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14 - Adenosine Receptors: Therapeutic Aspects for Inflammatory and Immune Diseases

from PART III - CHEMICAL MEDIATORS

Published online by Cambridge University Press:  05 April 2014

By
György Haskó  and
Bruce Cronstein
Edited by
Charles N. Serhan ,
Peter A. Ward  and
Derek W. Gilroy
With contributions by
Samir S. Ayoub
György Haskó
Affiliation:
University of Medicine and Dentistry of New Jersey
Bruce Cronstein
Affiliation:
New York University School of Medicine
Charles N. Serhan
Affiliation:
Harvard Medical School
Peter A. Ward
Affiliation:
University of Michigan, Ann Arbor
Derek W. Gilroy
Affiliation:
University College London
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Summary

Metabolic stress, hypoxia, and cell damage cause adenosine to accumulate in the extracellular space, and increases in extracellular adenosine levels are observed in hypoxia, ischemia, inflammation, and trauma [1, 2]. Extracellular adenosine levels accumulate following the release of adenosine from cells or as a consequence of extracellular degradation of released ATP and ADP. Intracellular adenosine, which can originate from increased intracellular metabolism of ATP during cellular stress or S-adenosyl homocysteine, is released through equilibrative nucleoside transporters ENT1 and ENT2. Extracellular ATP and ADP are catabolized by a cascade of ectoenzymes which consists of CD39 (ENTPD1 [ectonucleoside triphosphate diphosphohydrolase-1]), an enzyme that hydrolyzes ATP and ADP to AMP, and CD73 (ecto-5'nucleotidase), which in turn, rapidly dephosphorylates AMP to adenosine [3]. Owing to the widespread expression of equilibrative nucleoside transporters, adenosine derived from extracellular ATP is rapidly recycled from the extracellular space by uptake into cells. Adenosine in the cytosol is then either phosphorylated by adenosine kinase to AMP or metabolized by adenosine deaminase to inosine [4, 5]. As a net result of these various metabolic processes, adenosine levels in the extracellular space are maintained in a range of 10–200 nM in normal, healthy tissues. In contrast, under pathophysiological conditions adenosine is generated at a rate that is higher than the rate of degradation leading to markedly increased extracellular adenosine levels that can range between 10 and 100 μM.

Type
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Information
Fundamentals of Inflammation , pp. 186 - 197
Publisher: Cambridge University Press
Print publication year: 2010

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References

1. Linden, J. 2001. Molecular approach to adenosine receptors: receptor-mediated mechanisms of tissue protection. Annu Rev Pharmacol Toxicol 41:775–787.CrossRefGoogle ScholarPubMed
2. Fredholm, B.B., AP, I.J., Jacobson, K.A., Klotz, K.N., and Linden, J. 2001. International union of pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527–552.Google ScholarPubMed
3. Yegutkin, G.G. 2008. Nucleotide- and nucleoside-converting ectoenzymes: Important modulators of purinergic signalling cascade. Biochem Biophys Acta 1783:673–694.CrossRefGoogle ScholarPubMed
4. Hasko, G., and Cronstein, B.N. 2004. Adenosine: an endogenous regulator of innate immunity. Trends Immunol 25:33–39.CrossRefGoogle Scholar
5. Fredholm, B.B. 2007. Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ 14:1315–1323.CrossRefGoogle ScholarPubMed
6. Fredholm, B.B., Irenius, E., Kull, B., and Schulte, G. 2001. Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells. Biochem Pharmacol 61:443–448.CrossRefGoogle ScholarPubMed
7. Khoa, N.D., Montesinos, M.C., Reiss, A.B., Delano, D., Awadallah, N., and Cronstein, B.N. 2001. Inflammatory cytokines regulate function and expression of adenos-ine A(2A) receptors in human monocytic THP-1 cells. J Immunol 167:4026–4032.CrossRefGoogle Scholar
8. Chen, Y., Corriden, R., Inoue, Y., et al. 2006. ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314:1792–1795.CrossRefGoogle ScholarPubMed
9. Zhou, Q.Y., Li, C., Olah, M.E., Johnson, R.A., Stiles, G.L., and Civelli, O. 1992. Molecular cloning and characterization of an adenosine receptor: the A3 adenosine receptor. Proc Natl Acad Sci USA 89:7432–7436.CrossRefGoogle ScholarPubMed
10. van Calker, D., Muller, M., and Hamprecht, B. 1979. Adenosine regulates via two different types of receptors, the accumulation of cyclic AMP in cultured brain cells. J Neurochem 33:999–1005.Google ScholarPubMed
11. Bruns, R.F., Lu, G.H., and Pugsley, T.A. 1986. Characterization of the A2 adenosine receptor labeled by [3H]NECA in rat striatal membranes. Mol Pharmacol 29: 331–346.Google Scholar
12. Jin, X., Shepherd, R.K., Duling, B.R., and Linden, J. 1997. Inosine binds to A3 adenosine receptors and stimulates mast cell degranulation. J Clin Invest 100:2849–2857.CrossRefGoogle Scholar
13. Jacobson, K.A., and Gao, Z.G. 2006. Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 5:247–264.CrossRefGoogle ScholarPubMed
14. Nemeth, Z.H., Leibovich, S.J., Deitch, E.A., et al. 2003. Adenosine stimulates CREB activation in macrophages via a p38 MAPK-mediated mechanism. Biochem Biophys Res Commun 312:883–888.CrossRefGoogle Scholar
15. Fredholm, B.B., Chern, Y., Franco, R., and Sitkovsky, M. 2007. Aspects of the general biology of adenosine A2A signaling. Prog Neurobiol 83:263–276.CrossRefGoogle ScholarPubMed
16. Che, J., Chan, E.S., and Cronstein, B.N. 2007. 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.CrossRefGoogle ScholarPubMed
17. Revan, S., Montesinos, M.C., Naime, D., Landau, S., and Cronstein, B.N. 1996. Adenosine A2 receptor occupancy regulates stimulated neutrophil function via activation of a serine/threonine protein phosphatase. J Biol Chem 271:17114–17118.CrossRefGoogle ScholarPubMed
18. Csoka, B., Nemeth, Z.H., Virag, L., et al. 2007. A2A adenosine receptors and C/EBPbeta are crucially required for IL-10 production by macrophages exposed to Escherichia coli. Blood 110:2685–2695.CrossRefGoogle Scholar
19. Feoktistov, I., and Biaggioni, I. 1997. Adenosine A2B receptors. Pharmacol Rev 49:381–402.Google ScholarPubMed
20. Ryzhov, S., Goldstein, A.E., Biaggioni, I., and Feoktistov, I. 2006. Cross-talk between G(s)- and G(q)-coupled pathways in regulation of interleukin-4 by A(2B) adenos-ine receptors in human mast cells. Mol Pharmacol 70:727–735.CrossRefGoogle Scholar
21. Gessi, S., Merighi, S., Varani, K., Leung, E., Mac Lennan, S., and Borea, P.A. 2008. The A3 adenosine receptor: an enigmatic player in cell biology. Pharmacol Ther 117:123–140.CrossRefGoogle ScholarPubMed
22. Zhong, H., Shlykov, S.G., Molina, J.G., et al. 2003. Activation of murine lung mast cells by the adenosine A3 receptor. J Immunol 171:338–345.CrossRefGoogle ScholarPubMed
23. Cronstein, B.N., Rosenstein, E.D., Kramer, S.B., Weissmann, G., and Hirschhorn, R. 1985. 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.Google ScholarPubMed
24. Cronstein, B.N., Kramer, S.B., Weissmann, G., and Hirschhorn, R. 1983. Adenosine: a physiological modulator of superoxide anion generation by human neutrophils. J Exp Med 158:1160–1177.CrossRefGoogle ScholarPubMed
25. Visser, S.S., Theron, A.J., Ramafi, G., Ker, J.A., and Anderson, R. 2000. Apparent involvement of the A(2A) subtype adenosine receptor in the anti-inflammatory interactions of CGS 21680, cyclopentyladenosine, and IB-MECA with human neutrophils. Biochem Pharmacol 60:993–999.CrossRefGoogle ScholarPubMed
26. Varani, K., Gessi, S., Dionisotti, S., Ongini, E., and Borea, P.A. 1998. [3H]-SCH 58261 labeling of functional A2A adenosine receptors in human neutrophil membranes. Br J Pharmacol 123:1723–1731.CrossRefGoogle Scholar
27. Nishida, Y., Honda, Z., and Miyamoto, T. 1987. Suppression of human polymorphonuclear leukocyte phagocytosis by adenosine analogs. Inflammation 11:365–369.CrossRefGoogle ScholarPubMed
28. Salmon, J.E., and Cronstein, B.N. 1990. Fc gamma receptor-mediated functions in neutrophils are modulated by adenosine receptor occupancy. A1 receptors are stimulatory and A2 receptors are inhibitory. J Immunol 145:2235–2240.Google ScholarPubMed
29. McColl, S.R., St-Onge, M., Dussault, A.A., et al. 2006. Immunomodulatory impact of the A2A adenosine receptor on the profile of chemokines produced by neutrophils. FASEB J 20:187–189.CrossRefGoogle Scholar
30. Cronstein, B.N., Levin, R.I., Philips, M., Hirschhorn, R., Abramson, S.B., and Weissmann, G. 1992. Neutrophil adherence to endothelium is enhanced via adenosine A1 receptors and inhibited via adenosine A2 receptors. J Immunol 148:2201–2206.Google ScholarPubMed
31. Lesch, M.E., Ferin, M.A., Wright, C.D., and Schrier, D.J. 1991. The effects of (R)-N-(1-methyl-2-phenylethyl) adenosine (L-PIA), a standard A1-selective adenosine agonist on rat acute models of inflammation and neutrophil function. Agents Actions 34:25–27.CrossRefGoogle Scholar
32. Firestein, G.S., Bullough, D.A., Erion, M.D., et al. 1995. Inhibition of neutrophil adhesion by adenosine and an adenosine kinase inhibitor. The role of selectins. J Immunol 154:326–334.Google ScholarPubMed
33. Derian, C.K., Santulli, R.J., Rao, P.E., Solomon, H.F., and Barrett, J.A. 1995. Inhibition of chemotactic peptide-induced neutrophil adhesion to vascular endothelium by cAMP modulators. J Immunol 154:308–317.Google ScholarPubMed
34. Bullough, D.A., Magill, M.J., Firestein, G.S., and Mullane, K.M. 1995. Adenosine activates A2 receptors to inhibit neutrophil adhesion and injury to isolated cardiac myocytes. J Immunol 155:2579–2586.Google ScholarPubMed
35. Jordan, J.E., Zhao, Z.Q., Sato, H., Taft, S., and Vinten-Johansen, J. 1997. Adenosine A2 receptor activation attenuates reperfusion injury by inhibiting neutrophil accumulation, superoxide generation and coronary endothelial adherence. J Pharmacol Exp Ther 280:301–309.Google ScholarPubMed
36. Zhao, Z.Q., Sato, H., Williams, M.W., Fernandez, A.Z., and Vinten-Johansen, J. 1996. Adenosine A2-receptor activation inhibits neutrophil-mediated injury to coronary endothelium. Am J Physiol 271:H1456–H1464.Google ScholarPubMed
37. Okusa, M.D., Linden, J., Huang, L., Rieger, J.M., Macdonald, T.L., and Huynh, L.P. 2000. A(2A) adenosine receptor-mediated inhibition of renal injury and neutrophil adhesion. Am J Physiol Renal Physiol 279: F809–F818.CrossRefGoogle ScholarPubMed
38. Sullivan, G.W., Lee, D.D., Ross, W.G., et al. 2004. Activation of A2A adenosine receptors inhibits expression of alpha 4/beta 1 integrin (very late antigen-4) on stimulated human neutrophils. J Leukoc Biol 75: 127–134.CrossRefGoogle ScholarPubMed
39. Rose, F.R., Hirschhorn, R., Weissmann, G., and Cronstein, B.N. 1988. Adenosine promotes neutrophil chemotaxis. J Exp Med 167:1186–1194.CrossRefGoogle ScholarPubMed
40. Cronstein, B.N., Daguma, L., Nichols, D., Hutchison, A.J., and Williams, M. 1990. 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.CrossRefGoogle ScholarPubMed
41. Mayne, M., Fotheringham, J., Yan, H.J., et al. 2001. Adenosine A2A receptor activation reduces proinflam-matory events and decreases cell death following intracerebral hemorrhage. Ann Neurol 49:727–735.CrossRefGoogle Scholar
42. Yasui, K., Agematsu, K., Shinozaki, K., et al. 2000. Theophylline induces neutrophil apoptosis through adenosine A2A receptor antagonism. J Leukoc Biol 67:529–535.CrossRefGoogle ScholarPubMed
43. Walker, B.A., Rocchini, C., Boone, R.H., Ip, S., and Jacobson, M.A. 1997. Adenosine A2a receptor activation delays apoptosis in human neutrophils. J Immunol 158:2926–2931.Google ScholarPubMed
44. Kreckler, L.M., Wan, T.C., Ge, Z.D., and Auchampach, J.A. 2006. Adenosine inhibits tumor necrosis factor-alpha release from mouse peritoneal macrophages via A2A and A2B but not the A3 adenosine receptor. J Pharmacol Exp Ther 317:172–180.Google Scholar
45. Ryzhov, S., Zaynagetdinov, R., Goldstein, A.E., et al. 2008. Effect of A2B adenosine receptor gene ablation on adenosine-dependent regulation of proinflammatory cytokines. J Pharmacol Exp Ther 324:694–700.Google ScholarPubMed
46. Hasko, G., Kuhel, D.G., Chen, J.F., et al. 2000. Adenosine inhibits IL-12 and TNF-[alpha] production via adenosine A2a receptor-dependent and independent mechanisms. FASEB J 14:2065–2074.CrossRefGoogle ScholarPubMed
47. Nemeth, Z.H., Lutz, C.S., Csoka, B., et al. 2005. Adenosine augments IL-10 production by macrophages through an A2B receptor-mediated posttranscriptional mechanism. J Immunol 175:8260–8270.CrossRefGoogle ScholarPubMed
48. Hasko, G., Pacher, P., Deitch, E.A., and Vizi, E.S. 2007. Shaping of monocyte and macrophage function by adenosine receptors. Pharmacol Ther 113:264–275.CrossRefGoogle ScholarPubMed
49. Levy, O., Coughlin, M., Cronstein, B.N., Roy, R.M., Desai, A., and Wessels, M.R. 2006. The adenosine system selectively inhibits TLR-mediated TNF-alpha production in the human newborn. J Immunol 177:1956–1966.CrossRefGoogle ScholarPubMed
50. Panther, E., Idzko, M., Herouy, Y., et al. 2001. Expression and function of adenosine receptors in human dendritic cells. FASEB J 15:1963–1970.CrossRefGoogle ScholarPubMed
51. Schnurr, M., Toy, T., Shin, A., et al. 2004. Role of adenosine receptors in regulating chemotaxis and cytokine production of plasmacytoid dendritic cells. Blood 103:1391–1397.Google ScholarPubMed
52. Panther, E., Corinti, S., Idzko, M., et al. 2003. Adenosine affects expression of membrane molecules, cytokine and chemokine release, and the T-cell stimulatory capacity of human dendritic cells. Blood 101:3985–3990.CrossRefGoogle ScholarPubMed
53. Cushley, M.J., Tattersfield, A.E., and Holgate, S.T. 1983. Inhaled adenosine and guanosine on airway resistance in normal and asthmatic subjects. Br J Clin Pharmacol 15:161–165.CrossRefGoogle ScholarPubMed
54. Polosa, R., and Holgate, S.T. 2006. Adenosine receptors as promising therapeutic targets for drug development in chronic airway inflammation. Curr Drug Targets 7:699–706.CrossRefGoogle ScholarPubMed
55. Ryzhov, S., Zaynagetdinov, R., Goldstein, A.E., et al. 2008. Effect of A2B adenosine receptor gene ablation on proinflammatory adenosine signaling in mast cells. J Immunol 180:7212–7220.CrossRefGoogle ScholarPubMed
56. Hua, X., Kovarova, M., Chason, K.D., Nguyen, M., Koller, B.H., and Tilley, S.L. 2007. Enhanced mast cell activation in mice deficient in the A2b adenosine receptor. J Exp Med 204:117–128.CrossRefGoogle ScholarPubMed
57. Salvatore, C.A., Tilley, S.L., Latour, A.M., Fletcher, D.S., Koller, B.H., and Jacobson, M.A. 2000. Disruption of the A(3) adenosine receptor gene in mice and its effect on stimulated inflammatory cells. J Biol Chem 275:4429–4434.CrossRefGoogle ScholarPubMed
58. Feoktistov, I., and Biaggioni, I. 1995. 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.CrossRefGoogle ScholarPubMed
59. Auchampach, J.A., Jin, X., Wan, T.C., Caughey, G.H., and Linden, J. 1997. 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.CrossRefGoogle ScholarPubMed
60. Naganuma, M., Wiznerowicz, E.B., Lappas, C.M., Linden, J., Worthington, M.T., and Ernst, P.B. 2006. Cutting edge: critical role for A2A adenosine receptors in the T cell-mediated regulation of colitis. J Immunol 177:2765–2769.CrossRefGoogle Scholar
61. Sevigny, C.P., Li, L., Awad, A.S., et al. 2007. Activation of adenosine 2A receptors attenuates allograft rejection and alloantigen recognition. J Immunol 178: 4240–4249.CrossRefGoogle ScholarPubMed
62. Lappas, C.M., Rieger, J.M., and Linden, J. 2005. A2A adenosine receptor induction inhibits IFN-gamma production in murine CD4+ T cells. J Immunol 174:1073–1080.CrossRefGoogle ScholarPubMed
63. Csoka, B., Himer, L., Nemeth, Z.H., et al. 2008. Adenosine A2A receptor activation inhibits T helper 1and T helper 2 cell development and effector function. FASEB J 22:3491–3499.CrossRefGoogle Scholar
64. Erdmann, A.A., Gao, Z.G., Jung, U., et al. 2005. 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.CrossRefGoogle ScholarPubMed
65. Koshiba, M., Kojima, H., Huang, S., Apasov, S., and Sitkovsky, M.V. 1997. Memory of extracellular adenosine A2A purinergic receptor-mediated signaling in murine T cells. J Biol Chem 272:25881–25889.CrossRefGoogle ScholarPubMed
66. Hoskin, D.W., Butler, J.J., Drapeau, D., Haeryfar, S.M., and Blay, J. 2002. Adenosine acts through an A3 receptor to prevent the induction of murine anti-CD3-activated killer T cells. Int J Cancer 99:386–395.CrossRefGoogle ScholarPubMed
67. Raskovalova, T., Huang, X., Sitkovsky, M., Zacharia, L.C., Jackson, E.K., and Gorelik, E. 2005. Gs proteincoupled adenosine receptor signaling and lytic function of activated NK cells. J Immunol 175:4383–4391.CrossRefGoogle Scholar
68. Deaglio, S., Dwyer, K.M., Gao, W., et al. 2007. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204:1257–1265.CrossRefGoogle ScholarPubMed
69. Kobie, J.J., Shah, P.R., Yang, L., Rebhahn, J.A., Fowell, D.J., and Mosmann, T.R. 2006. 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.CrossRefGoogle Scholar
70. Borsellino, G., Kleinewietfeld, M., Di Mitri, D., et al. 2007. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110:1225–1232.CrossRefGoogle ScholarPubMed
71. Zarek, P.E., Huang, C.T., Lutz, E.R., et al. 2008. A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood 111:251–259.CrossRefGoogle ScholarPubMed
72. Zajonc, D.M., Maricic, I., Wu, D., et al. 2005. Structural basis for CD1d presentation of a sulfatide derived from myelin and its implications for autoimmunity. J Exp Med 202:1517–1526.CrossRefGoogle ScholarPubMed
73. Kaneko, S., Okumura, K., Numaguchi, Y., et al. 2000. Melatonin scavenges hydroxyl radical and protects isolated rat hearts from ischemic reperfusion injury. Life Sci 67:101–112.CrossRefGoogle ScholarPubMed
74. Lappas, C.M., Day, Y.J., Marshall, M.A., Engelhard, V.H., and Linden, J. 2006. Adenosine A2A receptor activation reduces hepatic ischemia reperfusion injury by inhibiting CD1d-dependent NKT cell activation. J Exp Med 203:2639–2648.CrossRefGoogle ScholarPubMed
75. Yamamura, T., Sakuishi, K., Illes, Z., and Miyake, S. 2007. Understanding the behavior of invariant NKT cells in autoimmune diseases. J Neuroimmunol 191:8–15.CrossRefGoogle ScholarPubMed
76. Sands, W.A., and Palmer, T.M. 2005. Adenosine receptors and the control of endothelial cell function in inflammatory disease. Immunol Lett 101:1–11.CrossRefGoogle ScholarPubMed
77. Bouma, M.G., van den Wildenberg, F.A., and Buurman, W.A. 1996. Adenosine inhibits cytokine release and expression of adhesion molecules by activated human endothelial cells. Am J Physiol 270:C522–C529.CrossRefGoogle ScholarPubMed
78. Sands, W.A., Martin, A.F., Strong, E.W., and Palmer, T.M. 2004. Specific inhibition of nuclear factor-kappaB-dependent inflammatory responses by cell type-specific mechanisms upon A2A adenosine receptor gene transfer. Mol Pharmacol 66:1147–1159.CrossRefGoogle ScholarPubMed
79. Yang, D., Zhang, Y., Nguyen, H.G., et al. 2006. The A2B adenosine receptor protects against inflammation and excessive vascular adhesion. J Clin Invest 116:1913–1923.CrossRefGoogle ScholarPubMed
80. Deussen, A., Moser, G., and Schrader, J. 1986. Contribution of coronary endothelial cells to cardiac adenosine production. Pflugers Arch 406:608–614.CrossRefGoogle ScholarPubMed
81. Deussen, A., Bading, B., Kelm, M., and Schrader, J. 1993. Formation and salvage of adenosine by macrovascular endothelial cells. Am J Physiol 264:H692–H700.Google ScholarPubMed
82. Zernecke, A., Bidzhekov, K., Ozuyaman, B., et al. 2006. CD73/ecto-5'-nucleotidase protects against vascular inflammation and neointima formation. Circulation 113:2120–2127.CrossRefGoogle ScholarPubMed
83. Narravula, S., Lennon, P.F., Mueller, B.U., and Colgan, S.P. 2000. Regulation of endothelial CD73 by adenosine: paracrine pathway for enhanced endothelial barrier function. J Immunol 165:5262–5268.CrossRefGoogle ScholarPubMed
84. Thompson, L.F., Eltzschig, H.K., Ibla, J.C., et al. 2004. Crucial role for ecto-5'-nucleotidase (CD73) in vascular leakage during hypoxia. J Exp Med 200:1395–1405.CrossRefGoogle ScholarPubMed
85. Eltzschig, H.K., Thompson, L.F., Karhausen, J., et al. 2004. Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism. Blood 104:3986–3992.CrossRefGoogle ScholarPubMed
86. Niemela, J., Henttinen, T., Yegutkin, G.G., et al. 2004. IFN-alpha induced adenosine production on the endothe-lium: a mechanism mediated by CD73 (ecto-5'-nucleoti-dase) up-regulation. J Immunol 172:1646–1653.CrossRefGoogle Scholar
87. Kalsi, K., Lawson, C., Dominguez, M., Taylor, P., Yacoub, M.H., and Smolenski, R.T. 2002. Regulation of ecto-5'-nucleotidase by TNF-alpha in human endothelial cells. Mol Cell Biochem 232:113–119.CrossRefGoogle ScholarPubMed
88. Cronstein, B.N., Levin, R.I., Belanoff, J., Weissmann, G., and Hirschhorn, R. 1986. Adenosine: an endogenous inhibitor of neutrophil-mediated injury to endothelial cells. J Clin Invest 78:760–770.CrossRefGoogle ScholarPubMed
89. Rosengren, S., Bong, G.W., and Firestein, G.S. 1995. Anti-inflammatory effects of an adenosine kinase inhibitor. Decreased neutrophil accumulation and vascular leakage. J Immunol 154:5444–5451.Google ScholarPubMed
90. Eckle, T., Faigle, M., Grenz, A., Laucher, S., Thompson, L.F., and Eltzschig, H.K. 2008. A2B adenosine receptor dampens hypoxia-induced vascular leak. Blood 111:2024–2035.CrossRefGoogle ScholarPubMed
91. Eckle, T., Krahn, T., Grenz, A., et al. 2007. Cardioprotection by ecto-5'-nucleotidase (CD73) and A2B adenosine receptors. Circulation 115:1581–1590.CrossRefGoogle ScholarPubMed
92. Montesinos, M.C., Gadangi, P., Longaker, M., et al. 1997. Wound healing is accelerated by agonists of adenosine A2 (G alpha s-linked) receptors. J Exp Med 186:1615–1620.CrossRefGoogle Scholar
93. Victor-Vega, C., Desai, A., Montesinos, M.C., and Cronstein, B.N. 2002. Adenosine A2A receptor agonists promote more rapid wound healing than recombinant human platelet-derived growth factor (Becaplermin gel). Inflammation 26:19–24.CrossRefGoogle Scholar
94. Montesinos, M.C., Desai, A., Chen, J.F., et al. 2002. Adenosine promotes wound healing and mediates angiogenesis in response to tissue injury via occupancy of A(2A) receptors. Am J Pathol 160:2009–2018.CrossRefGoogle ScholarPubMed
95. Montesinos, M.C., Shaw, J.P., Yee, H., Shamamian, P., and Cronstein, B.N. 2004. Adenosine A(2A) receptor activation promotes wound neovascularization by stimulating angiogenesis and vasculogenesis. Am J Pathol 164:1887–1892.CrossRefGoogle ScholarPubMed
96. Leibovich, S.J., Chen, J.F., Pinhal-Enfield, G., et al. 2002. Synergistic up-regulation of vascular endothelial growth factor expression in murine macrophages by adenosine A(2A) receptor agonists and endotoxin. Am J Pathol 160:2231–2244.CrossRefGoogle ScholarPubMed
97. Desai, A., Victor-Vega, C., Gadangi, S., Montesinos, M.C., Chu, C.C., and Cronstein, B.N. 2005. Adenosine A2A receptor stimulation increases angiogenesis by down-regulating production of the antiangiogenic matrix protein thrombospondin 1. Mol Pharmacol 67: 1406–1413.CrossRefGoogle ScholarPubMed
98. Nguyen, D.K., Montesinos, M.C., Williams, A.J., Kelly, M., and Cronstein, B.N. 2003. Th1 cytokines regulate adenosine receptors and their downstream signaling elements in human microvascular endothelial cells. J Immunol 171:3991–3998.Google ScholarPubMed
99. Grant, M.B., Davis, M.I., Caballero, S., Feoktistov, I., Biaggioni, I., and Belardinelli, L. 2001. Proliferation, migration, and ERK activation in human retinal endothelial cells through A(2B) adenosine receptor stimulation. Invest Ophthalmol Vis Sci 42:2068–2073.Google ScholarPubMed
100. Grant, M.B., Tarnuzzer, R.W., Caballero, S., et al. 1999. Adenosine receptor activation induces vascular endothelial growth factor in human retinal endothelial cells. Circ Res 85:699–706.CrossRefGoogle ScholarPubMed
101. Feoktistov, I., Goldstein, A.E., Ryzhov, S., et al. 2002. Differential expression of adenosine receptors in human endothelial cells: role of A2B receptors in angiogenic factor regulation. Circ Res 90:531–538.CrossRefGoogle ScholarPubMed
102. Zhong, H., Belardinelli, L., Maa, T., Feoktistov, I., Biaggioni, I., and Zeng, D. 2004. A(2B) adenosine receptors increase cytokine release by bronchial smooth muscle cells. Am J Respir Cell Mol Biol 30:118–125.CrossRefGoogle ScholarPubMed
103. Zhong, H., Wu, Y., Belardinelli, L., and Zeng, D. 2006. A2B adenosine receptors induce IL-19 from bronchial epithelial cells, resulting in TNF-alpha increase. Am J Respir Cell Mol Biol 35:587–592.CrossRefGoogle ScholarPubMed
104. Zhong, H., Belardinelli, L., Maa, T., and Zeng, D. 2005. Synergy between A2B adenosine receptors and hypoxia in activating human lung fibroblasts. Am J Respir Cell Mol Biol 32:2–8.CrossRefGoogle ScholarPubMed
105. Sun, C.X., Zhong, H., Mohsenin, A., et al. 2006. Role of A2B adenosine receptor signaling in adenosine-depen-dent pulmonary inflammation and injury. J Clin Invest 116:2173–2182.CrossRefGoogle ScholarPubMed
106. Mustafa, S.J., Nadeem, A., Fan, M., Zhong, H., Belardinelli, L., and Zeng, D. 2007. Effect of a specific and selective A(2B) 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.Google Scholar
107. Holgate, S.T. 2005. 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.CrossRefGoogle ScholarPubMed
108. Reutershan, J., Cagnina, R.E., Chang, D., Linden, J., and Ley, K. 2007. Therapeutic anti-inflammatory effects of myeloid cell adenosine receptor A2a stimulation in lipopolysaccharide-induced lung injury. J Immunol 179:1254–1263.CrossRefGoogle ScholarPubMed
109. Nadeem, A., Fan, M., Ansari, H.R., Ledent, C., and Jamal Mustafa, S. 2007. Enhanced airway reactivity and inflammation in A2A adenosine receptor-deficient allergic mice. Am J Physiol Lung Cell Mol Physiol 292:L1335–1344.CrossRefGoogle ScholarPubMed
110. Luijk, B., van den Berge, M., Kerstjens, H.A., et al. 2008. Effect of an inhaled adenosine A2A agonist on the allergen-induced late asthmatic response. Allergy 63:75–80.Google ScholarPubMed
111. Day, Y.J., Li, Y., Rieger, J.M., Ramos, S.I., Okusa, M.D., and Linden, J. 2005. A2A adenosine receptors on bone marrow-derived cells protect liver from ischemia-rep-erfusion injury. J Immunol 174:5040–5046.CrossRefGoogle Scholar
112. Day, Y.J., Huang, L., McDuffie, M.J., et al. 2003. Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow-derived cells. J Clin Invest 112:883–891.CrossRefGoogle ScholarPubMed
113. Yang, Z., Day, Y.J., Toufektsian, M.C., et al. 2006. Myocardial infarct-sparing effect of adenosine A2A receptor activation is due to its action on CD4+ T lymphocytes. Circulation 114:2056–2064.CrossRefGoogle ScholarPubMed
114. Peirce, S.M., Skalak, T.C., Rieger, J.M., Macdonald, T.L., and Linden, J. 2001. Selective A(2A) adenosine receptor activation reduces skin pressure ulcer formation and inflammation. Am J Physiol Heart Circ Physiol 281:H67–H74.CrossRefGoogle ScholarPubMed
115. Li, Y., Oskouian, R.J., Day, Y.J., et al. 2006. 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.CrossRefGoogle ScholarPubMed
116. Reece, T.B., Kron, I.L., Okonkwo, D.O., et al. 2006. Functional and cytoarchitectural spinal cord protection by ATL-146e after ischemia/reperfusion is mediated by adenosine receptor agonism. J Vasc Surg 44:392–397.CrossRefGoogle ScholarPubMed
117. Reece, T.B., Ellman, P.I., Maxey, T.S., et al. 2005. 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.CrossRefGoogle Scholar
118. Li, L., Huang, L., Sung, S.S., et al. 2007. NKT cell activation mediates neutrophil IFN-gamma production and renal ischemia-reperfusion injury. J Immunol 178:5899–5911.CrossRefGoogle ScholarPubMed
119. Chabner, B.A., Allegra, C.J., Curt, G.A., et al. 1985. Polyglutamation of methotrexate. Is methotrexate a prodrug?J Clin Invest 76:907–912.CrossRefGoogle ScholarPubMed
120. Allegra, C.J., Drake, J.C., Jolivet, J., and Chabner, B.A. 1985. Inhibition of phosphoribosylaminoimidazolecar-boxamide transformylase by methotrexate and dihy-drofolic acid polyglutamates. Proc Natl Acad Sci USA 82:4881–4885.CrossRefGoogle ScholarPubMed
121. Baggott, J.E., Vaughn, W.H., and Hudson, B.B. 1986. Inhibition of 5-aminoimidazole-4-carboxamide ribotide transformylase, adenosine deaminase and 5'-adenylate deaminase by polyglutamates of metho-trexate and oxidized folates and by 5-aminoimidazole-4-carboxamide riboside and ribotide. Biochem J 236: 193–200.CrossRefGoogle Scholar
122. Cronstein, B.N., Naime, D., and Ostad, E. 1993. 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.CrossRefGoogle Scholar
123. Moser, G.H., Schrader, J., and Deussen, A. 1989. Turnover of adenosine in plasma of human and dog blood. Am J Physiol 256:C799–806.CrossRefGoogle ScholarPubMed
124. Riksen, N.P., Barrera, P., van den Broek, P. H., van Riel, P. L., Smits, P., and Rongen, G.A. 2006. Methotrexate modulates the kinetics of adenosine in humans in vivo. Ann Rheum Dis 65:465–470.CrossRefGoogle ScholarPubMed
125. Baggott, J.E., Morgan, S.L., Sams, W.M., and Linden, J. 1999. Urinary adenosine and aminoimidazolecarbox-amide excretion in methotrexate-treated patients with psoriasis. Arch Dermatol 135:813–817.CrossRefGoogle ScholarPubMed
126. Cronstein, B.N., Eberle, M.A., Gruber, H.E., and Levin, R.I. 1991. Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells. Proc Natl Acad Sci USA 88:2441–2445.CrossRefGoogle ScholarPubMed
127. Morabito, L., Montesinos, M.C., Schreibman, D.M., et al. 1998. 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.CrossRefGoogle ScholarPubMed
128. Montesinos, M.C., Yap, J.S., Desai, A., Posadas, I., McCrary, C.T., and Cronstein, B.N. 2000. Reversal of the antiinflammatory effects of methotrexate by the nonse-lective 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 43:656–663.3.0.CO;2-H>CrossRefGoogle ScholarPubMed
129. Montesinos, M.C., Desai, A., Delano, D., et al. 2003. Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX-68. Arthritis Rheum 48:240–247.CrossRefGoogle ScholarPubMed
130. Delano, D.L., Montesinos, M.C., Desai, A., et al. 2005. Genetically based resistance to the antiinflammatory effects of methotrexate in the air-pouch model of acute inflammation. Arthritis Rheum 52:2567–2575.CrossRefGoogle ScholarPubMed
131. Montesinos, M.C., Desai, A., and Cronstein, B.N. 2006. Suppression of inflammation by low-dose methotrex-ate is mediated by adenosine A2A receptor but not A3 receptor activation in thioglycollate-induced peritonitis. Arthritis Res Ther 8:R53.CrossRefGoogle Scholar
132. Montesinos, M.C., Takedachi, M., Thompson, L.F., Wilder, T.F., Fernandez, P., and Cronstein, B.N. 2007. 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.CrossRefGoogle Scholar
133. Nesher, G., Mates, M., and Zevin, S. 2003. Effect of caffeine consumption on efficacy of methotrexate in rheumatoid arthritis. Arthritis Rheum 48:571–572.CrossRefGoogle ScholarPubMed
134. Szabo, C., Scott, G.S., Virag, L., et al. 1998. Suppression of macrophage inflammatory protein (MIP)-1alpha production and collagen-induced arthritis by adenosine receptor agonists. Br J Pharmacol 125: 379–387.CrossRefGoogle ScholarPubMed
135. Silverman, M.H., Strand, V., Markovits, D., et al. 2008. 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.Google ScholarPubMed
136. Law, W.R. 2006. Adenosine receptors in the response to sepsis: what do receptor-specific knockouts tell us?Am J Physiol Regul Integr Comp Physiol 291:R957–R958.CrossRefGoogle ScholarPubMed
137. Gallos, G., Ruyle, T.D., Emala, C.W., and Lee, H.T. 2005. 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.CrossRefGoogle ScholarPubMed
138. Lee, H.T., Kim, M., Joo, J.D., Gallos, G., Chen, J.F., and Emala, C.W. 2006. 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.CrossRefGoogle ScholarPubMed
139. Nemeth, Z.H., Csoka, B., Wilmanski, J., et al. 2006. Adenosine A2A receptor inactivation increases survival in polymicrobial sepsis. J Immunol 176:5616–5626.CrossRefGoogle ScholarPubMed
140. Sullivan, G.W., Fang, G., Linden, J., and Scheld, W.M. 2004. A2A adenosine receptor activation improves survival in mouse models of endotoxemia and sepsis. J Infect Dis 189:1897–1904.CrossRefGoogle ScholarPubMed
141. Bamias, G., and Cominelli, F. 2007. Immunopathogenesis of inflammatory bowel disease: current concepts. Curr Opin Gastroenterol 23:365–369.CrossRefGoogle ScholarPubMed
142. Izcue, A., Coombes, J.L., and Powrie, F. 2006. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol Rev 212:256–271.CrossRefGoogle ScholarPubMed
143. Odashima, M., Bamias, G., Rivera-Nieves, J., et al. 2005. Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease. Gastroenterology 129:26–33.CrossRefGoogle ScholarPubMed
144. Sitaraman, S.V., Merlin, D., Wang, L., et al. 2001. Neutrophil-epithelial crosstalk at the intestinal lumenal surface mediated by reciprocal secretion of adenosine and IL-6. J Clin Invest 107:861–869.CrossRefGoogle ScholarPubMed
145. Kolachala, V., Asamoah, V., Wang, L., et al. 2005. TNF-alpha 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.CrossRefGoogle ScholarPubMed
146. Kolachala, V.L., Ruble, B.K., Vijay-Kumar, M., et al. 2008. Blockade of adenosine A(2B) receptors ameliorates murine colitis. Br J Pharmacol 155:127–137.CrossRefGoogle ScholarPubMed
147. Kolachala, V.L., Bajaj, R., Chalasani, M., and Sitaraman, S.V. 2008. Purinergic receptors in gastrointestinal inflammation. Am J Physiol Gastrointest Liver Physiol 294:G401–G410.CrossRefGoogle ScholarPubMed
148. Mabley, J.G., Pacher, P., Liaudet, L., et al. 2003. Inosine reduces inflammation and improves survival in a murine model of colitis. Am J Physiol Gastrointest Liver Physiol 284:G138–G144.CrossRefGoogle Scholar
149. Gomez, G., and Sitkovsky, M.V. 2003. Differential requirement for A2a and A3 adenosine receptors for the protective effect of inosine in vivo. Blood 102:4472–4478.CrossRefGoogle ScholarPubMed
150. Hasko, G., Sitkovsky, M.V., and Szabo, C. 2004. Immunomodulatory and neuroprotective effects of inosine. Trends Pharmacol Sci 25:152–157.CrossRefGoogle ScholarPubMed
151. Hasko, G., Kuhel, D.G., Nemeth, Z.H., et al. 2000. Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock. J Immunol 164:1013–1019.CrossRefGoogle ScholarPubMed
152. Macedo, L., Pinhal-Enfield, G., Alshits, V., Elson, G., Cronstein, B.N., and Leibovich, S.J. 2007. 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.CrossRefGoogle ScholarPubMed
153. Meininger, C.J., Schelling, M.E., and Granger, H.J. 1988. Adenosine and hypoxia stimulate proliferation and migration of endothelial cells. Am J Physiol 255:H554–H562.Google ScholarPubMed
154. Ethier, M.F., Chander, V., and Dobson, J.G. Jr. 1993. Adenosine stimulates proliferation of human endothelial cells in culture. Am J Physiol 265:H131–H138.Google ScholarPubMed
155. Sexl, V., Mancusi, G., Baumgartner-Parzer, S., Schutz, W., and Freissmuth, M. 1995. Stimulation of human umbilical vein endothelial cell proliferation by A2-adenosine and beta 2-adrenoceptors. Br J Pharmacol 114:1577–1586.CrossRefGoogle ScholarPubMed
156. Sexl, V., Mancusi, G., Holler, C., Gloria-Maercker, E., Schutz, W., and Freissmuth, M. 1997. Stimulation of the mitogen-activated protein kinase via the A2A-adenosine receptor in primary human endothelial cells. J Biol Chem 272:5792–5799.CrossRefGoogle ScholarPubMed
157. Takagi, H., King, G.L., Ferrara, N., and Aiello, L.P. 1996. Hypoxia regulates vascular endothelial growth factor receptor KDR/Flk gene expression through adenosine A2 receptors in retinal capillary endothelial cells. Invest Ophthalmol Vis Sci 37:1311–1321.Google ScholarPubMed
158. Takagi, H., King, G.L., Robinson, G.S., Ferrara, N., and Aiello, L.P. 1996. Adenosine mediates hypoxic induction of vascular endothelial growth factor in retinal pericytes and endothelial cells. Invest Ophthalmol Vis Sci 37:2165–2176.Google ScholarPubMed
159. Merighi, S., Benini, A., Mirandola, P., et al. 2007. Caffeine inhibits adenosine-induced accumulation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and interleukin-8 expression in hypoxic human colon cancer cells. Mol Pharmacol 72:395–406.CrossRefGoogle ScholarPubMed
160. Pinhal-Enfield, G., Ramanathan, M., Hasko, G., et al. 2003. An angiogenic switch in macrophages involving synergy between Toll-like receptors 2, 4, 7, and 9 and adenosine A(2A) receptors. Am J Pathol 163: 711–721.CrossRefGoogle ScholarPubMed
161. Chan, E.S., Fernandez, P., Merchant, A.A., et al. 2006. 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.CrossRefGoogle Scholar
162. Chunn, J.L., Mohsenin, A., Young, H.W., et al. 2006. Partially adenosine deaminase-deficient mice develop pulmonary fibrosis in association with adenosine elevations. Am J Physiol Lung Cell Mol Physiol 290:L579–L587.CrossRefGoogle ScholarPubMed
163. Chen, Y., Epperson, S., Makhsudova, L., et al. 2004. Functional effects of enhancing or silencing adenosine A2b receptors in cardiac fibroblasts. Am J Physiol Heart Circ Physiol 287:H2478–H2486.CrossRefGoogle ScholarPubMed
Khoa, N.D., Montesinos, C.M., Williams, A.J., Kelly, M., and Cronstein, B.N. 2003. Th1 cytokines regulate adenosine receptors and their downstream signalling elements in human microvascular endothelial cells. J Immunol 171:3991–3998.CrossRefGoogle Scholar
Lappas, C.M., Day, Y.J., Marshall, M.A., Engelhard, V.H., and Linden, J. 2006. Adenosine A2A receptor activation reduces hepatic ischemia reperfusion injury by inhibiting CD1d-dependent NKT cell activation. J Exp Med 203:2639–2648.CrossRefGoogle ScholarPubMed
Nemeth, Z.H., Lutz, C.S., Csoka, B., et al. 2005. Adenosine augments IL-10 production by macrophages through an A2B receptor-mediated posttranscriptional mechanism. J Immunol 175:8260–8270.CrossRefGoogle ScholarPubMed

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