Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It was previously shown that CD26 (DPP IV, EC 3.4.14.5) is a binding site for adenosine deaminase (ADA, EC 3.5.4.4) on T cells and that costimulation by some anti-CD26 monoclonal antibodies (mAbs) and anti-CD3 induces CD4+ T cell proliferation. The CD26 epitopes involved in costimulation, the precise sequence of the events preceding proliferation, and the response of CD8+ compared with CD4+ T cells to CD26 were not extensively studied. We therefore compared the effects of the novel TA5.9 anti-CD26 mAb, recognizing an ADA-binding epitope, and the clearly distinct anti-Ta1 reference anti-CD26 mAb for their costimulatory properties in various T cell subsets. Both purified CD4+ and CD8+ T cells proliferated upon costimulation with anti-CD3 and either anti-CD26 mAb, but anti-TA5.9 mAb induced a more potent response than anti-Ta1. Either anti-CD26 mAb, together with anti-CD3, caused a similar sequential up-regulation of CD69, CD25 (IL-2R alpha), and CD71 (transferrin receptor) expression on CD4+ and CD8+ T cells. The activation markers appeared faster on the CD45R0+ than on the CD45R0- subsets. After costimulation, CD4+ T cell cultures contained significant amounts of the Th1 cytokines IL-2, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha). In CD8+ T cell cultures relatively more IFN-gamma and TNF-alpha but almost no IL-2 was measured after triggering of CD3 and CD26. Our data demonstrate that the recognition of the ADA-binding epitope is not a prerequisite for the costimulatory capacity of anti-CD26 mAbs. Both CD4+ and CD8+ T cells and their CD45R0- and CD45R0+ subsets are sensitive to various aspects of activation via CD26, but the magnitude and/or kinetics differ according to the anti-CD26 used and the T cell subset studied.
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PMID:Costimulation of CD4+ and CD8+ T cells through CD26: the ADA-binding epitope is not essential for complete signaling. 766 88

We hypothesized that adenosine, known to be release from inflammatory sites, could lessen the potentially damaging activity of neutrophils (PMN) primed by tumor necrosis factor-alpha (TNF alpha) at sites of infection. We investigated the effect of adenosine on PMN primed with cell-free medium from mononuclear leukocytes (MNL) that had been treated with lipopolysaccharide (LPS) yielding a conditioned medium rich in TNF alpha and on PMN primed with recombinant human TNF alpha (rhTNF alpha). LPS (10 ng/mL) minimally primed PMN, but LPS-MNL-conditioned medium increased PMN chemiluminescence in response to f-Met-Leu-Phe (fMLP) 1242% compared with unprimed PMN. LPS-MNL-conditioned medium contained adenosine (approximately 30 nM). Converting the adenosine in the LPS-MNL-conditioned medium to inosine with adenosine deaminase (ADA) or blocking adenosine binding to PMN with the adenosine receptor antagonist 1,3-dipropyl-8-(phenyl-p-acrylate)-xanthine (BW A1433U) resulted in a near doubling of chemiluminescence. The LPS-MNL-conditioned medium contained TNF alpha (836 pg/mL; approximately 1 U/mL). Recombinant human TNF alpha (1 U/mL) primed PMN for a 1033% increase in chemiluminescence. Added adenosine decreased rhTNF alpha-primed PMN chemiluminescence (IC50 approximately 100 nM), and adenosine (100 nM) decreased both superoxide and myeloperoxidase release from rhTNF alpha-primed fMLP-stimulated PMN. The activity of adenosine was counteracted by ADA and BW A1433U, and the modulating effect of adenosine was on the primed response rather than on priming per se. Thus, physiological concentrations of adenosine reduce the effects of recombinant human TNF alpha and native human TNF alpha (released from LPS-treated MNL) on PMN activity. Endogenous adenosine may preclude or minimize damage to infected tissue by damping the TNF alpha-primed PMN oxidative response.
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PMID:Adenosine modulation of tumor necrosis factor-alpha-induced neutrophil activation. 861 64

Methylxanthines are best known as phosphodiesterase inhibitors that cause a rise in intracellular cAMP. One would expect the two methylxanthines, caffeine and pentoxifylline, to have similar actions on neutrophils (PMN). However, caffeine stimulated and pentoxifylline inhibited PMN oxidative activity. Micromolar concentrations of pentoxifylline decreased native and recombinant tumor necrosis factor-alpha (TNF alpha)-primed formyl met-leu-phe (fMLP)-stimulated PMN chemiluminescence, superoxide production and myeloperoxidase (MPO) release. In contrast, equal concentrations of caffeine increased chemiluminescence and MPO release with no effect on superoxide production. These activities of the methylxanthines were only observed in the presence of physiological concentrations of adenosine, and were abolished by the treatment of the PMN with adenosine deaminase. The activities of adenosine, pentoxifylline and caffeine on PMN activity could not be readily explained by changes in PMN [cAMP]. Thus for TNF alpha-primed PMN, pentoxifylline decreases PMN activity by enhancing the effect of adenosine on degranulation and superoxide production; whereas caffeine increases PMN activity by counteracting the effect of adenosine on degranulation.
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PMID:Methylxanthines with adenosine alter TNF alpha-primed PMN activation. 865 88

The level of tumor necrosis factor (TNF)-alpha, soluble TNF receptors p75 (sTNFR-75) and sTNFR-55, interferon (IFN)-gamma, and interleukin (IL)-10 and IL-12 were measured in 59 cerebrospinal fluid (CSF) samples from 15 patients with tuberculous meningitis (TBM). TBM was associated with elevated concentrations of TNF-alpha, sTNFR-75, sTNFR-55, IFN-gamma, and IL-10, while CSF IL-12 was undetectable in all TBM patients. A significant correlation between cytokines and CSF adenosine deaminase activity was also found. The levels of TNF-alpha did not decrease over time, being still detectable in the CSF 16 months after starting antibiotic therapy, whereas IFN-gamma along with anti-inflammatory mediators sTNFR-75, sTNFR-55, and IL-10 remained elevated in the CSF for 4-8 months. The chronic release of cytokines in the CSF compartment was related neither to the TBM stage nor to the clinical outcome of the disease, thus suggesting the presence of a continuous activity of the inflammatory process at the site of infection.
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PMID:Cerebrospinal fluid cytokines in patients with tuberculous meningitis. 924 49

We measured the activity of adenosine deaminase (ADA) and the concentration of interleukin-1 beta (IL-1 beta), interleukin-2 (IL-2), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the pleural effusions from 28 patients with tuberculosis, 30 with neoplastic diseases, 25 with bacterial infections and 18 with congestive heart failure or liver cirrhosis. The levels of ADA (83.0 +/- 32.1 IU/L) and IFN-gamma (795.0 +/- 666.4 pg/ml) in tuberculous effusions were significantly higher than those in other groups (p < 0.0001). IL-1 beta level in the effusions of bacterial infections (265.2 +/- 379.2 pg/ml) was higher than that in other groups (p < 0.0001). TNF-alpha level in the effusions of tuberculosis (31.7 +/- 36.7 pg/ml) and bacterial infections (69.5 +/- 232.9 pg/ml) was higher than that in other groups. IL-8 level of exudative effusions was higher than that of transudates. IL-2 was only present in 4 effusions from tuberculosis and 1 effusion from bacterial infections. Diagnostic utilities of cytokines and ADA for tuberculous effusion were evaluated using receiver operating characteristics (ROC) curve analysis. The cut-off points of ADA, IL-1 beta, IL-8, TNF-alpha and IFN-gamma determined in this analysis were 54 IU/L, 5.5 pg/ml, 405 pg/ml, 4.5 pg/ml and 28 pg/ml, respectively and the sensitivity and the specificity of them were 88.0% and 95.9%, 19.1% and 74.1%, 57.1% and 63.2%, 81.0% and 77.2%, and 96.2% and 98.5%, respectively. In ADA, TNF-alpha and IFN-gamma, the areas under the curve (AUC) that represent the diagnostic accuracy were 0.968, 0.719 and 0.993, respectively. AUC of IFN-gamma was significantly higher than that of ADA or TNF-alpha. In tuberculous pleural effusion, IFN-gamma was significantly correlated with TNF-alpha, IL-1 beta and ADA. The correlation was also present between TNF-alpha and ADA.
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PMID:[Clinical significance of cytokine measurement in pleural effusion]. 938 55

By pharmacological manipulation of endogenous adenosine, using chemically distinct methods, we tested the hypothesis that endogenous adenosine tempers proinflammatory cytokine responses and oxyradical-mediated tissue damage during endotoxemia and sepsis. Rats were pretreated with varying doses of pentostatin (PNT; adenosine deaminase inhibitor) or 8-sulfophenyltheophylline (8-SPT; adenosine receptor antagonist) and then received either E. coli endotoxin (lipopolysaccharide; 0.01 or 2.0 mg/kg) or a slurry of cecal matter in 5% dextrose in water (200 mg/kg). Resultant levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-10 were measured in serum and in liver and spleen. Untreated, 2 mg/kg lipopolysaccharide elevated serum TNF-alpha, IL-1beta, and IL-10. PNT dose dependently attenuated, without ablating, the elevation in serum TNF-alpha and IL-1beta and raised liver and spleen IL-10. PNT also attenuated elevation of TNF-alpha in serum, liver, and spleen at 4 and 24 h after sepsis induction, and 8-SPT resulted in higher proinflammatory cytokines. Modulating endogenous adenosine was also effective in exacerbated (8-SPT) or diminished (PNT) tissue peroxidation. Survival from sepsis was also improved when PNT was used as a posttreatment. These data indicate that endogenous adenosine is an important modulatory component of systemic inflammatory response syndromes. These data also indicate that inhibition of adenosine deaminase may be a novel and viable therapeutic approach to managing the systemic inflammatory response syndrome without ablating important physiological functions.
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PMID:Inhibiting adenosine deaminase modulates the systemic inflammatory response syndrome in endotoxemia and sepsis. 1195 72

Adenosine, a purine nucleoside found at high levels in solid tumors, is able to suppress the recognition/adhesion and effector phases of killer lymphocyte-mediated tumor cell destruction. Here, we demonstrate that adenosine, at concentrations that are typically present in the extracellular fluid of solid tumors, exerts a profound inhibitory effect on the induction of mouse cytotoxic T cells, without substantially affecting T-cell viability. T-cell proliferation in response to mitogenic anti-CD3 antibody was impaired in the presence of 10 microM adenosine (plus coformycin to inhibit endogenous adenosine deaminase). Antigen-specific T-cell proliferation was similarly inhibited by adenosine. Anti-CD3-activated killer T (AK-T) cells induced in the presence of adenosine exhibited reduced major histocompatibility complex-unrestricted cytotoxicity against P815 mastocytoma cells in JAM and (51)Cr-release assays. Diminished tumoricidal activity correlated with reduced expression of mRNAs coding for granzyme B, perforin, Fas ligand and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), as well as with diminished Nalpha-CBZ-L-lysine thiobenzylester (BLT) esterase activity. Interleukin-2 and interferon-gamma synthesis by AK-T cells was also inhibited by adenosine. AK-T cells express mRNA coding for A(2A), A(2B) and A(3) receptors, but little or no mRNA coding for A(1) receptors. The inhibitory effect of adenosine on AK-T cell proliferation was blocked by an A(3) receptor antagonist (MRS1191) but not by an A(2) receptor antagonist (3,7-dimethyl-1-propargylxanthine [DMPX]). The A(3) receptor agonists (N(6)-2-(4-aminophenyl)ethyladenosine [APNEA] and N(6)-benzyl-5'-N-ethylcarboxamidoadenosine [N(6)-benzyl-NECA]) also inhibited AK-T cell proliferation. Adenosine, therefore, acts through an A(3) receptor to prevent AK-T cell induction. Tumor-associated adenosine may act through the same mechanism to impair the development of tumor-reactive T cells in cancer patients.
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PMID:Adenosine acts through an A3 receptor to prevent the induction of murine anti-CD3-activated killer T cells. 1199 7

The ability of increased endogenous adenosine to mitigate microvascular derangements in sepsis was studied. Pentostatin (2'-deoxycoformycin), an inhibitor of adenosine deaminase, was administered to mice immediately after induction of sepsis by cecal ligation and puncture. Intravital video microscopy of cremasteric postcapillary venules was performed. Leukocyte rolling and adhesion were significantly increased in septic mice compared with control mice. Treatment of septic mice with pentostatin significantly decreased leukocyte rolling and adhesion (6.02 +/- 0.09 versus 1.72 +/- 0.12 rolling cells/min, 2.07 +/- 0.04 versus 0.62 +/- 0.05 adherent cells/100 microm per minute; p < 0.001). Albumin leakage (ratio) was significantly attenuated in septic animals treated with pentostatin (0.42 +/- 0.05 versus 0.21 +/- 0.04; p < 0.01). Circulating levels of interleukin-6, tumor necrosis factor-alpha, and soluble tumor necrosis factor type II receptor were decreased in septic mice treated with pentostatin. Survival was significantly improved at 48 hours in mice treated with pentostatin. These results suggest an important role for adenosine in modulating both leukocyte-dependent and -independent mechanisms of endothelial injury in sepsis. Exploiting the advantageous action of endogenous adenosine represents a potentially useful and novel therapeutic approach for the treatment of sepsis.
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PMID:Adenosine deaminase inhibition attenuates microvascular dysfunction and improves survival in sepsis. 1209 Nov 65

At examination of 160 patients with acute cholecystitis (ACH) it was stated that on 1st-2nd day after cholecystectomy the patients with complicated course of ACH have had a real increase of levels of interleukin-6, tumor necrosis factor-alpha, homocysteine, metabolites of nitric oxide, indexes of cytopathic hypoxia (hypoxanthine and xanthine, activity of adenosine deaminase, xanthine oxidase and xanthine dehydrogenase). These alterations were the most significant and lingering at the patients who has postoperative complications. Addition of levels of proinflammatory cytokines was over 50% and of indexes of cytopathic hypoxia--over 30-40% on the 1st-2nd day after operation what makes it possible to prognose the postoperative pyoinflammatory complications appearance at more that 60% of patients and to forecast favourable course of postoperative period with reliability over 90%--for its absence.
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PMID:[Dynamics of the cytokines, homocysteine contents, indices of oxydative and nitrosative stress and cytopathic hypoxia in patients after cholecystectomy for acute cholecystitis. Connection with rate of postoperative purulent-inflammatory complications]. 1562 40

Recent reports have described purinergic modulation of tumor necrosis factor-alpha (TNF-alpha) signaling in neutrophils and astrocytes. In Sertoli cells, both TNF-R1 and TNF-R2 TNF-alpha receptors are present and this cytokine modulates many functions of these cells related to the maintenance of spermatogenesis. Sertoli cells express distinct purinoreceptors and previous work has shown that these cells secrete extracellular nucleotides and their metabolites. In this work, we studied the possible role of extracellular purines in TNF-alpha signaling in cultured Sertoli cells. This cytokine increased inosine concentration from 30 min to 6 h, with no effect at 24 h. Both TNF-alpha and inosine increased nitrite accumulation and nitric oxide synthase activity. Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase inhibitor, abolished the TNF-alpha induced inosine increase, nitrite accumulation and nitric oxide synthase activity. These results suggest that extracellular inosine acts as intermediary in TNF-alpha stimulated nitric oxide production in cultured Sertoli cells.
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PMID:Extracellular inosine participates in tumor necrosis factor-alpha induced nitric oxide production in cultured Sertoli cells. 1632 64


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