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-4.1512 0.4683 -3.9943 -2.0196 l -3.7914 1.1891 l -6.9897 13.5137 c -1.0866 0.4835 -1.1854 4.2814 -5.2016 -1.4437 l -6.5245 10.3792 c 0.0088 1.241 -0.8255 3.9905 -3.206 3.0763 l -0.0107 3.88 l 11.0342 10.6513 c 0.1363 1.1562 3.8138 2.4212 -3.0169 4.3728 l 8.1176 9.2517 c 1.2143 0.3754 3.6409 1.9979 2.0127 3.9208 l 3.7849 1.2088 l 13.8091 -6.9308 c 1.171 0.231 3.5424 -2.7849 3.3372 4.1462 l 11.5413 -4.6613 c 0.7416 -1.0091 3.0756 -2.7557 4.4501 -0.6531 l 2.3499 -3.1329 z" /> </svg> PMID: 17056121, 11111829 Under hypoxic conditions, the increased intracellular dephosphorylation of adenosine 5′-triphosphate (ATP) to adenosine by the metabolic enzyme 5′-nucleotidase is accompanied by a suppression of the activity of the salvage enzyme adenosine kinase, which prevents the rephosphorylation of adenosine. PMID: 17056121, 11111829 Under hypoxic conditions, the increased intracellular dephosphorylation of adenosine 5′-triphosphate (ATP) to adenosine by the metabolic enzyme 5′-nucleotidase is accompanied by a suppression of the activity of the salvage enzyme adenosine kinase, which prevents the rephosphorylation of adenosine. PMID: 17056121, 11396612, 11396615 These processes lead to adenosine reaching high concentrations inside the cell and the release of adenosine into the extracellular space through nucleoside transporters. indirect PMID: 17056121, 8955160, 9553767, 10470068, 15319286, 15583013, 16697102 The other major pathway that contributes to high extracellular adenosine concentrations during metabolic stress is release of precursor adenine nucleotides (ATP, ADP and AMP) from the cell. This is followed by extracellular degradation to adenosine by a cascade of ectonucleotidases, which include CD39 (nucleoside triphosphate diphosphohydrolase [NTPDase]) and CD73 (5′-ectonucleotidase). PMID: 17056121, 9759915 bacterial lipopolysaccharide (LPS) augmented the release of ATP from macrophages. PMID: 17056121, 8955160, 9553767, 10470068, 15319286, 15583013, 16697102 The other major pathway that contributes to high extracellular adenosine concentrations during metabolic stress is release of precursor adenine nucleotides (ATP, ADP and AMP) from the cell. This is followed by extracellular degradation to adenosine by a cascade of ectonucleotidases, which include CD39 (nucleoside triphosphate diphosphohydrolase [NTPDase]) and CD73 (5′-ectonucleotidase). PMID: 17056121, 8955160, 9553767, 10470068, 15319286, 15583013, 16697102 The other major pathway that contributes to high extracellular adenosine concentrations during metabolic stress is release of precursor adenine nucleotides (ATP, ADP and AMP) from the cell. This is followed by extracellular degradation to adenosine by a cascade of ectonucleotidases, which include CD39 (nucleoside triphosphate diphosphohydrolase [NTPDase]) and CD73 (5′-ectonucleotidase). PMID: 17056121, 8955160, 9553767, 10470068, 15319286, 15583013, 16697102 The other major pathway that contributes to high extracellular adenosine concentrations during metabolic stress is release of precursor adenine nucleotides (ATP, ADP and AMP) from the cell. This is followed by extracellular degradation to adenosine by a cascade of ectonucleotidases, which include CD39 (nucleoside triphosphate diphosphohydrolase [NTPDase]) and CD73 (5′-ectonucleotidase). PMID: 17056121, 8955160, 9553767, 10470068, 15319286, 15583013, 16697102 The other major pathway that contributes to high extracellular adenosine concentrations during metabolic stress is release of precursor adenine nucleotides (ATP, ADP and AMP) from the cell. This is followed by extracellular degradation to adenosine by a cascade of ectonucleotidases, which include CD39 (nucleoside triphosphate diphosphohydrolase [NTPDase]) and CD73 (5′-ectonucleotidase). PMID: 17056121, 8955160, 9553767, 10470068, 15319286, 15583013, 16697102 The other major pathway that contributes to high extracellular adenosine concentrations during metabolic stress is release of precursor adenine nucleotides (ATP, ADP and AMP) from the cell. This is followed by extracellular degradation to adenosine by a cascade of ectonucleotidases, which include CD39 (nucleoside triphosphate diphosphohydrolase [NTPDase]) and CD73 (5′-ectonucleotidase). PMID: 17056121, 10623851, 2581508, 11223861, 15019271 Adenosine accumulation is limited by its catabolism to inosine by adenosine deaminase. Inosine is finally degraded to the stable end product uric acid. PMID: 17056121, 10623851, 2581508, 11223861, 15019271 Adenosine accumulation is limited by its catabolism to inosine by adenosine deaminase. Inosine is finally degraded to the stable end product uric acid. PMID: 17056121 Lower concentrations of adenosine activate the high affinity A1, A2A, and A3 receptors, and high adenosine concentrations stimulate the low affinity A2B receptors. PMID: 17056121 Lower concentrations of adenosine activate the high affinity A1, A2A, and A3 receptors, and high adenosine concentrations stimulate the low affinity A2B receptors. PMID: 17056121 Lower concentrations of adenosine activate the high affinity A1, A2A, and A3 receptors, and high adenosine concentrations stimulate the low affinity A2B receptors. PMID: 17056121 Lower concentrations of adenosine activate the high affinity A1, A2A, and A3 receptors, and high adenosine concentrations stimulate the low affinity A2B receptors. PMID: 17056121, 956374 The first evidence supporting the concept that endogenous adenosine is capable of preventing human monocyte maturation was provided by demonstrating that adenosine deaminase activity is increased during early monocyte differentiation and that adenosine deaminase inhibition during this period delayed the maturation process. PMID: 17056121, 2159513 High concentrations of exogenous adenosine seem to prevent monocyte development into macrophages and arrest monocyte development at a stage with high accessory function, a phenotype that is similar to dendritic cells. indirect PMID: 17056121 The mechanism of action of adenosine involves induction, in a PKA-dependent manner, of the expression of p27kip-1, a cyclin-dependent kinase inhibitor that leads to growth arrest at the G1 phase of the cell cycle. indirect PMID: 17056121 The mechanism of action of adenosine involves induction, in a PKA-dependent manner, of the expression of p27kip-1, a cyclin-dependent kinase inhibitor that leads to growth arrest at the G1 phase of the cell cycle. PMID: 17056121 The mechanism of action of adenosine involves induction, in a PKA-dependent manner, of the expression of p27kip-1, a cyclin-dependent kinase inhibitor that leads to growth arrest at the G1 phase of the cell cycle. PMID: 17056121, 15466916 When a small particle is coated (opsonized) with IgG, the Fc regions of the IgG antibody molecules bind to Fc receptors that are expressed on the macrophage plasma membrane and trigger a phagocytic response. PMID: 17056121 In human monocytes, the non-selective adenosine receptor agonist 5′-N-ethylcarboxamidoadenosine (NECA) but not 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethyl-carboxamidoadenosine (CGS 21680), a selective agonist of A2A receptors, down-regulated the proliferation of human peripheral blood mononuclear cells obtained from healthy subjects. PMID: 17056121 In human monocytes, the non-selective adenosine receptor agonist 5′-N-ethylcarboxamidoadenosine (NECA) but not 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethyl-carboxamidoadenosine (CGS 21680), a selective agonist of A2A receptors, down-regulated the proliferation of human peripheral blood mononuclear cells obtained from healthy subjects. PMID: 17056121, 10725262 On the other hand, the selective A1 receptor agonist N6-cyclopentyladenosine (CPA), but not other agonists, inhibited the proliferation of mononuclear cells in asthmatic patients. indirect PMID: 17056121, 10496321, 14977938 Two later studies, one using fMLP and the other LPS to stimulate oxidative burst, confirmed that the effect of adenosine could be attributed primarily to A3 receptor stimulation. indirect PMID: 17056121, 10496321, 14977938 Two later studies, one using fMLP and the other LPS to stimulate oxidative burst, confirmed that the effect of adenosine could be attributed primarily to A3 receptor stimulation. indirect PMID: 17056121, 8619882 Nitric oxide (NO) synthases (NOS) catalyze the oxidation of one of the guanidino nitrogens of l-arginine to the reactive nitrogen species NO. PMID: 17056121 Of the several NOS isoforms that can catalyze NO synthesis, iNOS is the primary one that is responsible for antimicrobial activity by producing high levels of NO. PMID: 17056121, 8906843 We demonstrated that both the selective A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA) and A2A agonist CGS 21680 suppressed NO production by LPS-stimulated RAW264.7 macrophages, both with low efficacy. indirect PMID: 17056121, 1711326 Host expression of iNOS is first and foremost regulated at the transcriptional level and can be stimulated in response to microbial products or by cytokines such as IL-1, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) indirect PMID: 17056121, 1711326 Host expression of iNOS is first and foremost regulated at the transcriptional level and can be stimulated in response to microbial products or by cytokines such as IL-1, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) indirect PMID: 17056121, 1711326 Host expression of iNOS is first and foremost regulated at the transcriptional level and can be stimulated in response to microbial products or by cytokines such as IL-1, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) PMID: 17056121, 10092821, 10510349 treatment of IFN-γ-activated bone marrow macrophages with NECA decreased both iNOS induction and NO production in these cells. PMID: 17056121, 8906843 We demonstrated that both the selective A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA) and A2A agonist CGS 21680 suppressed NO production by LPS-stimulated RAW264.7 macrophages, both with low efficacy. indirect PMID: 17056121, 10092821, 10510349 treatment of IFN-γ-activated bone marrow macrophages with NECA decreased both iNOS induction and NO production in these cells. indirect PMID: 17056121, 7945378 Stimulation of A2 receptors in U-937 human macrophages elicits VEGF mRNA accumulation. PMID: 17056121, 12057925 A2A receptor stimulation and LPS through TLR4 activation synergistically facilitated the production of VEGF. indirect PMID: 17056121, 7945378 Stimulation of A2 receptors in U-937 human macrophages elicits VEGF mRNA accumulation. PMID: 17056121, 12057925 A2A receptor stimulation and LPS through TLR4 activation synergistically facilitated the production of VEGF. indirect PMID: 17056121, 12057925 A2A receptor stimulation and LPS through TLR4 activation synergistically facilitated the production of VEGF. indirect PMID: 17056121 Adenosine is a strong inhibitor of TNF-α production by monocytes and macrophages. PMID: 17056121 IL-10 was also described as cytokine synthesis inhibitory factor, because IL-10 can inhibit the secretion of a variety of proinflammatory cytokines, including TNF-α and IL-12 indirect PMID: 17056121 Adenosine is a strong inhibitor of TNF-α production by monocytes and macrophages. PMID: 17056121, 12875990 The inhibitory effect of adenosine on TNF-α production by macrophages is not limited to TLR4-mediated (LPS) induction of this cytokine because adenosine down-regulates TNF-α production when induced by agonists of TLR2, TLR3, TLR4, TLR7 and TLR9. PMID: 17056121 adenosine receptor agonists were shown to suppress TNF-α production by LPS (TLR4 ligand)-challenged human monocytes with the following rank order of potency: NECA > R-PIA = CGS 21680 > 2-CADO (2-chloroadenosine) = CHA (N6-cyclohexyladenosine). PMID: 17056121, 11023991 In addition, CGS 21680 potently decreased TNF-α production by A2A WT macrophages but it failed to influence TNF-α release by KO cells. indirect PMID: 17056121, 11023991 Using A2A receptor knockout mice, our group documented that adenosine down-regulates IL-12 p40 production by LPS-stimulated mouse peritoneal macrophages and that this effect is dependent, in part, on A2A receptors. PMID: 17056121 Further evidence implicating A2A receptors came from studies with human monocytes, in which CGS 21680 potently blunted LPS-induced IL-12 (both IL-12p40 and IL-12) production, which effect was reversed by A2A antagonists. indirect PMID: 17056121, 11023991 Using A2A receptor knockout mice, our group documented that adenosine down-regulates IL-12 p40 production by LPS-stimulated mouse peritoneal macrophages and that this effect is dependent, in part, on A2A receptors. PMID: 17056121 Further evidence implicating A2A receptors came from studies with human monocytes, in which CGS 21680 potently blunted LPS-induced IL-12 (both IL-12p40 and IL-12) production, which effect was reversed by A2A antagonists. PMID: 17056121, 9822893 A3 receptor stimulation can also negatively regulate IL-12 production, because the selective A3 receptor agonist IB-MECA moderates IL-12 production both in LPS-treated mice. PMID: 17056121, 16116186 IB-MECA activated the phosophatidyl inositol-3-kinase (PI3K) pathway, and the activity of both PI3K and Akt was required for its suppressive effect indirect PMID: 17056121, 9822893 A3 receptor stimulation can also negatively regulate IL-12 production, because the selective A3 receptor agonist IB-MECA moderates IL-12 production both in LPS-treated mice. PMID: 17056121, 16116186 IB-MECA activated the phosophatidyl inositol-3-kinase (PI3K) pathway, and the activity of both PI3K and Akt was required for its suppressive effect. indirect PMID: 17056121, 9822893 A3 receptor stimulation can also negatively regulate IL-12 production, because the selective A3 receptor agonist IB-MECA moderates IL-12 production both in LPS-treated mice. PMID: 17056121, 16116186 IB-MECA activated the phosophatidyl inositol-3-kinase (PI3K) pathway, and the activity of both PI3K and Akt was required for its suppressive effect. indirect PMID: 17056121, 9822893 A3 receptor stimulation can also negatively regulate IL-12 production, because the selective A3 receptor agonist IB-MECA moderates IL-12 production both in LPS-treated mice. PMID: 17056121, 16116186 IB-MECA activated the phosophatidyl inositol-3-kinase (PI3K) pathway, and the activity of both PI3K and Akt was required for its suppressive effect. PMID: 17056121 Further evidence implicating A2A receptors came from studies with human monocytes, in which CGS 21680 potently blunted LPS-induced IL-12 (both IL-12p40 and IL-12) production, which effect was reversed by A2A antagonists. indirect PMID: 17056121, 9822893 A3 receptor stimulation can also negatively regulate IL-12 production, because the selective A3 receptor agonist IB-MECA moderates IL-12 production both in LPS-treated mice. PMID: 17056121 Further evidence implicating A2A receptors came from studies with human monocytes, in which CGS 21680 potently blunted LPS-induced IL-12 (both IL-12p40 and IL-12) production, which effect was reversed by A2A antagonists. PMID: 17056121 IL-10 was also described as cytokine synthesis inhibitory factor, because IL-10 can inhibit the secretion of a variety of proinflammatory cytokines, including TNF-α and IL-12 indirect indirect PMID: 17056121, 8666814 In human monocytes activated with TNF-α, H2O2, or LPS, adenosine up-regulated IL-10 production, an effect that was not mimicked by administering NECA, 2-CADO, or R-PIA indirect indirect PMID: 17056121, 8666814 In human monocytes activated with TNF-α, H2O2, or LPS, adenosine up-regulated IL-10 production, an effect that was not mimicked by administering NECA, 2-CADO, or R-P indirect indirect PMID: 17056121, 8666814 In human monocytes activated with TNF-α, H2O2, or LPS, adenosine up-regulated IL-10 production, an effect that was not mimicked by administering NECA, 2-CADO, or R-PIA. indirect indirect PMID: 17056121, 8666814 In human monocytes activated with TNF-α, H2O2, or LPS, adenosine up-regulated IL-10 production, an effect that was not mimicked by administering NECA, 2-CADO, or R-PIA. indirect indirect PMID: 17056121, 8666814 In human monocytes activated with TNF-α, H2O2, or LPS, adenosine up-regulated IL-10 production, an effect that was not mimicked by administering NECA, 2-CADO, or R-PIA. indirect indirect PMID: 17056121, 8666814 In human monocytes activated with TNF-α, H2O2, or LPS, adenosine up-regulated IL-10 production, an effect that was not mimicked by administering NECA, 2-CADO, or R-PIA. indirect PMID: 17056121 A2A receptor activation stimulates adenylate cyclase (AC) leading to elevated intracellular cAMP levels. PMID: 17056121 A2A receptor activation stimulates adenylate cyclase (AC) leading to elevated intracellular cAMP levels. PMID: 17056121 A2A receptor activation augments IL-10 production by monocytes and macrophages through a cyclic adenosine monophosphate (cAMP)-mediated pathway indirect PMID: 17056121 A2A receptor activation augments IL-10 production by monocytes and macrophages through a cyclic adenosine monophosphate (cAMP)-mediated pathway. indirect PMID: 17056121 A2B receptor activation also facilitates IL-10 production indirect PMID: 17056121 A2B receptor activation also facilitates IL-10 production PMID: 17056121, 9310485, 15226179 In addition to its direct effects on platelets that are mediated via binding to A2A receptors, dilazep was reported to also block TF expression on monocytes and thereby inhibit blood coagulation. PMID: 17056121, 9310485, 15226179 In addition to its direct effects on platelets that are mediated via binding to A2A receptors, dilazep was reported to also block TF expression on monocytes and thereby inhibit blood coagulation. PMID: 17056121, 9310485, 15226179 In addition to its direct effects on platelets that are mediated via binding to A2A receptors, dilazep was reported to also block TF expression on monocytes and thereby inhibit blood coagulation. indirect PMID: 17056121, 12152652 Adenosine inhibits TF expression on LPS-stimulated human monocytes through the activation of A3 receptors, because IB-MECA is the most potent agonist in reducing TF expression and the mixed A1/A3 antagonist XAC, but not selective A1, A2A, or A2B antagonists prevented the effect of adenosine. indirect PMID: 17056121, 12152652 Adenosine inhibits TF expression on LPS-stimulated human monocytes through the activation of A3 receptors, because IB-MECA is the most potent agonist in reducing TF expression and the mixed A1/A3 antagonist XAC, but not selective A1, A2A, or A2B antagonists prevented the effect of adenosine.