登革病毒 (Dengue virus) 是屬於黃熱病毒科 (Flavivirus) 中由蚊子傳播的核糖核酸病毒，在全球主要分布在熱帶以及亞熱帶的國家。雖然大多數人受到感染後只會出現輕微的登革熱，但仍然有一小部分的病患可能發展成嚴重登革熱，而體內發炎細胞激素及趨化因子的大量上升是發展嚴重登革熱重要的風險因素之一。由三磷酸腺苷 (ATP) 代謝而來的腺苷 (Adenosine) 被證實能夠在細胞外抑制發炎反應，細胞外腺苷最主要的來源為細胞外三磷酸腺苷的代謝和細胞內腺苷的釋放，細胞在受到壓力、感染或是發炎的刺激後會釋放出細胞內的三磷酸腺苷和腺苷，釋放到細胞外的三磷酸腺苷會被細胞膜上的CD39和CD73兩個酵素代謝成腺苷。細胞外腺苷作用在腺苷接收器 (A1、A2A、A2B、A3) 進而活化訊息傳遞，其中又以腺苷A2A接收器主要負責抗發炎反應的活化。在本研究中，我們目標在調查腺苷的訊息傳遞於登革病毒感染的巨噬細胞中所扮演的角色。從實驗結果發現，在登革病毒感染後，病人血清中以及巨噬細胞外的腺苷和其下游的代謝物會增加，另外，登革病毒感染會進一步調控巨噬細胞的A2A接收器表現上升，但此現象並未在肺上皮細胞中觀察到，其他與腺苷訊息傳遞的相關蛋白，例如：細胞內的腺苷脫氨酶 (Adenosine deaminase)，在登革病毒感染後並未出現明顯的變化。接下來，我們以三種不同的藥物：腺苷、腺苷脫氨酶的抑制劑 (EHNA)、腺苷A2A接收器的拮抗劑 (SCH58261) 進一步測試腺苷的訊息傳遞於登革病毒感染巨噬細胞中發炎反應的效果。出乎意料，腺苷不但未抑制發炎反應，反而大幅促進了發炎物質：介白素-6和介白素-8的上升，而腺苷脫氨酶的抑制劑更進一步強化腺苷所誘導的發炎反應，此外，給予腺苷A2A接收器的拮抗劑則是阻斷了腺苷所誘導的發炎反應。總結而言，在本研究中我們發現腺苷的訊息傳遞於調控巨噬細胞免疫反應中鮮為人知的促發炎效果。

Dengue virus (DENV), a mosquito-borne RNA virus of the genus Flavivirus, is commonly found in tropical and sub-tropical country worldwide. Although most infected people only experience asymptomatic or mild dengue fever, a small portion of patients may develop into severe dengue. The inflammatory cytokine storm is a critical risk factor for development of severe dengue. Extracellular adenosine, the ATP metabolite, is shown to promote the anti-inflammatory responses. Extracellular adenosine primarily originates from the metabolism of extracellular ATP and release of intracellular adenosine, while intracellular ATP and adenosine will be released from cells under stress, inflammation, or infection. Extracellular ATP will be converted to adenosine by CD39 and CD73. These extracellular adenosine acts on adenosine receptors, A1, A2A, A2B, and A3, to transmit the signaling. Especially, adenosine A2A receptors are mainly responsible for anti-inflammatory effects. In this study, we investigated the role of adenosine in DENV-infected macrophages. The results showed that there was an increase in extracellular adenosine and its metabolites in serums and macrophages after DENV infection. Besides, DENV infection up-regulated the expression of adenosine A2A receptor in macrophages rather than A549 cells. However, the expression of adenosine deaminase (ADA) did not show difference after DENV infection. Furthermore, DENV-infected macrophages were treated with three drugs: adenosine, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA; adenosine deaminase inhibitor), and SCH58261 (selective adenosine A2A receptor antagonist), to explore the effects of adenosine system on the inflammatory responses. Interestingly, adenosine significantly promoted instead of suppress the production of IL-6 and IL-8 in DENV-infected macrophages. EHNA further facilitated the adenosine to induce stronger inflammatory responses, while SCH58261 diminished the pro-inflammatory effects of adenosine. These results revealed the lesser-known pro-inflammatory effects of adenosine on regulating immune responses in DENV-infected macrophages.

1. Brady, O.J., et al., Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLoS Negl Trop Dis, 2012. 6(8): p. e1760.
2. Sridhar, S., et al., Effect of Dengue Serostatus on Dengue Vaccine Safety and Efficacy. New England Journal of Medicine, 2018. 379(4): p. 327-340.
3. Bhatt, S., et al., The global distribution and burden of dengue. Nature, 2013. 496: p. 504.
4. Chang, S.C., Raising clinical awareness for better dengue fever outbreak control. J Formos Med Assoc, 2015. 114(11): p. 1025-6.
5. Wang, S.F., et al., Severe Dengue Fever Outbreak in Taiwan. Am J Trop Med Hyg, 2016. 94(1): p. 193-7.
6. Idrees, S. and U.A. Ashfaq, A brief review on dengue molecular virology, diagnosis, treatment and prevalence in Pakistan. Genet Vaccines Ther, 2012. 10(1): p. 6.
7. Luo, D., et al., Crystal structure of the NS3 protease-helicase from dengue virus. J Virol, 2008. 82(1): p. 173-83.
8. Matusan, A.E., et al., Mutagenesis of the Dengue virus type 2 NS3 protein within and outside helicase motifs: effects on enzyme activity and virus replication. J Virol, 2001. 75(20): p. 9633-43.
9. Zou, J., et al., Characterization of dengue virus NS4A and NS4B protein interaction. J Virol, 2015. 89(7): p. 3455-70.
10. Miller, S., et al., The non-structural protein 4A of dengue virus is an integral membrane protein inducing membrane alterations in a 2K-regulated manner. J Biol Chem, 2007. 282(12): p. 8873-82.
11. G Roy, S., et al., The NS4A Proteins from 4 Dengue Serotypes, Substantially Different in Sequence, Function Similarly to Induce Autophagy and Protect Mammalian Cells using ATM Pathways. Vol. 4. 2018.
12. Ackermann, M. and R. Padmanabhan, De novo synthesis of RNA by the dengue virus RNA-dependent RNA polymerase exhibits temperature dependence at the initiation but not elongation phase. J Biol Chem, 2001. 276(43): p. 39926-37.
13. Deen, J.L., et al., The WHO dengue classification and case definitions: time for a reassessment. Lancet, 2006. 368(9530): p. 170-3.
14. Organization, W.H., Dengue haemorrhagic fever: diagnosis, treatment, prevention and control. 1997.
15. Organization, W.H., et al., Dengue: guidelines for diagnosis, treatment, prevention and control. 2009: World Health Organization.
16. John, D.V., Y.-S. Lin, and G.C. Perng, Biomarkers of severe dengue disease - a review. Journal of biomedical science, 2015. 22: p. 83-83.
17. Martina, B.E.E., P. Koraka, and A.D.M.E. Osterhaus, Dengue virus pathogenesis: an integrated view. Clinical microbiology reviews, 2009. 22(4): p. 564-581.
18. Kyle, J.L., P.R. Beatty, and E. Harris, Dengue virus infects macrophages and dendritic cells in a mouse model of infection. J Infect Dis, 2007. 195(12): p. 1808-17.
19. Marchette, N.J., et al., Studies on the pathogenesis of dengue infection in monkeys. 3. Sequential distribution of virus in primary and heterologous infections. J Infect Dis, 1973. 128(1): p. 23-30.
20. Green, S. and A. Rothman, Immunopathological mechanisms in dengue and dengue hemorrhagic fever. Curr Opin Infect Dis, 2006. 19(5): p. 429-36.
21. Green, S., et al., Early CD69 expression on peripheral blood lymphocytes from children with dengue hemorrhagic fever. J Infect Dis, 1999. 180(5): p. 1429-35.
22. Palmer, D.R., et al., Differential effects of dengue virus on infected and bystander dendritic cells. J Virol, 2005. 79(4): p. 2432-9.
23. Espina, L.M., et al., Increased apoptosis and expression of tumor necrosis factor-alpha caused by infection of cultured human monocytes with dengue virus. Am J Trop Med Hyg, 2003. 68(1): p. 48-53.
24. De Carvalho Bittencourt, M., et al., Decreased peripheral dendritic cell numbers in dengue virus infection. J Clin Immunol, 2012. 32(1): p. 161-72.
25. Pichyangkul, S., et al., A blunted blood plasmacytoid dendritic cell response to an acute systemic viral infection is associated with increased disease severity. J Immunol, 2003. 171(10): p. 5571-8.
26. Huang, Y.H., et al., Dengue virus infects human endothelial cells and induces IL-6 and IL-8 production. Am J Trop Med Hyg, 2000. 63(1-2): p. 71-5.
27. Avirutnan, P., et al., Dengue virus infection of human endothelial cells leads to chemokine production, complement activation, and apoptosis. J Immunol, 1998. 161(11): p. 6338-46.
28. Murgue, B., O. Cassar, and X. Deparis, Plasma concentrations of sVCAM-1 and severity of dengue infections. J Med Virol, 2001. 65(1): p. 97-104.
29. Koraka, P., et al., Elevation of soluble VCAM-1 plasma levels in children with acute dengue virus infection of varying severity. J Med Virol, 2004. 72(3): p. 445-50.
30. Chen, H.C., et al., Both virus and tumor necrosis factor alpha are critical for endothelium damage in a mouse model of dengue virus-induced hemorrhage. J Virol, 2007. 81(11): p. 5518-26.
31. Cardier, J.E., et al., Evidence of vascular damage in dengue disease: demonstration of high levels of soluble cell adhesion molecules and circulating endothelial cells. Endothelium, 2006. 13(5): p. 335-40.
32. Beaumier, C.M., et al., Cross-reactive memory CD8(+) T cells alter the immune response to heterologous secondary dengue virus infections in mice in a sequence-specific manner. J Infect Dis, 2008. 197(4): p. 608-17.
33. Mongkolsapaya, J., et al., T cell responses in dengue hemorrhagic fever: are cross-reactive T cells suboptimal? J Immunol, 2006. 176(6): p. 3821-9.
34. Lin, C.F., et al., Endothelial cell apoptosis induced by antibodies against dengue virus nonstructural protein 1 via production of nitric oxide. J Immunol, 2002. 169(2): p. 657-64.
35. Saito, M., et al., Association of increased platelet-associated immunoglobulins with thrombocytopenia and the severity of disease in secondary dengue virus infections. Clin Exp Immunol, 2004. 138(2): p. 299-303.
36. Sun, D.S., et al., Antiplatelet autoantibodies elicited by dengue virus non-structural protein 1 cause thrombocytopenia and mortality in mice. J Thromb Haemost, 2007. 5(11): p. 2291-9.
37. Sridharan, A., et al., Inhibition of megakaryocyte development in the bone marrow underlies dengue virus-induced thrombocytopenia in humanized mice. J Virol, 2013. 87(21): p. 11648-58.
38. Clark, K.B., et al., Multiploid CD61+ cells are the pre-dominant cell lineage infected during acute dengue virus infection in bone marrow. PLoS One, 2012. 7(12): p. e52902.
39. Thomas, L., et al., Influence of the dengue serotype, previous dengue infection, and plasma viral load on clinical presentation and outcome during a dengue-2 and dengue-4 co-epidemic. Am J Trop Med Hyg, 2008. 78(6): p. 990-8.
40. Sangkawibha, N., et al., Risk factors in dengue shock syndrome: a prospective epidemiologic study in Rayong, Thailand. I. The 1980 outbreak. Am J Epidemiol, 1984. 120(5): p. 653-69.
41. Kliks, S.C., et al., Evidence that maternal dengue antibodies are important in the development of dengue hemorrhagic fever in infants. Am J Trop Med Hyg, 1988. 38(2): p. 411-9.
42. Graham, R.R., et al., A prospective seroepidemiologic study on dengue in children four to nine years of age in Yogyakarta, Indonesia I. studies in 1995-1996. Am J Trop Med Hyg, 1999. 61(3): p. 412-9.
43. Halstead, S.B., Observations related to pathogensis of dengue hemorrhagic fever. VI. Hypotheses and discussion. Yale J Biol Med, 1970. 42(5): p. 350-62.
44. Libraty, D.H., et al., Differing influences of virus burden and immune activation on disease severity in secondary dengue-3 virus infections. J Infect Dis, 2002. 185(9): p. 1213-21.
45. Simmons, C.P., et al., Maternal antibody and viral factors in the pathogenesis of dengue virus in infants. J Infect Dis, 2007. 196(3): p. 416-24.
46. Ho, L.J., et al., Infection of human dendritic cells by dengue virus activates and primes T cells towards Th0-like phenotype producing both Th1 and Th2 cytokines. Immunol Invest, 2004. 33(4): p. 423-37.
47. Azizan, A., et al., Differential proinflammatory and angiogenesis-specific cytokine production in human pulmonary endothelial cells, HPMEC-ST1.6R infected with dengue-2 and dengue-3 virus. J Virol Methods, 2006. 138(1-2): p. 211-7.
48. Medin, C.L., K.A. Fitzgerald, and A.L. Rothman, Dengue virus nonstructural protein NS5 induces interleukin-8 transcription and secretion. J Virol, 2005. 79(17): p. 11053-61.
49. Chen, Y.C. and S.Y. Wang, Activation of terminally differentiated human monocytes/macrophages by dengue virus: productive infection, hierarchical production of innate cytokines and chemokines, and the synergistic effect of lipopolysaccharide. J Virol, 2002. 76(19): p. 9877-87.
50. Boonnak, K., et al., Role of dendritic cells in antibody-dependent enhancement of dengue virus infection. J Virol, 2008. 82(8): p. 3939-51.
51. Green, S., et al., Elevated plasma interleukin‐10 levels in acute dengue correlate with disease severity. Journal of medical virology, 1999. 59(3): p. 329-334.
52. van de Weg, C.A., et al., Microbial translocation is associated with extensive immune activation in dengue virus infected patients with severe disease. PLoS Negl Trop Dis, 2013. 7(5): p. e2236.
53. Pinto, L.M., et al., Increased pro-inflammatory cytokines (TNF-alpha and IL-6) and anti-inflammatory compounds (sTNFRp55 and sTNFRp75) in Brazilian patients during exanthematic dengue fever. Mem Inst Oswaldo Cruz, 1999. 94(3): p. 387-94.
54. Mustafa, A.S., et al., Elevated levels of interleukin-13 and IL-18 in patients with dengue hemorrhagic fever. FEMS Immunol Med Microbiol, 2001. 30(3): p. 229-33.
55. Juffrie, M., et al., Inflammatory mediators in dengue virus infection in children: interleukin-8 and its relationship to neutrophil degranulation. Infect Immun, 2000. 68(2): p. 702-7.
56. Shresta, S., et al., Murine model for dengue virus-induced lethal disease with increased vascular permeability. J Virol, 2006. 80(20): p. 10208-17.
57. Zimmermann, H., Extracellular metabolism of ATP and other nucleotides. Naunyn-Schmiedeberg's archives of pharmacology, 2000. 362(4): p. 299-309.
58. Jonzon, B. and B.B. Fredholm, Release of purines, noradrenaline, and GABA from rat hippocampal slices by field stimulation. Journal of neurochemistry, 1985. 44(1): p. 217-224.
59. Deussen, A. and J. Schrader, Cardiac adenosine production is linked to myocardial pO2. Journal of molecular and cellular cardiology, 1991. 23(4): p. 495-504.
60. Spicuzza, L., G. Di Maria, and R. Polosa, Adenosine in the airways: implications and applications. Eur J Pharmacol, 2006. 533(1-3): p. 77-88.
61. Grenz, A., et al., Contribution of E-NTPDase1 (CD39) to renal protection from ischemia-reperfusion injury. Faseb j, 2007. 21(11): p. 2863-73.
62. Reutershan, J., et al., Adenosine and inflammation: CD39 and CD73 are critical mediators in LPS-induced PMN trafficking into the lungs. Faseb j, 2009. 23(2): p. 473-82.
63. Hart, M.L., et al., SP1-dependent induction of CD39 facilitates hepatic ischemic preconditioning. J Immunol, 2010. 184(7): p. 4017-24.
64. Eltzschig, H.K., et al., ATP release from activated neutrophils occurs via connexin 43 and modulates adenosine-dependent endothelial cell function. Circ Res, 2006. 99(10): p. 1100-8.
65. Eltzschig, H.K., et al., Nucleotide metabolism and cell-cell interactions. Methods Mol Biol, 2006. 341: p. 73-87.
66. Picher, M., et al., Ecto 5′-nucleotidase and nonspecific alkaline phosphatase two AMP-hydrolyzing ectoenzymes with distinct roles in human airways. Journal of Biological Chemistry, 2003. 278(15): p. 13468-13479.
67. Robson, S.C., et al. Ectonucleotidases of CD39 family modulate vascular inflammation and thrombosis in transplantation. in Seminars in thrombosis and hemostasis. 2005. Copyright© 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New ….
68. 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. The Journal of Immunology, 2006. 177(10): p. 6780-6786.
69. Rosas, M., et al., The transcription factor Gata6 links tissue macrophage phenotype and proliferative renewal. Science, 2014. 344(6184): p. 645-648.
70. Okabe, Y. and R. Medzhitov, Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell, 2014. 157(4): p. 832-844.
71. Zavialov, A.V. and A. Engstrom, Human ADA2 belongs to a new family of growth factors with adenosine deaminase activity. Biochem J, 2005. 391(Pt 1): p. 51-7.
72. Vitiello, L., et al., Immunoregulation through extracellular nucleotides. Blood, 2012. 120(3): p. 511-8.
73. Spooner, R., et al., Danger signal adenosine via adenosine 2a receptor stimulates growth of Porphyromonas gingivalis in primary gingival epithelial cells. Mol Oral Microbiol, 2014. 29(2): p. 67-78.
74. Hasko, G. and B.N. Cronstein, Adenosine: an endogenous regulator of innate immunity. Trends Immunol, 2004. 25(1): p. 33-9.
75. Linden, J., Adenosine in tissue protection and tissue regeneration. Molecular pharmacology, 2005. 67(5): p. 1385-1387.
76. Akkari, R., et al., Recent progress in the development of adenosine receptor ligands as antiinflammatory drugs. Current topics in medicinal chemistry, 2006. 6(13): p. 1375-1399.
77. Bours, M., et al., Adenosine 5′-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharmacology & therapeutics, 2006. 112(2): p. 358-404.
78. Lukashev, D., et al., Cutting edge: physiologic attenuation of proinflammatory transcription by the Gs protein-coupled A2A adenosine receptor in vivo. The Journal of Immunology, 2004. 173(1): p. 21-24.
79. Cronstein, B.N., Adenosine, an endogenous anti-inflammatory agent. Journal of applied Physiology, 1994. 76(1): p. 5-13.
80. Fredholm, B.B., Purines and neutrophil leukocytes. General Pharmacology: The Vascular System, 1997. 28(3): p. 345-350.
81. Ohta, A. and M. Sitkovsky, Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature, 2001. 414(6866): p. 916-20.
82. Eltzschig, H.K., et al., Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism. Blood, 2004. 104(13): p. 3986-92.
83. Johnston-Cox, H.A., M. Koupenova, and K. Ravid, A2 adenosine receptors and vascular pathologies. Arteriosclerosis, thrombosis, and vascular biology, 2012. 32(4): p. 870-878.
84. Kiss, J., et al., IFN-beta protects from vascular leakage via up-regulation of CD73. Eur J Immunol, 2007. 37(12): p. 3334-8.
85. Thompson, L.F., et al., Crucial role for ecto-5'-nucleotidase (CD73) in vascular leakage during hypoxia. J Exp Med, 2004. 200(11): p. 1395-405.
86. Kak, V., et al., Immunotherapies in infectious diseases. Med Clin North Am, 2012. 96(3): p. 455-74, ix.
87. Kas-Deelen, A.M., et al., Cytomegalovirus infection increases the expression and activity of ecto-ATPase (CD39) and ecto-5'nucleotidase (CD73) on endothelial cells. FEBS Lett, 2001. 491(1-2): p. 21-5.
88. Russo-Abrahao, T., et al., Biochemical properties of Candida parapsilosis ecto-5'-nucleotidase and the possible role of adenosine in macrophage interaction. FEMS Microbiol Lett, 2011. 317(1): p. 34-42.
89. Thammavongsa, V., et al., Staphylococcus aureus synthesizes adenosine to escape host immune responses. J Exp Med, 2009. 206(11): p. 2417-27.
90. Paletta-Silva, R. and J.R. Meyer-Fernandes, Adenosine and immune imbalance in visceral leishmaniasis: the possible role of ectonucleotidases. J Trop Med, 2012. 2012: p. 650874.
91. Leal, D.B., et al., HIV infection is associated with increased NTPDase activity that correlates with CD39-positive lymphocytes. Biochim Biophys Acta, 2005. 1746(2): p. 129-34.
92. Schulze Zur Wiesch, J., et al., Comprehensive analysis of frequency and phenotype of T regulatory cells in HIV infection: CD39 expression of FoxP3+ T regulatory cells correlates with progressive disease. J Virol, 2011. 85(3): p. 1287-97.
93. Patkar, C., K. Giaya, and D.H. Libraty, Dengue virus type 2 modulates endothelial barrier function through CD73. The American journal of tropical medicine and hygiene, 2013. 88(1): p. 89-94.
94. Butthep, P., et al., Elevated soluble thrombomodulin in the febrile stage related to patients at risk for dengue shock syndrome. Pediatr Infect Dis J, 2006. 25(10): p. 894-7.
95. Puerta-Guardo, H., et al., Antibody-dependent enhancement of dengue virus infection in U937 cells requires cholesterol-rich membrane microdomains. Journal of General Virology, 2010. 91(2): p. 394-403.
96. Murphree, L.J., et al., Lipopolysaccharide rapidly modifies adenosine receptor transcripts in murine and human macrophages: role of NF-kappaB in A(2A) adenosine receptor induction. Biochem J, 2005. 391(Pt 3): p. 575-80.
97. Haskó, G. and P. Pacher, A2A receptors in inflammation and injury: lessons learned from transgenic animals. Journal of leukocyte biology, 2008. 83(3): p. 447-455.
98. Fredholm, B.B., Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death & Differentiation, 2007. 14(7): p. 1315-1323.
99. Murphy, P.S., et al., CD73 regulates anti-inflammatory signaling between apoptotic cells and endotoxin-conditioned tissue macrophages. Cell Death & Differentiation, 2017. 24(3): p. 559-570.
100. Hasko, G., et al., Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov, 2008. 7(9): p. 759-70.
101. Jacobson, K.A. and Z.G. Gao, Adenosine receptors as therapeutic targets. Nat Rev Drug Discov, 2006. 5(3): p. 247-64.
102. Junger, W.G., Immune cell regulation by autocrine purinergic signalling. Nature Reviews Immunology, 2011. 11(3): p. 201.
103. Trautmann, A., Extracellular ATP in the immune system: more than just a “danger signal”. Sci. Signal., 2009. 2(56): p. pe6-pe6.
104. Haskó, G., et al., Shaping of monocyte and macrophage function by adenosine receptors. Pharmacology & therapeutics, 2007. 113(2): p. 264-275.
105. Kumar, V. and A. Sharma, Adenosine: an endogenous modulator of innate immune system with therapeutic potential. Eur J Pharmacol, 2009. 616(1-3): p. 7-15.
106. Bours, M.J., et al., Adenosine 5'-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharmacol Ther, 2006. 112(2): p. 358-404.
107. Sitkovsky, M.V., et al., Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu Rev Immunol, 2004. 22: p. 657-82.
108. Blackburn, M.R., Too much of a good thing: adenosine overload in adenosine-deaminase-deficient mice. Trends Pharmacol Sci, 2003. 24(2): p. 66-70.
109. Sajjadi, F.G., et al., Inhibition of TNF-alpha expression by adenosine: role of A3 adenosine receptors. The Journal of Immunology, 1996. 156(9): p. 3435-3442.
110. Parmely, M.J., et al., Adenosine and a related carbocyclic nucleoside analogue selectively inhibit tumor necrosis factor-alpha production and protect mice against endotoxin challenge. The Journal of Immunology, 1993. 151(1): p. 389-396.
111. Le Moine, O., et al., Adenosine enhances IL-10 secretion by human monocytes. The Journal of immunology, 1996. 156(11): p. 4408-4414.
112. Hasko, G., et al., Adenosine receptor agonists differentially regulate IL-10, TNF-alpha, and nitric oxide production in RAW 264.7 macrophages and in endotoxemic mice. The Journal of Immunology, 1996. 157(10): p. 4634-4640.
113. Bouma, M.G., et al., Differential regulatory effects of adenosine on cytokine release by activated human monocytes. The Journal of Immunology, 1994. 153(9): p. 4159-4168.
114. Forsythe, P. and M. Ennis, Adenosine, mast cells and asthma. Inflamm Res, 1999. 48(6): p. 301-7.
115. Laffargue, M., et al., Phosphoinositide 3-kinase gamma is an essential amplifier of mast cell function. Immunity, 2002. 16(3): p. 441-51.
116. Murakami, S., et al., Adenosine regulates the IL-1β-induced cellular functions of human gingival fibroblasts. International Immunology, 2001. 13(12): p. 1533-1540.
117. Schingnitz, U., et al., Signaling through the A2B adenosine receptor dampens endotoxin-induced acute lung injury. J Immunol, 2010. 184(9): p. 5271-9.
118. Köklü, S., et al., Serum adenosine deaminase levels in pancreatic diseases. Pancreatology, 2007. 7(5-6): p. 526-530.
119. Hitoglou, S., et al., Adenosine deaminase activity and its isoenzyme pattern in patients with juvenile rheumatoid arthritis and systemic lupus erythematosus. Clinical rheumatology, 2001. 20(6): p. 411-416.
120. Erer, B., et al., Assessment of adenosine deaminase levels in rheumatoid arthritis patients receiving anti-TNF-α therapy. Rheumatology international, 2009. 29(6): p. 651-654.
121. Kobayashi, F., et al., Adenosine deaminase isoenzymes in liver disease. Am J Gastroenterol, 1993. 88(2): p. 266-71.
122. Nilius, R., et al., [Adenosine deaminase activity--an indicator of inflammation in liver disease]. Dtsch Z Verdau Stoffwechselkr, 1987. 47(5): p. 224-9.
123. Baba, K., et al., Adenosine deaminase activity is a sensitive marker for the diagnosis of tuberculous pleuritis in patients with very low CD4 counts. PloS one, 2008. 3(7): p. e2788-e2788.
124. Afrasiabian, S., et al., Diagnostic value of serum adenosine deaminase level in pulmonary tuberculosis. Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences, 2013. 18(3): p. 252-254.
125. Castro, V.S., et al., Adenosine deaminase activity in serum and lymphocytes of rats infected with Sporothrix schenckii. Mycopathologia, 2012. 174(1): p. 31-9.
126. Martin, C., et al., High adenosine plasma concentration as a prognostic index for outcome in patients with septic shock. Critical care medicine, 2000. 28(9): p. 3198-3202.
127. Haskó, G. and B.N. Cronstein, Adenosine: an endogenous regulator of innate immunity. Trends in immunology, 2004. 25(1): p. 33-39.
128. Jacobson, K.A. and Z.-G. Gao, Adenosine receptors as therapeutic targets. Nature reviews Drug discovery, 2006. 5(3): p. 247.