Adenosine is a key endogenous molecule that is released from cells and regulates tissue function via activating four G-protein-coupled adenosine receptors: A1, A2A, A2B and A3. These receptors are abundantly expressed on the surface of immune cells as well as on endothelial, smooth muscle, epithelial cells, fibroblasts and cardiomyocytes.
Adenosine serves as an endogenous modulator of inflammatory and immune processes. Its release can be triggered from almost all cell types by ischaemia, hypoxia, inflammation and oxidative/nitrosative stress.
Adenosine receptors can be targeted for the treatment of various inflammatory diseases.
In asthma and chronic obstructive pulmonary disease, A2A receptor agonists prevent inflammatory cell infiltration into the lung. A2B receptor antagonists prevent mast-cell degranulation and the overproduction of pro-inflammatory mediators in the lung.
In ischaemia, A2A receptor agonists potently down-regulate inflammatory cell infiltration into tissues, production of deleterious free radicals and pro-inflammatory cytokines.
In arthritis, A2A receptor agonists have a wide range of anti-inflammatory effects in the inflamed joint. A3 receptor agonists decrease tumour necrosis factor-a production by monocytes and synoviocytes.
In sepsis, A1 receptor agonists can prevent inflammation-mediated organ injury in animal models. A2A receptor antagonists are beneficial in sepsis by boosting the eradication of bacteria.
In inflammatory bowel disease, A2A receptor agonists attenuate inflammatory cell sequestration in the gut and increase the activity of regulatory T cells thereby ameliorating the course of disease. A2B receptor antagonists prevent intestinal epithelial-cell-mediated inflammatory events and thereby prevent mucosal inflammation.
Topical administration of A2A receptor agonists increases the rate of wound healing in part by stimulating angiogenesis in the skin. Thus, A2A receptor agonists are good candidates for the treatment of diabetic foot ulcer.
In the clinic, A2A receptor agonists are being tested as therapeutic agents in wound healing and asthma. A2B receptor agonists have shown promise in clinical trials in patients with asthma and A3 receptor agonists improve symptoms in patients with rheumatoid arthritis.
Adenosine is a key endogenous molecule that regulates tissue function by activating four G-protein-coupled adenosine receptors: A1, A2A, A2B and A3. Cells of the immune system express these receptors and are responsive to the modulatory effects of adenosine in an inflammatory environment. Animal models of asthma, ischaemia, arthritis, sepsis, inflammatory bowel disease and wound healing have helped to elucidate the regulatory roles of the various adenosine receptors in dictating the development and progression of disease. This recent heightened awareness of the role of adenosine in the control of immune and inflammatory systems has generated excitement regarding the potential use of adenosine-receptor-based therapies in the treatment of infection, autoimmunity, ischaemia and degenerative diseases.
Subscribe to Journal
Get full journal access for 1 year
only $21.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Drury, A. N. & Szent-Gyorgyi, A. The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart. J. Physiol. 68, 213–237 (1929).
diMarco, J. P. et al. Diagnostic and therapeutic use of adenosine in patients with supraventricular tachyarrhythmias. J. Am. Coll. Cardiol. 6, 417–425 (1985).
Travain, M. I. & Wexler, J. P. Pharmacological stress testing. Semin. Nucl. Med. 29, 298–318 (1999).
Linden, J. Molecular approach to adenosine receptors: receptor-mediated mechanisms of tissue protection. Annu. Rev. Pharmacol. Toxicol. 41, 775–787 (2001).
Fredholm, B. B., AP, I. J., Jacobson, K. A., Klotz, K. N. & Linden, J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol. Rev. 53, 527–552 (2001).
Fredholm, B. B., Chern, Y., Franco, R. & Sitkovsky, M. Aspects of the general biology of adenosine A2A signaling. Prog. Neurobiol. 83, 263–276 (2007).
van Calker, D., Muller, M. & Hamprecht, B. Adenosine regulates via two different types of receptors, the accumulation of cyclic AMP in cultured brain cells. J. Neurochem. 33, 999–1005 (1979).
Bruns, R. F., Lu, G. H. & Pugsley, T. A. Characterization of the A2 adenosine receptor labeled by [3H]NECA in rat striatal membranes. Mol. Pharmacol. 29, 331–346 (1986).
Jin, X., Shepherd, R. K., Duling, B. R. & Linden, J. Inosine binds to A3 adenosine receptors and stimulates mast cell degranulation. J. Clin. Invest. 100, 2849–2857 (1997).
Jacobson, K. A. & Gao, Z. G. Adenosine receptors as therapeutic targets. Nature Rev. Drug Discov. 5, 247–264 (2006). Comprehensive review of the role of adenosine receptors in regulating the disease processes of various organs.
Nemeth, Z. H. et al. Adenosine stimulates CREB activation in macrophages via a p38 MAPK-mediated mechanism. Biochem. Biophys. Res. Commun. 312, 883–888 (2003).
Che, J., Chan, E. S. & Cronstein, B. N. Adenosine A2A receptor occupancy stimulates collagen expression by hepatic stellate cells via pathways involving protein kinase A, Src, and extracellular signal-regulated kinases 1/2 signaling cascade or p38 mitogen-activated protein kinase signaling pathway. Mol. Pharmacol. 72, 1626–1636 (2007).
Revan, S., Montesinos, M. C., Naime, D., Landau, S. & Cronstein, B. N. Adenosine A2 receptor occupancy regulates stimulated neutrophil function via activation of a serine/threonine protein phosphatase. J. Biol. Chem. 271, 17114–17118 (1996).
Csoka, B. et al. A2A adenosine receptors and C/EBPb are crucially required for IL-10 production by macrophages exposed to Escherichia coli. Blood 110, 2685–2695 (2007).
Feoktistov, I. & Biaggioni, I. Adenosine A2B receptors. Pharmacol. Rev. 49, 381–402 (1997).
Ryzhov, S., Goldstein, A. E., Biaggioni, I. & Feoktistov, I. Cross-talk between Gs- and Gq-coupled pathways in regulation of interleukin-4 by A2B adenosine receptors in human mast cells. Mol. Pharmacol. 70, 727–735 (2006).
Gessi, S. et al. The A3 adenosine receptor: an enigmatic player in cell biology. Pharmacol. Ther. 117, 123–140 (2008).
Zhong, H. et al. Activation of murine lung mast cells by the adenosine A3 receptor. J. Immunol. 171, 338–345 (2003).
Hasko, G. et al. Adenosine inhibits IL-12 and TNF-a production via adenosine A2a receptor-dependent and independent mechanisms. FASEB J. 14, 2065–2074 (2000). First use of adenosine receptor (A 2A ) knockout mice in investigating the effect of adenosine on the immune system.
Kreckler, L. M., Wan, T. C., Ge, Z. D. & Auchampach, J. A. Adenosine inhibits tumor necrosis factor-a release from mouse peritoneal macrophages via A2A and A2B but not the A3 adenosine receptor. J. Pharmacol. Exp. Ther. 317, 172–180 (2006).
Ryzhov, S. et al. Effect of A2B adenosine receptor gene ablation on adenosine-dependent regulation of proinflammatory cytokines. J. Pharmacol. Exp. Ther. 324, 694–700 (2008). This paper demonstrates using A 2B receptor knockout mice that A 2B receptors mediate the stimulatory effect of adenosine on IL13 and VEGF secretion by mast cells.
Nemeth, Z. H. et al. Adenosine augments IL-10 production by macrophages through an A2B receptor-mediated posttranscriptional mechanism. J. Immunol. 175, 8260–8270 (2005).
Hasko, G., Pacher, P., Deitch, E. A. & Vizi, E. S. Shaping of monocyte and macrophage function by adenosine receptors. Pharmacol. Ther. 113, 264–275 (2007).
Levy, O. et al. The adenosine system selectively inhibits TLR-mediated TNF-a production in the human newborn. J. Immunol. 177, 1956–1966 (2006). Highlights the importance of the physiological role of adenosine in human immunity by showing that human newborn plasma contains elevated concentrations of adenosine when compared with adult plasma. Also degradation of adenosine with adenosine deaminase or interrupting adenosine signaling by adenosine receptor blockade augments TNF-a production by neonatal but not adult blood.
Panther, E. et al. Expression and function of adenosine receptors in human dendritic cells. FASEB J. 15, 1963–1970 (2001). First demonstration for a role of adenosine receptors in shaping dendritic cell function.
Schnurr, M. et al. Role of adenosine receptors in regulating chemotaxis and cytokine production of plasmacytoid dendritic cells. Blood 103, 1391–1397 (2004).
Panther, E. et al. Adenosine affects expression of membrane molecules, cytokine and chemokine release, and the T-cell stimulatory capacity of human dendritic cells. Blood 101, 3985–3990 (2003).
Cronstein, B. N., Kramer, S. B., Weissmann, G. & Hirschhorn, R. Adenosine: a physiological modulator of superoxide anion generation by human neutrophils. J. Exp. Med. 158, 1160–1177 (1983).
Cronstein, B. N., Rosenstein, E. D., Kramer, S. B., Weissmann, G. & Hirschhorn, R. Adenosine; a physiologic modulator of superoxide anion generation by human neutrophils. Adenosine acts via an A2 receptor on human neutrophils. J. Immunol. 135, 1366–1371 (1985).
Varani, K., Gessi, S., Dionisotti, S., Ongini, E. & Borea, P. A. [3H]-SCH 58261 labelling of functional A2A adenosine receptors in human neutrophil membranes. Br. J. Pharmacol. 123, 1723–1731 (1998).
McColl, S. R. et al. Immunomodulatory impact of the A2A adenosine receptor on the profile of chemokines produced by neutrophils. FASEB J. 20, 187–189 (2006).
Cronstein, B. N. et al. Neutrophil adherence to endothelium is enhanced via adenosine A1 receptors and inhibited via adenosine A2 receptors. J. Immunol. 148, 2201–2206 (1992).
Sullivan, G. W. et al. Activation of A2A adenosine receptors inhibits expression of a4/b1 integrin (very late antigen-4) on stimulated human neutrophils. J. Leukoc. Biol. 75, 127–134 (2004).
Zhao, Z. Q., Sato, H., Williams, M. W., Fernandez, A. Z. & Vinten-Johansen, J. Adenosine A2-receptor activation inhibits neutrophil-mediated injury to coronary endothelium. Am. J. Physiol. 271, H1456–H1464 (1996).
Chen, Y. et al. ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314, 1792–1795 (2006). Describes that A 3 receptors clustered at the leading edge of neutrophils are instrumental in promoting directed migration of these cells.
Cronstein, B. N., Daguma, L., Nichols, D., Hutchison, A. J. & Williams, M. The adenosine/neutrophil paradox resolved: human neutrophils possess both A1 and A2 receptors that promote chemotaxis and inhibit O2 generation, respectively. J. Clin. Invest. 85, 1150–1157 (1990).
Rose, F. R., Hirschhorn, R., Weissmann, G. & Cronstein, B. N. Adenosine promotes neutrophil chemotaxis. J. Exp. Med. 167, 1186–1194 (1988).
Mayne, M. et al. Adenosine A2A receptor activation reduces proinflammatory events and decreases cell death following intracerebral hemorrhage. Ann. Neurol. 49, 727–735 (2001).
Walker, B. A., Rocchini, C., Boone, R. H., Ip, S. & Jacobson, M. A. Adenosine A2a receptor activation delays apoptosis in human neutrophils. J. Immunol. 158, 2926–2931 (1997).
Yasui, K. et al. Theophylline induces neutrophil apoptosis through adenosine A2A receptor antagonism. J. Leukoc. Biol. 67, 529–535 (2000).
Cushley, M. J., Tattersfield, A. E. & Holgate, S. T. Inhaled adenosine and guanosine on airway resistance in normal and asthmatic subjects. Br. J. Clin. Pharmacol. 15, 161–165 (1983).
Polosa, R. & Holgate, S. T. Adenosine receptors as promising therapeutic targets for drug development in chronic airway inflammation. Curr. Drug Targets 7, 699–706 (2006).
Ryzhov, S. et al. Effect of A2B adenosine receptor gene ablation on proinflammatory adenosine signaling in mast cells. J. Immunol. 180, 7212–7220 (2008).
Hua, X. et al. Enhanced mast cell activation in mice deficient in the A2b adenosine receptor. J. Exp. Med. 204, 117–128 (2007).
Salvatore, C. A. et al. Disruption of the A3 adenosine receptor gene in mice and its effect on stimulated inflammatory cells. J. Biol. Chem. 275, 4429–4434 (2000).
Feoktistov, I. & Biaggioni, I. Adenosine A2b receptors evoke interleukin-8 secretion in human mast cells. An enprofylline-sensitive mechanism with implications for asthma. J. Clin. Invest. 96, 1979–1986 (1995).
Auchampach, J. A., Jin, X., Wan, T. C., Caughey, G. H. & Linden, J. Canine mast cell adenosine receptors: cloning and expression of the A3 receptor and evidence that degranulation is mediated by the A2B receptor. Mol. Pharmacol. 52, 846–860 (1997).
Naganuma, M. et al. Cutting edge: Critical role for A2A adenosine receptors in the T cell-mediated regulation of colitis. J. Immunol. 177, 2765–2769 (2006).
Sevigny, C. P. et al. Activation of adenosine 2A receptors attenuates allograft rejection and alloantigen recognition. J. Immunol. 178, 4240–4249 (2007).
Lappas, C. M., Rieger, J. M. & Linden, J. A2A adenosine receptor induction inhibits IFN-g production in murine CD4+ T cells. J. Immunol. 174, 1073–1080 (2005).
Csoka, B. H. et al. Adenosine A2A receptor activation inhibits T helper 1and T helper 2 cell development and effector function. FASEB J. 14 Jul 2008 (doi:10.1096/fj.08-107458).
Erdmann, A. A. et al. Activation of Th1 and Tc1 cell adenosine A2A receptors directly inhibits IL-2 secretion in vitro and IL-2-driven expansion in vivo. Blood 105, 4707–4714 (2005).
Koshiba, M., Kojima, H., Huang, S., Apasov, S. & Sitkovsky, M. V. Memory of extracellular adenosine A2A purinergic receptor-mediated signaling in murine T cells. J. Biol. Chem. 272, 25881–25889 (1997). One of the early studies describing the inhibitory effects of A 2A receptor stimulation on T-cell activation.
Hoskin, D. W., Butler, J. J., Drapeau, D., Haeryfar, S. M. & Blay, J. Adenosine acts through an A3 receptor to prevent the induction of murine anti-CD3-activated killer T cells. Int. J. Cancer 99, 386–395 (2002).
Raskovalova, T. et al. Gs protein-coupled adenosine receptor signaling and lytic function of activated NK cells. J. Immunol. 175, 4383–4391 (2005).
Deaglio, S. et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204, 1257–1265 (2007). Demonstrates that T Reg cells release adenosine, which then suppresses T-effector cell activation via A 2A receptors.
Kobie, J. J. et al. 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. 177, 6780–6786 (2006).
Borsellino, G. et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110, 1225–1232 (2007).
Zarek, P. E. et al. A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood 111, 251–259 (2008). This paper shows that A 2A receptor signalling induces T-cell anergy in vivo.
Zajonc, D. M. et al. Structural basis for CD1d presentation of a sulfatide derived from myelin and its implications for autoimmunity. J. Exp. Med. 202, 1517–1526 (2005).
Kaneko, S. et al. Melatonin scavenges hydroxyl radical and protects isolated rat hearts from ischemic reperfusion injury. Life Sci. 67, 101–112 (2000).
Lappas, C. M., Day, Y. J., Marshall, M. A., Engelhard, V. H. & Linden, J. Adenosine A2A receptor activation reduces hepatic ischemia reperfusion injury by inhibiting CD1d-dependent NKT cell activation. J. Exp. Med. 203, 2639–2648 (2006). Describes a crucial role for NKT cells in instigating tissue injury following ischaemia–reperfusion and as central targets of the anti-inflammatory effects of adenosine.
Yamamura, T., Sakuishi, K., Illes, Z. & Miyake, S. Understanding the behavior of invariant NKT cells in autoimmune diseases. J. Neuroimmunol. 191, 8–15 (2007).
Zhong, H. et al. A2B adenosine receptors increase cytokine release by bronchial smooth muscle cells. Am. J. Respir. Cell. Mol. Biol. 30, 118–125 (2004).
Zhong, H., Wu, Y., Belardinelli, L. & Zeng, D. A2B adenosine receptors induce IL-19 from bronchial epithelial cells, resulting in TNF-a increase. Am. J. Respir. Cell. Mol. Biol. 35, 587–592 (2006).
Zhong, H., Belardinelli, L., Maa, T. & Zeng, D. Synergy between A2B adenosine receptors and hypoxia in activating human lung fibroblasts. Am. J. Respir. Cell. Mol. Biol. 32, 2–8 (2005).
Sun, C. X. et al. Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury. J. Clin. Invest. 116, 2173–2182 (2006).
Mustafa, S. J. et al. Effect of a specific and selective A2B adenosine receptor antagonist on adenosine agonist AMP and allergen-induced airway responsiveness and cellular influx in a mouse model of asthma. J. Pharmacol. Exp. Ther. 320, 1246–1251 (2007).
Holgate, S. T. The Quintiles Prize Lecture 2004. The identification of the adenosine A2B receptor as a novel therapeutic target in asthma. Br. J. Pharmacol. 145, 1009–1015 (2005).
Reutershan, J., Cagnina, R. E., Chang, D., Linden, J. & Ley, K. Therapeutic anti-inflammatory effects of myeloid cell adenosine receptor A2a stimulation in lipopolysaccharide-induced lung injury. J. Immunol. 179, 1254–1263 (2007).
Nadeem, A., Fan, M., Ansari, H. R., Ledent, C. & Jamal Mustafa, S. Enhanced airway reactivity and inflammation in A2A adenosine receptor-deficient allergic mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 292, L1335–L1344 (2007).
Luijk, B. et al. Effect of an inhaled adenosine A2A agonist on the allergen-induced late asthmatic response. Allergy 63, 75–80 (2008).
Day, Y. J. et al. A2A adenosine receptors on bone marrow-derived cells protect liver from ischemia-reperfusion injury. J. Immunol. 174, 5040–5046 (2005).
Day, Y. J. et al. Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow-derived cells. J. Clin. Invest. 112, 883–891 (2003).
Yang, Z. et al. Myocardial infarct-sparing effect of adenosine A2A receptor activation is due to its action on CD4+ T lymphocytes. Circulation 114, 2056–2064 (2006).
Peirce, S. M., Skalak, T. C., Rieger, J. M., Macdonald, T. L. & Linden, J. Selective A2A adenosine receptor activation reduces skin pressure ulcer formation and inflammation. Am. J. Physiol. Heart Circ. Physiol. 281, H67–H74 (2001).
Li, Y. et al. Mouse spinal cord compression injury is reduced by either activation of the adenosine A2A receptor on bone marrow-derived cells or deletion of the A2A receptor on non-bone marrow-derived cells. Neuroscience 141, 2029–2039 (2006).
Reece, T. B. et al. Functional and cytoarchitectural spinal cord protection by ATL-146e after ischemia/reperfusion is mediated by adenosine receptor agonism. J. Vasc. Surg. 44, 392–397 (2006).
Reece, T. B. et al. Adenosine A2A receptor activation reduces inflammation and preserves pulmonary function in an in vivo model of lung transplantation. J. Thorac. Cardiovasc. Surg. 129, 1137–1143 (2005).
Li, L. et al. NKT cell activation mediates neutrophil IFN-g production and renal ischemia-reperfusion injury. J. Immunol. 178, 5899–5911 (2007).
Chabner, B. A. et al. Polyglutamation of methotrexate. Is methotrexate a prodrug? J. Clin. Invest. 76, 907–912 (1985).
Allegra, C. J., Drake, J. C., Jolivet, J. & Chabner, B. A. Inhibition of phosphoribosylaminoimidazolecarboxamide transformylase by methotrexate and dihydrofolic acid polyglutamates. Proc. Natl Acad. Sci. USA 82, 4881–4885 (1985).
Baggott, J. E., Vaughn, W. H. & Hudson, B. B. Inhibition of 5-aminoimidazole-4-carboxamide ribotide transformylase, adenosine deaminase and 5′-adenylate deaminase by polyglutamates of methotrexate and oxidized folates and by 5-aminoimidazole-4-carboxamide riboside and ribotide. Biochem. J. 236, 193–200 (1986).
Cronstein, B. N., Naime, D. & Ostad, E. The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation. J. Clin. Invest. 92, 2675–2682 (1993).
Moser, G. H., Schrader, J. & Deussen, A. Turnover of adenosine in plasma of human and dog blood. Am. J. Physiol. 256, C799–C806 (1989).
Baggott, J. E., Morgan, S. L., Sams, W. M. & Linden, J. Urinary adenosine and aminoimidazolecarboxamide excretion in methotrexate-treated patients with psoriasis. Arch. Dermatol. 135, 813–817 (1999).
Riksen, N. P. et al. Methotrexate modulates the kinetics of adenosine in humans in vivo. Ann. Rheum. Dis. 65, 465–470 (2006).
Cronstein, B. N., Eberle, M. A., Gruber, H. E. & Levin, R. I. Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells. Proc. Natl Acad. Sci. USA 88, 2441–2445 (1991).
Morabito, L. et al. Methotrexate and sulfasalazine promote adenosine release by a mechanism that requires ecto-5′-nucleotidase-mediated conversion of adenine nucleotides. J. Clin. Invest. 101, 295–300 (1998).
Montesinos, M. C. et al. Reversal of the antiinflammatory effects of methotrexate by the nonselective adenosine receptor antagonists theophylline and caffeine: evidence that the antiinflammatory effects of methotrexate are mediated via multiple adenosine receptors in rat adjuvant arthritis. Arthritis Rheum. 43, 656–663 (2000).
Montesinos, M. C. et al. Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX-68. Arthritis Rheum. 48, 240–247 (2003).
Delano, D. L. et al. Genetically based resistance to the antiinflammatory effects of methotrexate in the air-pouch model of acute inflammation. Arthritis Rheum. 52, 2567–2575 (2005).
Montesinos, M. C., Desai, A. & Cronstein, B. N. Suppression of inflammation by low-dose methotrexate is mediated by adenosine A2A receptor but not A3 receptor activation in thioglycollate-induced peritonitis. Arthritis Res. Ther. 8, R53 (2006).
Montesinos, M. C. et al. The antiinflammatory mechanism of methotrexate depends on extracellular conversion of adenine nucleotides to adenosine by ecto-5′-nucleotidase: findings in a study of ecto-5′-nucleotidase gene-deficient mice. Arthritis Rheum. 56, 1440–1445 (2007).
Nesher, G., Mates, M. & Zevin, S. Effect of caffeine consumption on efficacy of methotrexate in rheumatoid arthritis. Arthritis Rheum. 48, 571–572 (2003).
Baharav, E. et al. Antiinflammatory effect of A3 adenosine receptor agonists in murine autoimmune arthritis models. J. Rheumatol. 32, 469–476 (2005).
Bar-Yehuda, S. et al. The anti-inflammatory effect of A3 adenosine receptor agonists: a novel targeted therapy for rheumatoid arthritis. Expert Opin. Investig. Drugs 16, 1601–1613 (2007).
Szabo, C. et al. Suppression of macrophage inflammatory protein (MIP)-1a production and collagen-induced arthritis by adenosine receptor agonists. Br. J. Pharmacol. 125, 379–387 (1998).
Silverman, M. H. et al. Clinical evidence for utilization of the A3 adenosine receptor as a target to treat rheumatoid arthritis: data from a phase II clinical trial. J. Rheumatol. 35, 41–48 (2008).
Ochaion, A. et al. Methotrexate enhances the anti-inflammatory effect of CF101 via up-regulation of the A3 adenosine receptor expression. Arthritis Res. Ther. 8, R169 (2006).
Law, W. R. Adenosine receptors in the response to sepsis: what do receptor-specific knockouts tell us? Am. J. Physiol. Regul. Integr. Comp. Physiol. 291, R957–R958 (2006).
Gallos, G., Ruyle, T. D., Emala, C. W. & Lee, H. T. A1 adenosine receptor knockout mice exhibit increased mortality, renal dysfunction, and hepatic injury in murine septic peritonitis. Am. J. Physiol. Renal Physiol. 289, F369–F376 (2005).
Lee, H. T. et al. A3 adenosine receptor activation decreases mortality and renal and hepatic injury in murine septic peritonitis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291, R959–R969 (2006).
Nemeth, Z. H. et al. Adenosine A2A receptor inactivation increases survival in polymicrobial sepsis. J. Immunol. 176, 5616–5626 (2006).
Sullivan, G. W., Fang, G., Linden, J. & Scheld, W. M. A2A adenosine receptor activation improves survival in mouse models of endotoxemia and sepsis. J. Infect. Dis. 189, 1897–1904 (2004).
Bamias, G. & Cominelli, F. Immunopathogenesis of inflammatory bowel disease: current concepts. Curr. Opin. Gastroenterol. 23, 365–369 (2007).
Izcue, A., Coombes, J. L. & Powrie, F. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol. Rev. 212, 256–271 (2006).
Odashima, M. et al. Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease. Gastroenterology 129, 26–33 (2005).
Sitaraman, S. V. et al. Neutrophil-epithelial crosstalk at the intestinal lumenal surface mediated by reciprocal secretion of adenosine and IL-6. J. Clin. Invest. 107, 861–869 (2001).
Kolachala, V. et al. TNF-a upregulates adenosine 2b (A2b) receptor expression and signaling in intestinal epithelial cells: a basis for A2bR overexpression in colitis. Cell. Mol. Life Sci. 62, 2647–2657 (2005).
Kolachala, V. L., Bajaj, R., Chalasani, M. & Sitaraman, S. V. Purinergic receptors in gastrointestinal inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G401–G410 (2008).
Kolachala, V. L. et al. A2B adenosine receptor gene deletion attenuates murine colitis. Gastroenterology 22 May 2008 (doi:10.1053/j.gastro.2008.05.049).
Montesinos, M. C. et al. Wound healing is accelerated by agonists of adenosine A2 (Gas-linked) receptors. J. Exp. Med. 186, 1615–1620 (1997).
Victor-Vega, C., Desai, A., Montesinos, M. C. & Cronstein, B. N. Adenosine A2A receptor agonists promote more rapid wound healing than recombinant human platelet-derived growth factor (Becaplermin gel). Inflammation 26, 19–24 (2002).
Montesinos, M. C. et al. Adenosine promotes wound healing and mediates angiogenesis in response to tissue injury via occupancy of A2A receptors. Am. J. Pathol. 160, 2009–2018 (2002).
Macedo, L. et al. Wound healing is impaired in MyD88-deficient mice: a role for MyD88 in the regulation of wound healing by adenosine A2A receptors. Am. J. Pathol. 171, 1774–1788 (2007).
Feoktistov, I. et al. Differential expression of adenosine receptors in human endothelial cells: role of A2B receptors in angiogenic factor regulation. Circ. Res. 90, 531–538 (2002).
Merighi, S. et al. Caffeine inhibits adenosine-induced accumulation of hypoxia-inducible factor-1a, vascular endothelial growth factor, and interleukin-8 expression in hypoxic human colon cancer cells. Mol. Pharmacol. 72, 395–406 (2007).
Khoa, N. D. et al. Inflammatory cytokines regulate function and expression of adenosine A2A receptors in human monocytic THP-1 cells. J. Immunol. 167, 4026–4032 (2001).
Desai, A. et al. Adenosine A2A receptor stimulation increases angiogenesis by down-regulating production of the antiangiogenic matrix protein thrombospondin 1. Mol. Pharmacol. 67, 1406–1413 (2005).
Leibovich, S. J. et al. Synergistic up-regulation of vascular endothelial growth factor expression in murine macrophages by adenosine A2A receptor agonists and endotoxin. Am. J. Pathol. 160, 2231–2244 (2002).
Pinhal-Enfield, G. et al. An angiogenic switch in macrophages involving synergy between Toll-like receptors 2, 4, 7, and 9 and adenosine A2A receptors. Am. J. Pathol. 163, 711–721 (2003).
Chan, E. S. et al. Adenosine A2A receptors in diffuse dermal fibrosis: pathogenic role in human dermal fibroblasts and in a murine model of scleroderma. Arthritis Rheum. 54, 2632–2642 (2006).
Chunn, J. L. et al. Partially adenosine deaminase-deficient mice develop pulmonary fibrosis in association with adenosine elevations. Am. J. Physiol. Lung Cell. Mol. Physiol. 290, L579–L587 (2006).
Chen, Y. et al. Functional effects of enhancing or silencing adenosine A2b receptors in cardiac fibroblasts. Am. J. Physiol. Heart Circ. Physiol. 287, H2478–H2486 (2004).
Yegutkin, G. G. Nucleotide- and nucleoside-converting ectoenzymes: important modulators of purinergic signalling cascade. Biochim. Biophys. Acta 1783, 673–694 (2008).
Hasko, G. & Cronstein, B. N. Adenosine: an endogenous regulator of innate immunity. Trends Immunol. 25, 33–39 (2004).
Fredholm, B. B., Irenius, E., Kull, B. & Schulte, G. Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells. Biochem. Pharmacol. 61, 443–448 (2001).
Fredholm, B. B. Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ. 14, 1315–1323 (2007).
Zhou, Q. Y. et al. Molecular cloning and characterization of an adenosine receptor: the A3 adenosine receptor. Proc. Natl Acad. Sci. USA 89, 7432–7436 (1992).
This work was supported by the National Institutes of Health (NIH) Grant R01GM66189 and the Intramural Research Program of NIH, National Institute on Alcohol Abuse and Alcoholism.
Joel Linden owns equity in Adenosine Therapeutics, LLC and holds patents related to adenosine.
Bruce Cronstein is the inventor on the following patents: use of A2A receptor agonists to promote wound healing and use of A2A receptor antagonists to inhibit fibrosis; use of A1 receptor antagonists to treat osteoporosis and other diseases of bone; use of A1 and A2B receptor antagonists to treat fatty liver; and use of A2A receptor agonists to prevent prosthesis loosening. Cronstein is consultant (within the past 2 years), all <£10,000, to companies: King Pharmaceutical, CanFite Biopharmaceuticals, Cypress Bioscience, Inc., Bristol-Myers Squibb, Cellzome, Tap Pharmaceuticals, Prometheus Laboratories, Regeneron (Westat, DSMB), Sepracor, Amgen, Endocyte, Protalex, Allos, Inc., Combinatorx, Kyowa Hakka, Hoffman-LaRoche, and Savient. He received stocks from CanFite Biopharmaceuticals for membership in their Scientific Advisory Board. He holds a grant from King Pharmaceuticals.
An α-subunit of a heterotrimeric GTP-binding and GTP-hydrolysing protein (G protein) that inhibits the activity of a downstream enzyme such as adenylyl cyclase.
An α-subunit of a heterotrimeric GTP-binding and GTP-hydrolysing protein (G protein) that stimulates the activity of a downstream enzyme such as adenylyl cyclase.
An α-subunit of a heterotrimeric GTP-binding and GTP-hydrolysing protein (G protein) that stimulates the activity of a downstream enzyme such as phospholipase C.
NFATc1 is a member of the nuclear factor of activated T cells (NFAT) protein family, which are a family of transcription factors whose activation is controlled by calcineurin, a Ca2+-dependent phosphatase. They were originally identified in T cells as inducers of cytokine gene expression.
- Pertussis toxin
A compound that inhibits the guanine nucleotide binding proteins Gi and Go via ADP ribosylation.
One of the main types of professional phagocytes. Macrophages are long-lived and detrimental for many microbial pathogens. Intracellular bacteria can survive within the macrophages. They can mediate antibody-dependent cellular cytotoxicity through phagocytosis.
- Adenosine deaminase
Adenosine deaminase irreversibly deaminates adenosine, converting it to the related nucleoside inosine by the removal of an amino group.
- Alloimmune reaction
Alloimmunity is an immune reaction against non-self material from the same species.
- Dendritic cell
These professional antigen-presenting cells are increasingly recognized as having crucial immunoregulatory functions. They are found in various tissues where they take up antigens, process them, migrate to the lymph nodes and present the antigens to T cells.
- CD4+ cells
Cells expressing the CD4+ glycoprotein that recognises major histocompatibility class II molecules.
- TH1 and TH2 cells
The TH1/TH2 hypothesis came to prominence in the late 1980s, indicating that mouse T-helper (TH) cells broadly express differing cytokine profiles. T helper 1 (TH1) cells secrete interferon-γ and tumour necrosis factor-α. TH2 cells secrete interleukin 4 (IL4), IL5 and IL13. In addition, TH3 and regulatory CD4+CD25+ T cells exist that produce transforming growth factor-a and IL10, respectively.
- Mast cell
A bone marrow-derived cell that is present in various tissues; they are important contributors to allergic disease and possibly arthritis. They are granular cells that bear Fc receptors for immunoglobulin E (IgE), which, when crosslinked by IgE and antigen, causes degranulation and release of mediators such as histamine, leukotrienes and PGD2.
- Antigenic stimulation
When the body's immune system responds to a foreign substance.
- Inverse agonists
Inverse agonists reverse constitutive receptor activity, and are proposed to show selectively higher affinity for the inactive versus the active conformation of the receptor. In the absence of constitutive activity, inverse agonists function as competitive antagonists.
White blood cells of lymphoid origin that function as part of the immune system.
- TC1 and TC2 CD8+ cells
CD8+ T cells have been subdivided into CD8+ T cells secreting a TH1-like cytokine pattern, which are defined as TC1 (T cytotoxic type 1) cells, versus CD8+ T cells secreting a TH2-like pattern (TC2 cells).
- Natural killer (NK) cells
A lymphocyte subset that is part of the innate immune response and is able to recognize virus-infected or transformed cells that lack major histocompatibility class I expression. In contrast to T cells, NK cells do not require activation but are able to immediately kill these cells.
- Regulatory T (TReg) cells
TReg cells are a CD4+ T-cell subset that are characterized by the expression of CD25 (interleukin 2 receptor-(IL2R) subunit) and FOXP3. TReg cells are powerful suppressors of adaptive immune responses.
- MHC molecules
Originally named because they function as transplantation antigens. MHC molecules have a crucial role in antigen presentation, and serve as accessory binding proteins for T-helper and T-killer cells.
- Invariant NKT (iNKT) cells
A rare subset of lymphocytes that expresses an invariant T-cell receptor that recognizes certain glycolipids when bound to the major histocompatibility complex class I-like molecule, CD1d. Through secretion of cytokines they are powerful modulators of adaptive immune responses.
- Cecal ligation and puncture
An experimental model of polymicrobial sepsis that is generally considered more relevant to the human disease than rodents injected with bacterial lipopolysaccharide (endotoxin).
The growth of new blood vessels from pre-existing vessels. Angiogenesis is a normal process in growth and development but it also a fundamental process required for the growth of tumours.
About this article
Cite this article
Haskó, G., Linden, J., Cronstein, B. et al. Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov 7, 759–770 (2008). https://doi.org/10.1038/nrd2638
Influence of purinergic signaling on glucose transporters: A possible mechanism against insulin resistance?
European Journal of Pharmacology (2021)
Oxidative status and changes in the adenosine deaminase activity in experimental host infected with tropical liver fluke, Fasciola gigantica
Acta Tropica (2021)
CD73 alleviates GSDMD‐mediated microglia pyroptosis in spinal cord injury through PI3K/AKT/Foxo1 signaling
Clinical and Translational Medicine (2021)
Successful identification of predictive profiles for infection utilising systems‐level immune analysis: a pilot study in patients with relapsed and refractory multiple myeloma
Clinical & Translational Immunology (2021)
Frontiers in Immunology (2020)