist
CGS-21680 expressed the strongest effects. The potency of two different
A3 receptor agonists was also compared. Although IB-MECA induced a
slightly stronger effect than
N6-Benzyl-NECA, the effect of both A3
agonists was still much weaker than the effect of A2a receptor agonist
CGS-21680. Because freshly isolated, unprimed human monocytes produce
little IL-12 p70 when stimulated with LPS, the effect of ADO analogues
on IL-12 p70 could not be reliably evaluated in these experiments.
|
As shown in Fig. 5, the inhibitory
effect of the A2a agonist CGS-21680 was blocked in the presence of the
specific A2a antagonist CSC. Because the inhibitory effects of the A1
and A3 receptor agonists were observed only at high concentrations, we
subsequently investigated the possibility that these effects may have
resulted from nonspecific action via A2a receptors. As is visible in
Fig. 5, the A2a antagonist CSC was able to prevent the inhibitory
effect of the A1 and A3 receptor agonists.
|
We examined the levels of IL-12 p35 and p40 mRNA in human
peripheral monocytes with TaqMan cytokine gene expression plate I. As
shown in Fig. 6, A and
B, LPS increased the levels of IL-12 p40 mRNA by 10-fold.
Addition of the A2a agonist CGS-21680 dose-dependently suppressed LPS
effect, suggesting that the effect of this drug is at the
transcriptional level. On the other hand, the levels of IL-12 p35 mRNA
were not affected by LPS and the A2a agonist.
|
Stimulation of A2 receptors results in increased cAMP production
(8, 9). To analyze the role of cAMP, we antagonized the
effect of the A2a agonist CGS-21680 by application of Rp-cAMPS, a
diastereomer of adenosine-3',5' cyclic monophosphothiate. Rp-cAMP is
known to competitively inhibit the cAMP-induced activation of PKA.
Monocytes were stimulated by LPS in the presence of A2a agonist
CGS-21680 and, as shown in Fig. 7A, CGS-21680 inhibited IL-12
production by 50%. The presence of Rp-cAMP together with the A2a
agonist CGS-21680 reversed this inhibition dose-dependently.
Phosphodiesterase is an enzyme involved in the breakdown of cAMP. Thus,
inhibition of this enzyme results in an increase of cAMP levels. As
shown in Fig. 7B, the phosphodiesterase type IV inhibitor Ro
20-1724 had a dose-dependent inhibitory effect on the LPS-induced IL-12
production in the absence of CGS-21680. Moreover, the effect of Ro
20-1724 was additive to the effect of the A2a receptor agonist
CGS-21680. Thus, the presence of increasing concentrations of Ro
20-1724 resulted in about a 2-fold potentiation of the inhibition of
IL-12 production induced by CGS-21680. To further evaluate the role of
cAMP in this mechanism, we added 8-(chlorophenylthio)-cAMP, a cAMP
analogue, to our cultures. This drug dose-dependently inhibited
LPS-induced IL-12 production, mimicking the effect of the A2a agonist
CGS-21680 (Fig. 7C).
|
Previous studies indicate that IL-10 inhibits the secretion of
proinflammatory cytokines from monocytes (28). These
observations prompted us to consider the possibility that the
inhibitory effects of A2 receptor agonists on IL-12 release were caused
by induction of endogenous IL-10 production. Consequently, we
investigated the effect of adding neutralizing IL-10 Abs to monocyte
cultures stimulated with LPS in the presence of the A2a agonist
CGS-21680. The mean LPS-induced IL-10 levels in our experiments were
871.2 ± 194.3 pg/ml. Thus, the concentration of endogenously
produced IL-10 was 
6-fold less than the concentration at which
anti-IL-10 Abs express a 50% neutralizing dose (see
Materials and Methods). We concluded that the concentration
of neutralizing anti-IL-10 Abs used in these experiments was
sufficient to eliminate endogenously produced IL-10. In the presence of
10-6 M CGS-21680, the LPS-induced IL-10 levels
were 47.1 ± 10.1 pg/ml, whereas in the presence of anti-IL-10
Abs, the addition of this drug to the cultures resulted in IL-10
production of 41.6 ± 7.0 pg/ml (data not shown). These data
suggest that endogenous production of IL-10 induced by LPS does not
mediate the inhibitory effect of the A2a receptor agonist on IL-12
production.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
by human monocytes
(19, 20, 22). In our experiments, the A1 and A3 receptor agonists had an inhibitory effect on IL-12 production, but only at high concentrations. Moreover, CSC, a selective A2a receptor antagonist, prevented the inhibitory effects of A1 and A3 receptor agonists. Therefore, it appears that the A1 and A3 receptor agonists express weak A2a receptor agonist effects at high concentrations. This is substantiated by previous studies showing that mouse peripheral lymphocytes (13, 14) and freshly isolated human monocytes express only functionally active A2 receptors (16, 19, 20, 22, 29). In contrast, cultured blood monocyte-derived macrophages and macrophage cell lines might express, in addition, functionally active A1 and/or A3 receptors (21, 29).
IL-12 is a central inducer of Th1 differentiation and serves as a bridge between innate and specific immunity, whereas IL-10 antagonizes the activities of IL-12 (1, 2, 3). The Th1/Th2 pattern is often regarded as a balance between Th1/Th2 cell cytokine activities, but our observations suggest that increased local concentrations of ADO may also contribute to Th1/Th2 balance. In addition to IL-12 inhibition, the present study also demonstrates that NECA and CGS-21680 dose-dependently potentiate the production of IL-10 in human whole blood ex vivo. This is in accordance with recent studies showing similar effects of ADO analogues on IL-10 production in vitro by human monocytes and in vivo in endotoxemic mice (23, 24). Interestingly, ADO appears to express identical modulatory effects on the balance of proinflammatory/anti-inflammatory cytokines such as PGE2 (26), catecholamines (30, 31) and histamine (27). In this process the increase of cAMP seems to be the common intracellular mechanism used by these endogenous mediators. Thus, conditions related to increased local concentrations of ADO, through inhibition of IL-12 and potentiation of IL-10 production from monocytes, may simultaneously mediate an inhibition of Th1 responses and a shift toward Th2 dominance.
One such condition is ischemia. During ischemia or hypoxia, local ADO
concentrations increase to the micromolar range (11),
whereas the secretion of TNF- has been implicated in the
pathogenesis of ischemia-reperfusion injury (32). Recent
evidence indicates that ADO attenuates reperfusion injury following
ischemia partly through inhibition of TNF- production (33, 34). Our data suggest that during ischemia-reperfusion injury,
increased concentrations of ADO may act to attenuate injury by
inhibiting not only TNF- release, but also IL-12 production. In this
context, ADO might be a beneficial component of the normal host defense
in mild ischemic foci. However, in more severe ischemic events, the
systemic increase of ADO may have opposite, detrimental effects. Thus,
major injury, serious burns, and brain injury often lead to severe
immunosuppression causing increased susceptibility to infections
(31, 35). Although it is still a matter of speculation,
during major injury massive release of ADO may mediate, through
inhibition of IL-12 production, part of the severe immunosuppression
that occurs in these patients. The ADO-induced inhibition of
IL-12 production may also be relevant to the immunosuppression observed
in solid tumors, where hypoxic conditions cause accumulation of high
concentrations of extracellular ADO that may contribute to inhibition
of antitumor CTLs and NK activity (36).
Methotrexate and sulfasalazine are important second-line agents for the treatment of RA. Recent studies have indicated that these drugs enhance extracellular ADO concentrations (15, 18) and that ADO, via stimulation of A2 receptors, may be responsible in part for the anti-inflammatory effects of these drugs (15). Our results suggest that methotrexate, via release of ADO, may inhibit IL-12 production that may explain, at least in part, the beneficial effects of these drugs in RA patients.
In summary, we have shown that ADO analogues, via stimulation of A2a receptors and subsequent increase of cAMP, inhibit the production of IL-12 by activated human monocytes. Through this mechanism, increased concentrations of ADO may selectively suppress Th1 functions and skew the balance toward Th2 dominance. This may explain, at least in part, the anti-inflammatory properties of ADO and supports the rationale for development and use of selective A2a receptor agonists or antagonists in Th1- or Th2-mediated autoimmune processes, respectively.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Abbreviations used in this paper: ADO, adenosine; RA, rheumatoid arthritis; SAC, Staphylococcus aureus Cowan strain 1; NECA, 5'-N-ethylcarboxamidoadenosine; N6-Benzyl-NECA, N6-Benzyl-5'-N-ethylcarboxamidoadenosine; IB-MECA, 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-ß-D-ribofuranuronamide CGS-21680, 2-p-(2-carbonylethyl)-phenylethylamino-5'-N-ethylcarboxamidoadenosine; CCPA, 2-Chloro-N6-cyclopentyladenosine; CSC, 8-(3-Chlorostyryl)caffeine; PKA, protein kinase A.
Received for publication October 5, 1999. Accepted for publication October 19, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
production in human monocytes by adenosine (A2) receptor selective agonists. Int. J. Immunopharmacol. 17:221.[Medline]
expression by adenosine: role of A3 adenosine receptors. J. Immunol. 156:3442.
release from human monocytes by activation of the A2a receptor. FASEB J. 4:A484.
, and nitric oxide production in RAW 264.7 macrophages and in endotoxemic mice. J. Immunol. 157:4634.[Abstract]
in the pathophysiological alterations after hepatic ischemia/reperfusion injury in the rat. J. Clin. Invest. 85:1936.
production and human myocardial injury following ischemia-reperfusion. J. Surg. Res. 76:117.[Medline]
This article has been cited by other articles:
|
|
 |
|
  C. L. Lau, Y. Zhao, I. L. Kron, M. H. Stoler, V. E. Laubach, G. Ailawadi, and J. Linden The Role of Adenosine A(2A) Receptor Signaling in Bronchiolitis Obliterans. Ann. Thorac. Surg., October 1, 2009; 88(4): 1071 - 1078. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. van der Putten, E. A. Zuiderwijk-Sick, L. van Straalen, E. D. de Geus, L. A. Boven, I. Kondova, A. P. IJzerman, and J. J. Bajramovic Differential Expression of Adenosine A3 Receptors Controls Adenosine A2A Receptor-Mediated Inhibition of TLR Responses in Microglia J. Immunol., June 15, 2009; 182(12): 7603 - 7612. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Scheibner, S. Boodoo, S. Collins, K. E. Black, Y. Chan-Li, P. Zarek, J. D. Powell, and M. R. Horton The Adenosine A2a Receptor Inhibits Matrix-Induced Inflammation in a Novel Fashion Am. J. Respir. Cell Mol. Biol., March 1, 2009; 40(3): 251 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. C. Lisle, L. M. Gazoni, L. G. Fernandez, A. K. Sharma, A. M. Bellizzi, G. D. Schifflett, V. E. Laubach, and I. L. Kron Inflammatory lung injury after cardiopulmonary bypass is attenuated by adenosine A(2A) receptor activation. J. Thorac. Cardiovasc. Surg., November 1, 2008; 136(5): 1280 - 1288. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Huang, D. J. Moore, R. J. Ketchum, C. S. Nunemaker, B. Kovatchev, A. L. McCall, and K. L. Brayman Resolving the Conundrum of Islet Transplantation by Linking Metabolic Dysregulation, Inflammation, and Immune Regulation Endocr. Rev., August 1, 2008; 29(5): 603 - 630. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Sun, F. Wu, F. Sun, and P. Huang Adenosine Promotes IL-6 Release in Airway Epithelia J. Immunol., March 15, 2008; 180(6): 4173 - 4181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ohta, D. Lukashev, E. K. Jackson, B. B. Fredholm, and M. Sitkovsky 1,3,7-Trimethylxanthine (Caffeine) May Exacerbate Acute Inflammatory Liver Injury by Weakening the Physiological Immunosuppressive Mechanism J. Immunol., December 1, 2007; 179(11): 7431 - 7438. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Reutershan, R. E. Cagnina, D. Chang, J. Linden, and K. Ley Therapeutic Anti-Inflammatory Effects of Myeloid Cell Adenosine Receptor A2a Stimulation in Lipopolysaccharide-Induced Lung Injury J. Immunol., July 15, 2007; 179(2): 1254 - 1263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Polumuri, V. Y. Toshchakov, and S. N. Vogel Role of Phosphatidylinositol-3 Kinase in Transcriptional Regulation of TLR-Induced IL-12 and IL-10 by Fc{gamma} Receptor Ligation in Murine Macrophages J. Immunol., July 1, 2007; 179(1): 236 - 246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 J. Roman, H. N. Rivera, S. Roser-Page, S. V. Sitaraman, and J. D. Ritzenthaler Adenosine induces fibronectin expression in lung epithelial cells: implications for airway remodeling Am J Physiol Lung Cell Mol Physiol, February 1, 2006; 290(2): L317 - L325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
J. A. Ralph, A. N. McEvoy, D. Kane, B. Bresnihan, O. FitzGerald, and E. P. Murphy Modulation of Orphan Nuclear Receptor NURR1 Expression by Methotrexate in Human Inflammatory Joint Disease Involves Adenosine A2A Receptor-Mediated Responses J. Immunol., July 1, 2005; 175(1): 555 - 565. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Hakonarson, S. Thorvaldsson, A. Helgadottir, D. Gudbjartsson, F. Zink, M. Andresdottir, A. Manolescu, D. O. Arnar, K. Andersen, A. Sigurdsson, et al. Effects of a 5-Lipoxygenase-Activating Protein Inhibitor on Biomarkers Associated With Risk of Myocardial Infarction: A Randomized Trial JAMA, May 11, 2005; 293(18): 2245 - 2256. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. B. Reece, P. I. Ellman, T. S. Maxey, I. K. Crosby, P. S. Warren, T. W. Chong, R. D. LeGallo, J. Linden, J. A. Kern, C. G. Tribble, et al. Adenosine A2A receptor activation reduces inflammation and preserves pulmonary function in an in vivo model of lung transplantation J. Thorac. Cardiovasc. Surg., May 1, 2005; 129(5): 1137 - 1143. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Linden Adenosine in Tissue Protection and Tissue Regeneration Mol. Pharmacol., May 1, 2005; 67(5): 1385 - 1387. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Thiele, R. Kronstein, A. Wetzel, A. Gerth, K. Nieber, and S. Hauschildt Regulation of Adenosine Receptor Subtypes during Cultivation of Human Monocytes: Role of Receptors in Preventing Lipopolysaccharide-Triggered Respiratory Burst Infect. Immun., March 1, 2004; 72(3): 1349 - 1357. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
G. Gomez and M. V. Sitkovsky Differential requirement for A2a and A3 adenosine receptors for the protective effect of inosine in vivo Blood, December 15, 2003; 102(13): 4472 - 4478. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J F Kinsel and M V Sitkovsky Possible targeting of G protein coupled receptors to manipulate inflammation in vivo using synthetic and natural ligands Ann Rheum Dis, November 1, 2003; 62(90002): ii22 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 D. E. Lamendola, Z. Duan, R. Z. Yusuf, and M. V. Seiden Molecular Description of Evolving Paclitaxel Resistance in the SKOV-3 Human Ovarian Carcinoma Cell Line Cancer Res., May 1, 2003; 63(9): 2200 - 2205. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Mirani, I. Elenkov, S. Volpi, N. Hiroi, G. P. Chrousos, and T. Kino HIV-1 Protein Vpr Suppresses IL-12 Production from Human Monocytes by Enhancing Glucocorticoid Action: Potential Implications of Vpr Coactivator Activity for the Innate and Cellular Immunity Deficits Observed in HIV-1 Infection J. Immunol., December 1, 2002; 169(11): 6361 - 6368. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Bshesh, B. Zhao, D. Spight, I. Biaggioni, I. Feokistov, A. Denenberg, H. R. Wong, and T. P. Shanley The A2A receptor mediates an endogenous regulatory pathway of cytokine expression in THP-1 cells J. Leukoc. Biol., November 1, 2002; 72(5): 1027 - 1036. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 M. D. Okusa A2A adenosine receptor: a novel therapeutic target in renal disease Am J Physiol Renal Physiol, January 1, 2002; 282(1): F10 - F18. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
J. S. Gerber and D. M. Mosser Reversing Lipopolysaccharide Toxicity by Ligating the Macrophage Fc{{gamma}} Receptors J. Immunol., June 1, 2001; 166(11): 6861 - 6868. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. la Sala, D. Ferrari, S. Corinti, A. Cavani, F. Di Virgilio, and G. Girolomoni Extracellular ATP Induces a Distorted Maturation of Dendritic Cells and Inhibits Their Capacity to Initiate Th1 Responses J. Immunol., February 1, 2001; 166(3): 1611 - 1617. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. J. Elenkov, R. L. Wilder, G. P. Chrousos, and E. S. Vizi The Sympathetic Nerve---An Integrative Interface between Two Supersystems: The Brain and the Immune System Pharmacol. Rev., December 1, 2000; 52(4): 595 - 638. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-N. Avice, M. Rubio, M. Sergerie, G. Delespesse, and M. Sarfati CD47 Ligation Selectively Inhibits the Development of Human Naive T Cells into Th1 Effectors J. Immunol., October 15, 2000; 165(8): 4624 - 4631. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
, A1
agonist; *, A2a agonist; and +, A3 agonist).
, A3II agonist).
