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  • Review Article
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Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases

Nature Reviews Rheumatology volume 13, pages 41–51 (2017)Cite this article

Subjects

Key Points

  • Adenosine, generated from the extracellular hydrolysis of ATP, is a potent endogenous regulator of inflammation and immune reactions via interaction with one or more cell surface receptors

  • The principal adenosine receptor involved in regulation of adaptive T cell responses is A2a

  • A2a, A2b and A3 downregulate macrophage-mediated inflammatory actions, although A2b might indirectly stimulate type 17 T helper cell immune responses via increased IL-6 production

  • Adenosine mediates the anti-inflammatory effects of low-dose methotrexate treatment as well as some of the anti-inflammatory effects of sulfasalazine

Abstract

Adenosine, a nucleoside derived primarily from the extracellular hydrolysis of adenine nucleotides, is a potent regulator of inflammation. Adenosine mediates its effects on inflammatory cells by engaging one or more cell-surface receptors. The expression and function of adenosine receptors on different cell types change during the course of rheumatic diseases, such as rheumatoid arthritis (RA). Targeting adenosine receptors directly for the treatment of rheumatic diseases is currently under study; however, indirect targeting of adenosine receptors by enhancing adenosine levels at inflamed sites accounts for most of the anti-inflammatory effects of methotrexate, the anchor drug for the treatment of RA. In this Review, we discuss the regulation of extracellular adenosine levels and the role of adenosine in regulating the inflammatory and immune responses in rheumatic diseases such as RA, psoriasis and other types of inflammatory arthritis. In addition, adenosine and its receptors are involved in promoting fibrous matrix production in the skin and other organs, and the role of adenosine in fibrosis and fibrosing diseases is also discussed.

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Figure 1: Cellular adenosine production in response to hypoxia and medications.
Figure 2: Adenosine receptors.

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References

  1. Drury, A. N. & Szent-Gyorgi, A. The physiological activity of adenine compounds with special reference to their action upon the mammalian heart. J. Physiol. 68, 213–237 (1929).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sattin, A. & Rall, T. W. The effect of adenosine and adenine nucleotides on the cyclic adenosine 3′,5′-phosphate content of guinea pig cerebral cortex slices. Mol. Pharmacol. 6, 13–23 (1970).

    CAS  PubMed  Google Scholar 

  3. Fredholm, B. B. et al. International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors — an update. Pharmacol. Rev. 63, 1–34 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Newby, A. C., Holmquist, C. A., Illingworth, J. & Pearson, J. D. The control of adenosine concentration in polymorphonuclear leucocytes, cultured heart cells and isolated perfused heart from the rat. Biochem. J. 214, 317–323 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Beyer, E. C. & Steinberg, T. H. Evidence that the gap junction protein connexin-43 is the ATP-induced pore of mouse macrophages. J. Biol. Chem. 266, 7971–7974 (1991).

    CAS  PubMed  Google Scholar 

  6. Rosenthal, A. K. et al. The progressive ankylosis gene product ANK regulates extracellular ATP levels in primary articular chondrocytes. Arthritis Res. Ther. 15, R154 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bao, L., Locovei, S. & Dahl, G. Pannexin membrane channels are mechanosensitive conduits for ATP. FEBS Lett. 572, 65–68 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Iglesias, R. et al. P2X7 receptor–Pannexin1 complex: pharmacology and signaling. Am. J. Physiol. Cell Physiol. 295, C752–C760 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Baldwin, S. A. et al. The equilibrative nucleoside transporter family, SLC29. Pflügers Arch. 447, 735–743 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Dahl, G. & Muller, K. J. Innexin and pannexin channels and their signaling. FEBS Lett. 588, 1396–1402 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Adamson, S. E. & Leitinger, N. The role of pannexin1 in the induction and resolution of inflammation. FEBS Lett. 588, 1416–1422 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Alberto, A. V. et al. Is pannexin the pore associated with the P2X7 receptor? Naunyn Schmiedebergs Arch. Pharmacol. 386, 775–787 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Ambrosi, C. et al. Pannexin1 and Pannexin2 channels show quaternary similarities to connexons and different oligomerization numbers from each other. J. Biol. Chem. 285, 24420–24431 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Anselmi, F. et al. ATP release through connexin hemichannels and gap junction transfer of second messengers propagate Ca2+ signals across the inner ear. Proc. Natl Acad. Sci. USA 105, 18770–18775 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Beckel, J. M. et al. Mechanosensitive release of adenosine 5′-triphosphate through pannexin channels and mechanosensitive upregulation of pannexin channels in optic nerve head astrocytes: a mechanism for purinergic involvement in chronic strain. Glia 62, 1486–1501 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Iwamoto, T. et al. Pannexin 3 regulates intracellular ATP/cAMP levels and promotes chondrocyte differentiation. J. Biol. Chem. 285, 18948–18958 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Levick, J. R. Hypoxia and acidosis in chronic inflammatory arthritis; relation to vascular supply and dynamic effusion pressure. J. Rheumatol. 17, 579–582 (1990).

    CAS  PubMed  Google Scholar 

  18. Geborek, P., Forslind, K. & Wollheim, F. A. Direct assessment of synovial blood flow and its relation to induced hydrostatic pressure changes. Ann. Rheum. Dis. 48, 281–286 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kofoed, H. Synovitis causes hypoxia and acidity in synovial fluid and subchondral bone. Injury 17, 391–394 (1986).

    Article  CAS  PubMed  Google Scholar 

  20. Grenz, A., Homann, D. & Eltzschig, H. K. Extracellular adenosine: a safety signal that dampens hypoxia-induced inflammation during ischemia. Antioxid. Redox Signal. 15, 2221–2234 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fearon, U., Canavan, M., Biniecka, M. & Veale, D. J. Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis. Nat. Rev. Rheumatol. 12, 385–397 (2016).

    Article  CAS  PubMed  Google Scholar 

  22. Borea, P. A. et al. The A3 adenosine receptor: history and perspectives. Pharmacol. Rev. 67, 74–102 (2015).

    Article  CAS  PubMed  Google Scholar 

  23. Fredholm, B. B. et al. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol. Rev. 53, 527–552 (2001).

    CAS  PubMed  Google Scholar 

  24. Khoa, N. D., Montesinos, C. M., Williams, A. J., Kelly, M. & Cronstein, B. N. Th1 cytokines regulate adenosine receptors and their downstream signalling elements in human microvascular endothelial cells. J. Immunol. 171, 3991–3998 (2003).

    Article  CAS  Google Scholar 

  25. 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).

    Article  CAS  PubMed  Google Scholar 

  26. Bshesh, K. et al. The A2A receptor mediates an endogenous regulatory pathway of cytokine expression in THP-1 cells. J. Leukoc. Biol. 72, 1027–1036 (2002).

    CAS  PubMed  Google Scholar 

  27. Sun, W. C. et al. Lipopolysaccharide and TNF-α modify adenosine A2A receptor expression and function in equine monocytes. Vet. Immunol. Immunopathol. 135, 289–295 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Napieralski, R., Kempkes, B. & Gutensohn, W. Evidence for coordinated induction and repression of ecto-5′-nucleotidase (CD73) and the A2a adenosine receptor in a human B cell line. Biol. Chem. 384, 483–487 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Varani, K. et al. Normalization of A2A and A3 adenosine receptor up-regulation in rheumatoid arthritis patients by treatment with anti-tumor necrosis factor α but not methotrexate. Arthritis Rheum. 60, 2880–2891 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Vincenzi, F. et al. A2A adenosine receptors are differentially modulated by pharmacological treatments in rheumatoid arthritis patients and their stimulation ameliorates adjuvant-induced arthritis in rats. PLoS ONE 8, e54195 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Khoa, N. D., Postow, M., Danielsson, J. & Cronstein, B. N. Tumor necrosis factor-α prevents desensitization of GαS-coupled receptors by regulating GRK2 association with the plasma membrane. Mol. Pharmacol. 69, 1311–1319 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Nguyen, D. K., Montesinos, M. C., Williams, A. J., Kelly, M. & Cronstein, B. N. Th1 cytokines regulate adenosine receptors and their downstream signaling elements in human microvascular endothelial cells. J. Immunol. 171, 3991–3998 (2003).

    Article  PubMed  Google Scholar 

  33. Block, E. T. & Cronstein, B. N. Interferon-gamma inhibits adenosine A2A receptor function in hepatic stellate cells by STAT1-mediated repression of adenylyl cyclase. Int. J. Interferon Cytokine Mediat. Res. 2010, 113–126 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fishman, P. & Cohen, S. The A3 adenosine receptor (A3AR): therapeutic target and predictive biological marker in rheumatoid arthritis. Clin. Rheumatol. 35, 2359–2362 (2016).

    Article  PubMed  Google Scholar 

  35. Ochaion, A. et al. The anti-inflammatory target A3 adenosine receptor is over-expressed in rheumatoid arthritis, psoriasis and Crohn's disease. Cell. Immunol. 258, 115–122 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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).

    Article  CAS  PubMed  Google Scholar 

  38. 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).

    CAS  PubMed  Google Scholar 

  39. Marone, G., Petracca, R. & Vigorita, S. Adenosine receptors on human inflammatory cells. Int. Arch. Allergy Appl. Immunol. 77, 259–263 (1985).

    Article  CAS  PubMed  Google Scholar 

  40. Pasini, F. L., Capecchi, P. L., Orrico, A., Ceccatelli, L. & DiPierri, T. Adenosine inhibits polymorphonuclear leukocyte in vitro activation: a possible role as an endogenous calcium entry blocker. J. Immunopharmacol. 7, 203–215 (1985).

    Article  CAS  PubMed  Google Scholar 

  41. Roberts, P. A., Morgan, B. P. & Campbell, A. K. 2-chloroadenosine inhibits complement-induced reactive oxygen metabolite production and recovery of human polymorphonuclear leukocytes attacked by complement. Biochem. Biophys. Res. Commun. 126, 692–697 (1985).

    Article  CAS  PubMed  Google Scholar 

  42. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gurden, M. F. et al. Functional characterization of three adenosine receptor types. Br. J. Pharmacol. 109, 693–698 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Fredholm, B. B., Zhang, Y. & van der Ploeg, I. Adenosine A2A receptors mediate the inhibitory effect of adenosine on formyl-Met-Leu-Phe-stimulated respiratory burst in neutrophil leucocytes. Naunyn Schmiedebergs Arch. Pharmacol. 354, 262–267 (1996).

    Article  CAS  PubMed  Google Scholar 

  45. Thiel, M. et al. Effects of adenosine on the functions of circulating polymorphonuclear leukocytes during hyperdynamic endotoxemia. Infect. Immun. 65, 2136–2144 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Bullough, D. A., Magill, M. J., Mullane, K. M. & Firestein, G. S. Carbohydrate- and CD18-dependent neutrophil adhesion to cardiac myocytes: effects of adenosine. Cardiovasc. Res. 32, 328–334 (1996).

    Article  CAS  PubMed  Google Scholar 

  47. Firestein, G. S. et al. Inhibition of neutrophil adhesion by adenosine and an adenosine kinase inhibitor. The role of selectins. J. Immunol. 154, 326–334 (1995).

    CAS  PubMed  Google Scholar 

  48. 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).

    CAS  PubMed  Google Scholar 

  49. Cronstein, B. N., Levin, R. I., Belanoff, J., Weissmann, G. & Hirschhorn, R. Adenosine: an endogenous inhibitor of neutrophil-mediated injury to endothelial cells. J. Clin. Invest. 78, 760–770 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Rose, F. R., Hirschhorn, R., Weissmann, G. & Cronstein, B. N. Adenosine promotes neutrophil chemotaxis. J. Exp. Med. 167, 1186–1194 (1988).

    Article  CAS  PubMed  Google Scholar 

  51. Inoue, Y., Chen, Y., Hirsh, M. I., Yip, L. & Junger, W. G. A3 and P2Y2 receptors control the recruitment of neutrophils to the lungs in a mouse model of sepsis. Shock 30, 173–177 (2008).

    PubMed  PubMed Central  Google Scholar 

  52. Chen, Y. et al. ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314, 1792–1795 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Duro, E., Pallai, A., Koroskenyi, K., Sarang, Z. & Szondy, Z. Adenosine A3 receptors negatively regulate the engulfment-dependent apoptotic cell suppression of inflammation. Immunol. Lett. 162, 292–301 (2014).

    Article  CAS  PubMed  Google Scholar 

  54. Koroskenyi, K. et al. Involvement of adenosine A2A receptors in engulfment-dependent apoptotic cell suppression of inflammation. J. Immunol. 186, 7144–7155 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. Smail, E. H. et al. In vitro, Candida albicans releases the immune modulator adenosine and a second, high-molecular weight agent that blocks neutrophil killing. J. Immunol. 148, 3588–3595 (1992).

    CAS  PubMed  Google Scholar 

  56. Thammavongsa, V., Kern, J. W., Missiakas, D. M. & Schneewind, O. Staphylococcus aureus synthesizes adenosine to escape host immune responses. J. Exp. Med. 206, 2417–2427 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Liu, P. et al. Streptococcus suis adenosine synthase functions as an effector in evasion of PMN-mediated innate immunit. J. Infect. Dis. 210, 35–45 (2014).

    Article  CAS  PubMed  Google Scholar 

  58. Sica, A., Erreni, M., Allavena, P. & Porta, C. Macrophage polarization in pathology. Cell. Mol. Life Sci. 72, 4111–4126 (2015).

    Article  CAS  PubMed  Google Scholar 

  59. Laria, A. et al. The macrophages in rheumatic diseases. J. Inflamm. Res. 9, 1–11 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Csoka, B. et al. A2A adenosine receptors and C/EBPβ are crucially required for IL-10 production by macrophages exposed to Escherichia coli. Blood 110, 2685–2695 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ferrante, C. J. et al. The adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of interleukin-4 receptor alpha (IL-4Rα) signaling. Inflammation 36, 921–931 (2013).

    Article  CAS  PubMed  Google Scholar 

  62. Grinberg, S., Hasko, G., Wu, D. & Leibovich, S. J. Suppression of PLCβ2 by endotoxin plays a role in the adenosine A2A receptor-mediated switch of macrophages from an inflammatory to an angiogenic phenotype. Am. J. Pathol. 175, 2439–2453 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Hasko, G. et al. Adenosine inhibits IL-12 and TNF-α production via adenosine A2a receptor-dependent and independent mechanisms. FASEB J. 14, 2065–2074 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Hasko, G. et al. Adenosine receptor agonists differentially regulate IL-10, TNF-α, and nitric oxide production in RAW 264.7 macrophages and in endotoxemic mice. J. Immunol. 157, 4634–4640 (1996).

    CAS  PubMed  Google Scholar 

  65. 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).

    Article  CAS  PubMed  Google Scholar 

  66. 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).

    Article  CAS  PubMed  Google Scholar 

  67. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ramanathan, M. et al. Differential regulation of HIF-1α isoforms in murine macrophages by TLR4 and adenosine A2A receptor agonists. J. Leukoc. Biol. 86, 681–689 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Szabo, C. et al. Suppression of macrophage inflammatory protein (MIP)-1αproduction and collagen-induced arthritis by adenosine receptor agonists. Br. J. Pharmacol. 125, 379–387 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Leibovich, S. et al. Synergistic up-regulation of vascular endothelial growth factor expression in murine macrophages by adenosine A2A receptor agonists and endotoxin. Am. J. Path. 160, 2231–2244 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Williams, A. J. & Cronstein, B. N. The effect of A2A adenosine receptor activation on C-C chemokine receptor 7 expression in human THP1 macrophages during inflammation. Inflammation 35, 614–622 (2011).

    Article  CAS  Google Scholar 

  72. Crean, D. et al. Adenosine modulates NR4A orphan nuclear receptors to attenuate hyperinflammatory responses in monocytic cells. J. Immunol. 195, 1436–1448 (2015).

    Article  CAS  PubMed  Google Scholar 

  73. Murphy, E. P. & Crean, D. Molecular interactions between NR4A orphan nuclear receptors and NF-κB are required for appropriate inflammatory responses and immune cell homeostasis. Biomolecules 5, 1302–1318 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Tian, Y., Piras, B. A., Kron, I. L., French, B. A. & Yang, Z. Adenosine 2B receptor activation reduces myocardial reperfusion injury by promoting anti-inflammatory macrophages differentiation via PI3K/Akt pathway. Oxid. Med. Cell. Longev. 2015, 585297 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Sciaraffia, E. et al. Human monocytes respond to extracellular cAMP through A2A and A2B adenosine receptors. J. Leukoc. Biol. 96, 113–122 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Koscso, B. et al. Adenosine augments IL-10-induced STAT3 signaling in M2c macrophages. J. Leukoc. Biol. 94, 1309–1315 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Lee, H. S., Chung, H. J., Lee, H. W., Jeong, L. S. & Lee, S. K. Suppression of inflammation response by a novel A3 adenosine receptor agonist thio-Cl-IB-MECA through inhibition of Akt and NF-κB signaling. Immunobiology 216, 997–1003 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Ramakers, B. P. et al. The effect of adenosine receptor agonists on cytokine release by human mononuclear cells depends on the specific Toll-like receptor subtype used for stimulation. Cytokine 35, 95–99 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Levy, O. et al. The adenosine system selectively inhibits TLR-mediated TNF-α production in the human newborn. J. Immunol. 177, 1956–1966 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Mabley, J. et al. The adenosine A3 receptor agonist, N6-(3-iodobenzyl)-adenosine-5′-N-methyluronamide, is protective in two murine models of colitis. Eur. J. Pharmacol. 466, 323–329 (2003).

    Article  CAS  PubMed  Google Scholar 

  81. Knight, D. et al. Adenosine A3 receptor stimulation inhibits migration of human eosinophils. J. Leukoc. Biol. 62, 465–468 (1997).

    Article  CAS  PubMed  Google Scholar 

  82. Bowlin, T. L., Borcherding, D. R., Edwards, C. K. 3rd & McWhinney, C. D. Adenosine A3 receptor agonists inhibit murine macrophage tumor necrosis factor-alpha production in vitro and in vivo. Cell. Mol. Biol. (Noisy-le-Grand) 43, 345–349 (1997).

    CAS  Google Scholar 

  83. McWhinney, C. D. et al. Activation of adenosine A3 receptors on macrophages inhibits tumor necrosis factor-α. Eur. J. Pharmacol. 310, 209–216 (1996).

    Article  CAS  PubMed  Google Scholar 

  84. Sajjadi, F. G., Takabayashi, K., Foster, A. C., Domingo, R. C. & Firestein, G. S. Inhibition of TNF-alpha expression by adenosine: role of A3 adenosine receptors. J. Immunol. 156, 3435–3442 (1996).

    CAS  PubMed  Google Scholar 

  85. Hasko, G., Csoka, B., Nemeth, Z. H., Vizi, E. S. & Pacher, P. A2B adenosine receptors in immunity and inflammation. Trends Immunol. 30, 263–270 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wilson, J. M. et al. The A2B adenosine receptor promotes Th17 differentiation via stimulation of dendritic cell IL-6. J. Immunol. 186, 6746–6752 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. Liang, D. et al. A2B adenosine receptor activation switches differentiation of bone marrow cells to a CD11c+Gr-1+ dendritic cell subset that promotes the Th17 response. Immun. Inflamm. Dis. 3, 360–373 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Teramachi, J. et al. Adenosine abolishes MTX-induced suppression of osteoclastogenesis and inflammatory bone destruction in adjuvant-induced arthritis. Lab. Invest. 91, 719–731 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Merrill, J. T. et al. Adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes: a mechanism for methotrexate-induced nodulosis in rheumatoid arthritis. Arthritis Rheum. 40, 1308–1315 (1997).

    CAS  PubMed  Google Scholar 

  90. Kara, F. M. et al. Adenosine A1 receptors (A1Rs) play a critical role in osteoclast formation and function. FASEB J. 24, 2325–2333 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. He, W. & Cronstein, B. N. Adenosine A1 receptor regulates osteoclast formation by altering TRAF6/TAK1 signaling. Purinergic Signal. 8, 327–337 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. He, W., Mazumder, A., Wilder, T. & Cronstein, B. N. Adenosine regulates bone metabolism via A1, A2A, and A2B receptors in bone marrow cells from normal humans and patients with multiple myeloma. FASEB J. 27, 3446–3454 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Mediero, A., Kara, F. M., Wilder, T. & Cronstein, B. N. Adenosine A2A receptor ligation inhibits osteoclast formation. Am. J. Pathol. 180, 775–786 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Corciulo, C., Wilder, T. & Cronstein, B. N. Adenosine A2B receptors play an important role in bone homeostasis. Purinergic Signal. 12, 537–547 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Mediero, A., Frenkel, S., Wilder, T. & Cronstein, B. N. Activation of adenosine A2A receptors prevents wear particle-induced osteolysis [abstract]. Arthritis Rheum. 63 (Suppl. 10), 1781 (2011).

    Google Scholar 

  96. Mediero, A., Wilder, T., Perez-Aso, M. & Cronstein, B. N. Direct or indirect stimulation of adenosine A2A receptors enhances bone regeneration as well as bone morphogenetic protein-2. FASEB J. 29, 1577–1590 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Carroll, S. H. et al. A2B adenosine receptor promotes mesenchymal stem cell differentiation to osteoblasts and bone formation in vivo. J. Biol. Chem. 287, 15718–15727 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Strazzulla, L. C. & Cronstein, B. N. Regulation of bone and cartilage by adenosine signaling. Purinergic Signal. http://dx.doi.org/10.1007/s11302-016-9527-2 (2016).

  99. Ohta, A. & Sitkovsky, M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414, 916–920 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Ohta, A. et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc. Natl Acad. Sci. USA 103, 13132–13137 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Huang, S., Apasov, S., Koshiba, M. & Sitkovsky, M. Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood 90, 1600–1610 (1997).

    CAS  PubMed  Google Scholar 

  102. 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).

    Article  CAS  PubMed  Google Scholar 

  103. Lappas, C. M., Rieger, J. M. & Linden, J. A2A adenosine receptor induction inhibits IFN-γ production in murine CD4+ T cells. J. Immunol. 174, 1073–1080 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Lukashev, D., Ohta, A., Apasov, S., Chen, J. F. & Sitkovsky, M. Cutting edge: physiologic attenuation of proinflammatory transcription by the GS protein-coupled A2A adenosine receptor in vivo. J. Immunol. 173, 21–24 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Armstrong, J. M. et al. Gene dose effect reveals no Gs-coupled A2A adenosine receptor reserve in murine T-lymphocytes: studies of cells from A2A-receptor-gene-deficient mice. Biochem. J. 354, 123–130 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Hillger, J. M. et al. Getting personal: endogenous adenosine receptor signaling in lymphoblastoid cell lines. Biochem. Pharmacol. 115, 114–122 (2016).

    Article  CAS  PubMed  Google Scholar 

  107. Koshiba, M., Rosin, D. L., Hayashi, N., Linden, J. & Sitkovsky, M. V. Patterns of A2A extracellular adenosine receptor expression in different functional subsets of human peripheral T cells. Flow cytometry studies with anti-A2A receptor monoclonal antibodies. Mol. Pharmacol. 55, 614–624 (1999).

    CAS  PubMed  Google Scholar 

  108. Csoka, B. et al. Adenosine A2A receptor activation inhibits T helper 1 and T helper 2 cell development and effector function. FASEB J. 22, 3491–3499 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Alam, M. S. et al. A2A adenosine receptor (AR) activation inhibits pro-inflammatory cytokine production by human CD4+ helper T cells and regulates Helicobacter-induced gastritis and bacterial persistence. Mucosal Immunol. 2, 232–242 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Himer, L. et al. Adenosine A2A receptor activation protects CD4+ T lymphocytes against activation-induced cell death. FASEB J. 24, 2631–2640 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Cekic, C., Sag, D., Day, Y. J. & Linden, J. Extracellular adenosine regulates naive T cell development and peripheral maintenance. J. Exp. Med. 210, 2693–2706 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Apasov, S., Chen, J. F., Smith, P. & Sitkovsky, M. A2A receptor dependent and A2A receptor independent effects of extracellular adenosine on murine thymocytes in conditions of adenosine deaminase deficiency. Blood 95, 3859–3867 (2000).

    CAS  PubMed  Google Scholar 

  113. Takayama, H., Trenn, G. & Sitkovsky, M. V. Locus of inhibitory action of cAMP-dependent protein kinase in the antigen receptor-triggered cytotoxic T lymphocyte activation pathway. J. Biol. Chem. 263, 2330–2336 (1988).

    CAS  PubMed  Google Scholar 

  114. Sitkovsky, M. V., Trenn, G. & Takayama, H. Cyclic AMP-dependent protein kinase as a part of the possible down-regulating pathway in the antigen receptor-regulated cytotoxic T lymphocyte conjugate formation and granule exocytosis. Ann. NY Acad. Sci. 532, 350–358 (1988).

    Article  CAS  PubMed  Google Scholar 

  115. Sitkovsky, M. V. T regulatory cells: hypoxia-adenosinergic suppression and re-direction of the immune response. Trends Immunol. 30, 102–108 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Hatfield, S., Belikoff, B., Lukashev, D., Sitkovsky, M. & Ohta, A. The antihypoxia-adenosinergic pathogenesis as a result of collateral damage by overactive immune cells. J. Leukoc. Biol. 86, 545–548 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Chen, M. et al. An A2B adenosine receptor agonist promotes Th17 autoimmune responses in experimental autoimmune uveitis (EAU) via dendritic cell activation. PLoS ONE 10, e0132348 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ehrentraut, H., Westrich, J. A., Eltzschig, H. K. & Clambey, E. T. Adora2b adenosine receptor engagement enhances regulatory T cell abundance during endotoxin-induced pulmonary inflammation. PLoS ONE 7, e32416 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Cohen, M. V., Yang, X. & Downey, J. M. A2b adenosine receptors can change their spots. Br. J. Pharmacol. 159, 1595–1597 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Gessi, S. et al. Pharmacological and biochemical characterization of A3 adenosine receptors in Jurkat T cells. Br. J. Pharmacol. 134, 116–126 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Feoktistov, I., Biaggioni, I. & Cronstein, B. N. Adenosine receptors in wound healing, fibrosis and angiogenesis. Handb. Exp. Pharmacol. 193, 383–397 (2009).

    Article  CAS  Google Scholar 

  122. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Hassanian, S. M., Dinarvand, P. & Rezaie, A. R. Adenosine regulates the proinflammatory signaling function of thrombin in endothelial cells. J. Cell. Physiol. 229, 1292–1300 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Eckle, T., Grenz, A., Laucher, S. & Eltzschig, H. K. A2B adenosine receptor signaling attenuates acute lung injury by enhancing alveolar fluid clearance in mice. J. Clin. Invest. 118, 3301–3315 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Shaikh, G. & Cronstein, B. Signaling pathways involving adenosine A2A and A2B receptors in wound healing and fibrosis. Purinergic Signal. 12, 191–197 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Cronstein, B. N. Adenosine receptors and fibrosis: a translational review. F1000 Biol. Rep. 3, 21 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  127. 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).

    Article  CAS  PubMed  Google Scholar 

  128. Fernandez, P. et al. Pharmacological blockade of A2A receptors prevents dermal fibrosis in a model of elevated tissue adenosine. Am. J. Pathol. 172, 1675–1682 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Katebi, M., Fernandez, P., Chan, E. S. & Cronstein, B. N. Adenosine A2A receptor blockade or deletion diminishes fibrocyte accumulation in the skin in a murine model of scleroderma, bleomycin-induced fibrosis. Inflammation 31, 299–303 (2008).

    Article  CAS  PubMed  Google Scholar 

  130. Perez-Aso, M., Chiriboga, L. & Cronstein, B. N. Pharmacological blockade of adenosine A2A receptors diminishes scarring. FASEB J. 26, 4254–4263 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Blackburn, M. R. et al. Adenosine mediates IL-13-induced inflammation and remodeling in the lung and interacts in an IL-13-adenosine amplification pathway. J. Clin. Invest. 112, 332–344 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. 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).

    Article  CAS  PubMed  Google Scholar 

  133. Chunn, J. L. et al. Adenosine-dependent pulmonary fibrosis in adenosine deaminase-deficient mice. J. Immunol. 175, 1937–1946 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Ma, B. et al. Adenosine metabolism and murine strain-specific IL-4-induced inflammation, emphysema, and fibrosis. J. Clin. Invest. 116, 1274–1283 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Schneider, D. J., Lindsay, J. C., Zhou, Y., Molina, J. G. & Blackburn, M. R. Adenosine and osteopontin contribute to the development of chronic obstructive pulmonary disease. FASEB J. 24, 70–80 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Zhou, Y., Murthy, J. N., Zeng, D., Belardinelli, L. & Blackburn, M. R. Alterations in adenosine metabolism and signaling in patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. PLoS ONE 5, e9224 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Zhou, Y. et al. Distinct roles for the A2B adenosine receptor in acute and chronic stages of bleomycin-induced lung injury. J. Immunol. 186, 1097–1106 (2011).

    Article  CAS  PubMed  Google Scholar 

  139. Chan, E. S. et al. Adenosine A2A receptors play a role in the pathogenesis of hepatic cirrhosis. Br. J. Pharmacol. 148, 1144–1155 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Peng, Z. et al. Ecto-5′-nucleotidase (CD73) -mediated extracellular adenosine production plays a critical role in hepatic fibrosis. FASEB J. 22, 2263–2272 (2008).

    Article  CAS  PubMed  Google Scholar 

  141. Robson, S. C. & Schuppan, D. Adenosine: tipping the balance towards hepatic steatosis and fibrosis. J. Hepatol. 52, 941–943 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Corrao, G. et al. The effect of drinking coffee and smoking cigarettes on the risk of cirrhosis associated with alcohol consumption. A case–control study. Provincial group for the study of chronic liver disease. Eur. J. Epidemiol. 10, 657–664 (1994).

    Article  CAS  PubMed  Google Scholar 

  143. Corrao, G., Zambon, A., Bagnardi, V., D'Amicis, A. & Klatsky, A. Coffee, caffeine, and the risk of liver cirrhosis. Ann. Epidemiol. 11, 458–465 (2001).

    Article  CAS  PubMed  Google Scholar 

  144. Klatsky, A. L. & Armstrong, M. A. Alcohol, smoking, coffee, and cirrhosis. Am. J. Epidemiol. 136, 1248–1257 (1992).

    Article  CAS  PubMed  Google Scholar 

  145. Tverdal, A. & Skurtveit, S. Coffee intake and mortality from liver cirrhosis. Ann. Epidemiol. 13, 419–423 (2003).

    Article  PubMed  Google Scholar 

  146. Ferrari, D. et al. Purinergic signaling in scarring. FASEB J. 30, 3–12 (2016).

    Article  CAS  PubMed  Google Scholar 

  147. Nakav, S. et al. Blocking adenosine A2A receptor reduces peritoneal fibrosis in two independent experimental models. Nephrol. Dial. Transplant. 24, 2392–2399 (2009).

    Article  CAS  PubMed  Google Scholar 

  148. Mi, T. et al. Excess adenosine in murine penile erectile tissues contributes to priapism via A2B adenosine receptor signaling. J. Clin. Invest. 118, 1491–1501 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Wen, J. et al. Increased adenosine contributes to penile fibrosis, a dangerous feature of priapism, via A2B adenosine receptor signaling. FASEB J. 24, 740–749 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Berne, R. M. & Belardinelli, L. Effects of hypoxia and ischaemia on coronary vascular resistance, A-V node conduction and S-A node excitation. Acta Med. Scand. Suppl. 694, 9–19 (1985).

    CAS  PubMed  Google Scholar 

  151. Morote-Garcia, J. C., Rosenberger, P., Kuhlicke, J. & Eltzschig, H. K. HIF-1-dependent repression of adenosine kinase attenuates hypoxia-induced vascular leak. Blood 111, 5571–5580 (2008).

    Article  CAS  PubMed  Google Scholar 

  152. Waidmann, O. et al. Inhibition of the equilibrative nucleoside transporter 1 and activation of A2A adenosine receptors by 8-(4-chlorophenylthio)-modified cAMP analogs and their hydrolytic products. J. Biol. Chem. 284, 32256–32263 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Nagy, L. E., Diamond, I., Casso, D. J., Franklin, C. & Gordon, A. S. Ethanol increases extracellular adenosine by inhibiting adenosine uptake via the nucleoside transporter. J. Biol. Chem. 265, 1946–1951 (1990).

    CAS  PubMed  Google Scholar 

  154. Rothschild, B. M. & Masi, A. T. Pathogenesis of rheumatoid arthritis: a vascular hypothesis. Semin. Arthritis Rheum. 12, 11–31 (1982).

    Article  CAS  PubMed  Google Scholar 

  155. Richman, A. I., Su, E. Y. & Ho, G. Jr. Reciprocal relationship of synovial fluid volume and oxygen tension. Arthritis Rheum. 24, 701–705 (1981).

    Article  CAS  PubMed  Google Scholar 

  156. Zamani, B., Jamali, R. & Ehteram, H. Synovial fluid adenosine deaminase and high-sensitivity C-reactive protein activity in differentiating monoarthritis. Rheumatol. Int. 32, 183–188 (2012).

    Article  CAS  PubMed  Google Scholar 

  157. Huang, L. F., Guo, F. Q., Liang, Y. Z., Li, B. Y. & Cheng, B. M. Simple and rapid determination of adenosine in human synovial fluid with high performance liquid chromatography-mass spectrometry. J. Pharm. Biomed. Anal. 36, 877–882 (2004).

    Article  CAS  PubMed  Google Scholar 

  158. Ottonello, L. et al. Synovial fluid from patients with rheumatoid arthritis inhibits neutrophil apoptosis: role of adenosine and proinflammatory cytokines. Rheumatology 41, 1249–1260 (2002).

    Article  CAS  PubMed  Google Scholar 

  159. Cattaneo, M., Schulz, R. & Nylander, S. Adenosine-mediated effects of ticagrelor: evidence and potential clinical relevance. J. Am. Coll. Cardiol. 63, 2503–2509 (2014).

    Article  CAS  PubMed  Google Scholar 

  160. Armstrong, D. et al. Characterization of the adenosine pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside transporter 1. J. Cardiovasc. Pharmacol. Ther. 19, 209–219 (2014).

    Article  CAS  PubMed  Google Scholar 

  161. Nagy, L. E. et al. Adenosine is required for ethanol-induced heterologous desensitization. Mol. Pharmacol. 36, 744–748 (1989).

    CAS  PubMed  Google Scholar 

  162. Gordon, A. S., Nagy, L., Mochly-Rosen, D. & Diamond, I. Chronic ethanol-induced heterologous desensitization is mediated by changes in adenosine transport. Biochem. Soc. Symp. 56, 117–136 (1990).

    CAS  PubMed  Google Scholar 

  163. Diamond, I., Nagy, L., Mochly-Rosen, D. & Gordon, A. The role of adenosine and adenosine transport in ethanol-induced cellular tolerance and dependence. Possible biologic and genetic markers of alcoholism. Ann. NY Acad. Sci. 625, 473–487 (1991).

    Article  CAS  PubMed  Google Scholar 

  164. Peng, Z. et al. Adenosine signaling contributes to ethanol-induced fatty liver in mice. J. Clin. Invest. 119, 582–594 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Chouker, A. et al. Critical role of hypoxia and A2A adenosine receptors in liver tissue-protecting physiological anti-inflammatory pathway. Mol. Med. 14, 116–123 (2008).

    Article  CAS  PubMed  Google Scholar 

  166. Chan, E. S. & Cronstein, B. N. Methotrexate — how does it really work? Nat. Rev. Rheumatol. 6, 175–178 (2010).

    Article  CAS  PubMed  Google Scholar 

  167. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Montesinos, 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).

    Article  CAS  PubMed  Google Scholar 

  170. Nesher, G., Mates, M. & Zevin, S. Effect of caffeine consumption on efficacy of methotrexate in rheumatoid arthritis. Arthritis Rheum. 48, 571–572 (2003).

    Article  PubMed  Google Scholar 

  171. Silke, C. et al. The effects of caffeine ingestion on the efficacy of methotrexate. Rheumatology 40 (Suppl 1), 34 (2001).

    Google Scholar 

  172. Benito-Garcia, E. et al. Dietary caffeine intake does not affect methotrexate efficacy in patients with rheumatoid arthritis. J. Rheumatol. 33, 1275–1281 (2006).

    CAS  PubMed  Google Scholar 

  173. Peres, R. S. et al. Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 112, 2509–2514 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Olsen, N. J., Spurlock, C. F. III & Aune, T. M. Methotrexate induces production of IL-1 and IL-6 in the monocytic cell line U937. Arthritis Res. Ther. 16, R17 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Spurlock, C. F. III, Tossberg, J. T., Fuchs, H. A., Olsen, N. J. & Aune, T. M. Methotrexate increases expression of cell cycle checkpoint genes via JNK activation. Arthritis Rheum. 64, 1780–1789 (2012).

    Article  CAS  PubMed  Google Scholar 

  176. Spurlock, C. F. III et al. Methotrexate-mediated inhibition of nuclear factor κB activation by distinct pathways in T cells and fibroblast-like synoviocytes. Rheumatology 54, 178–187 (2015).

    Article  CAS  PubMed  Google Scholar 

  177. Lindenbaum, J. Drugs and vitamin B12 and folate metabolism. Curr. Concepts Nutr. 12, 73–87 (1983).

    CAS  PubMed  Google Scholar 

  178. Gadangi, P. et al. The anti-inflammatory mechanism of sulfasalazine is related to adenosine release at inflamed sites. J. Immunol. 156, 1937–1941 (1996).

    CAS  PubMed  Google Scholar 

  179. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Mehlman, M. A., Tobin, R. B., Madappally, M. M. & Hahn, H. K. Mode of action of aspirin. Effect of dietary aspirin on mitochondrial pyruvate metabolism in normal and thiamine-deficient rats. J. Biol. Chem. 246, 1618–1622 (1971).

    CAS  PubMed  Google Scholar 

  181. Thompkins, L. & Lee, K. H. Studies on the mechanism of action of salicylates. IV. Effect of salicylates on oxidative phosphorylation. J. Pharm. Sci. 58, 102–105 (1969).

    Article  CAS  PubMed  Google Scholar 

  182. Cronstein, B. N., Van de Stouwe, M., Druska, L., Levin, R. I. & Weissmann, G. Nonsteroidal antiinflammatory agents inhibit stimulated neutrophil adhesion to endothelium: adenosine dependent and independent mechanisms. Inflammation 18, 323–335 (1994).

    Article  CAS  PubMed  Google Scholar 

  183. Cronstein, B. N., Montesinos, M. C. & Weissmann, G. Salicylates and sulfasalazine, but not glucocorticoids, inhibit leukocyte accumulation by an adenosine-dependent mechanism that is independent of inhibition of prostaglandin synthesis and p105 of NFκB. Proc. Natl Acad. Sci. USA 96, 6377–6381 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Baharav, E. et al. Antiinflammatory effect of A3 adenosine receptor agonists in murine autoimmune arthritis models. J. Rheumatol. 32, 469–476 (2005).

    CAS  PubMed  Google Scholar 

  185. 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).

    CAS  PubMed  Google Scholar 

  186. David, M. et al. Treatment of plaque-type psoriasis with oral CF101: data from an exploratory randomized phase 2 clinical trial. J. Eur. Acad. Dermatol. Venereol. 26, 361–367 (2012).

    Article  CAS  PubMed  Google Scholar 

  187. Gubner, R., August, S. & Ginsberg, V. Therapeutic suppression of tissue reactivity. II. Effect of aminopterin in rheumatoid arthritis and psoriasis. Am. J. Med. Sci. 221, 176–182 (1951).

    Article  CAS  PubMed  Google Scholar 

  188. Weinblatt, M. E. Methotrexate in rheumatoid arthritis: a quarter century of development. Trans. Am. Clin. Climatol. Assoc. 124, 16–25 (2013).

    PubMed  PubMed Central  Google Scholar 

  189. Morgan, S. L. et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann. Internal Med. 121, 833–841 (1994).

    Article  CAS  Google Scholar 

  190. Morgan, S. L., Baggott, J. E., Koopman, W. J., Krumdieck, C. L. & Alarcon, G. S. Folate supplementation and methotrexate. Ann. Rheum. Dis. 52, 315–316 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Morgan, S. L. et al. The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 33, 9–18 (1990).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The work of B.N.C. is supported by grants from the NIH (R01 AR056672-07, R01 AR068593-02, 1UL1TR001445-02), Arthritis Foundation and Celgene. The work of M.S. is supported by a grant from the NIH (2R01 CA 111985–10).

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  1. NYU-HHC Clinical and Translational Science Institute, NYU School of Medicine, 550 First Avenue, New York, 10016, New York, USA

    Bruce N. Cronstein

  2. New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, 312 MU, Boston, 02115, Massachusetts, USA

    Michail Sitkovsky

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Correspondence to Bruce N. Cronstein.

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B.N.C. has acted as a consultant for Bristol–Myers Squibb and AstraZeneca; he has received grants from AstraZeneca, Celgene and Takeda and has equity in Can-Fite Biopharma. M.S. declares no competing interests.

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Cronstein, B., Sitkovsky, M. Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases. Nat Rev Rheumatol 13, 41–51 (2017). https://doi.org/10.1038/nrrheum.2016.178

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