Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activity of adenosine deaminase (ADA), an enzyme known to be deficient in some patients with severe combined immunodeficiency, increased three-fold within a 24-hour exposure of human peripheral blood lymphocytes to phytohaemagglutinin (PHA) in culture. This increase took place before the onset of DNA synthesis. Increased levels of ADA activity were also observed in lymphocytes incubated with pokeweed mitogen (PWM) for 60 hr. DNA synthesis induced by PHA, PWM or mixed lymphocyte cultures (MLC) was strongly inhibited by adenosine at concentrations of 10(-4) M or higher when human peripheral blood lymphocytes were cultured in a medium supplemented with horse serum, which lacks ADA. 10(-6)-10(-8) M coformycin, a potent inhibitor of ADA, inhibited PHA-, PWM- and MLC-induced DNA synthesis to a variable extent, whereas thymidine incorporation induced by Salmonella lipopolysaccharide (LPS) in mouse spleen cell cultures was strongly inhibited (by 75% or more) by 10(-6) M coformycin. Combination of 10(-7)-10(-8) M coformycin and 10(-4)-10(-5) M adenosine synergistically inhibited mitogen- or MLC-induced DNA synthesis in human and mouse lymphocyte cultures. These results, together with observations on children with ADA deficiency, provide evidence that adenosine deaminase is highly important for lymphocyte proliferation. Human peripheral blood lymphocytes incubated with PHA, 10(-5) M adenosine and 10(-7) M coformycin showed some cytotoxicity whereas the rate of 51Cr release from normal lymphocytes was not modified by the drugs. These findings suggest that in vivo clones of lymphocytes responding to specific antigens might be eliminated by coformycin, which may prove to be useful as a specific immunosuppressive agent.
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PMID:Role of adenosine deaminase in lymphocyte proliferation. 13 8

The in vitro effect of short-term culture as well as the effect of retinol (ROH), retinoic acid (RA), muramyl dipeptide [( Abu']MDP), lipopolysaccharide (LPS), and gamma interferon (IFN-gamma) on the induction of the purine metabolic enzymes, adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), and 5'nucleotidase (5NT) in human peripheral blood monocytes (HPBM) was examined. HPBM isolated by centrifugal elutriation were cultured for up to 96 h. Following an initial time lag of 24 h, mean ADA activity from seven separate experiments as measured in nmoles/10(6) cells/h increased from a baseline of 31.3 +/- 9.3 to 57.8 +/- 16.4 (P less than 0.005) at 72 h and to 72 +/- 21.5 (P less than .025) by 96 h. 5NT activity increased from a baseline of 2.2 +/- 0.9 to a maximum of 44 +/- 10.1 by 72 h and then declined to 29 +/- 18 (P less than 0.005) by 96 h, while no significant change in PNP activity was observed. HPBM incubated for 3 d with optimal concentrations of LPS, RA, and IFN-gamma had increases in ADA and 5NT activity ranging from three- to 10-fold compared to HPBM cultured in media alone, whereas no effect was observed with ROH and [Abu']MDP. RA, but not ROH, significantly enhanced ADA activity in a monocytic leukemia cell (THP-1) line. Addition of RA or the tumor promoter, phorbol 12-myristic 13-acetate (PMA), to HPBM or THP-1 cells resulted in significant increases in 5NT activity with opposite effects on ADA activity. These findings suggest that the biological mechanisms associated with differentiation in normal and malignant monocytes seem to be related and that the sequence and degree to which the various differentiation agents induce the enzyme elevations are also related to the mechanisms of activation/differentiation.
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PMID:Induction of adenosine deaminase and 5' nucleotidase activity in cultured human blood monocytes and monocytic leukemia (THP-1) cells by differentiating agents. 284 22

Activities of key enzymes of purine metabolism [adenosine deaminase (AD); purine nucleoside phosphorylase (PNP); 5'-nucleotidase] were studied; changes in DNA content, nucleus ploidity in thymocytes, T- and B-lymphocytes in the C3HA mouse spleen during solid 22 hepatoma growth and after the immunization were monitored. Immunological properties of lymphocytes were also investigated measuring antibody formation and the reaction of blasttransformation in response to phytohemagglutinin, concanavalin A and lipopolysaccharide. Within the first 48 hrs after the tumor implantation and immunization certain nonspecific biochemical mechanisms of lymphocytes activation (elevated AD activity, decreased activity of 5'-nucleotidase, augmented intracellular DNA levels, polyploidity) were revealed. As the solid 22 hepatoma reached the maximum growth rate specific alterations in the activities of the purine metabolism key enzymes were observed reflecting the response of thymus and spleen lymphocytes to the presence of the malignant tumor.
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PMID:[Biochemical and functional characteristics of thymus and spleen lymphocytes in C3HA mice during the growth of hepatoma 22 and after immunization with sheep erythrocytes]. 302 Jul 91

Analogues that are poor substrates for adenosine deaminase or purine nucleoside phosphorylase may mimic immunodeficiencies associated with the enzyme deficiencies, and their activities may be directed toward selected lymphocyte subpopulations. Four analogues were studied for their effects on primary antibody response to either a T-dependent (sheep erythrocytes) or T-independent (trinitrophenyl-conjugated Escherichia coli lipopolysaccharide) antigen as well as effects on T-cytotoxic and natural killer cell activities in mice. The nucleosides were: an adenosine analogue, tubercidin; two deoxyadenosine analogues, 2-chloro, 2'-deoxyadenosine and 2-fluoroadenine arabinoside-5'-phosphate; and a deoxyguanosine analogue, 9-beta-D-arabinosylguanine. Drugs were given i.p. once daily for 3 consecutive days. Immune responses were determined in spleen cell suspensions 1 day after the last dose. Tubercidin inhibited both T-cytotoxic and natural killer cell activities at doses that did not reduce primary antibody response, whereas the reverse was true for 2-chloro, 2'-deoxyadenosine and 2-fluoroadenine arabinoside-5'-phosphate. At higher doses, T-cytotoxic lymphocytes appeared to be more sensitive than natural killer cells to the deoxyadenosine analogues. 9-beta-D-Arabinosylguanine did not selectively inhibit the immune responses at doses that clearly reduced the yield of spleen lymphocytes. Assuming the analogues mimic endogenous nucleosides, the results suggest that natural killer cells are more sensitive to adenosine than are those cells responsible for primary antibody response, whereas the reverse is true for deoxyadenosine.
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PMID:Selective modulation of antibody response and natural killer cell activity by purine nucleoside analogues. 326 25

Coformycin, which is an inhibitor of adenosine deaminase, significantly inhibited in vitro blastogenic responses of human lymphocytes to both phytohaemagglutinin (PHA) and pokeweed mitogen (PWM), whereas blastogenic responses to bacterial lipopolysaccharide (LPS) were rather enhanced by the addition of coformycin. Blastogenic responses of lymphocytes to PHA and PWM were markedly suppressed by the addition of adenosine, which is a substrate of adenosine deaminase. Allopurinol, which is an inhibitor of xanthine oxidase, inhibited blastogenic responses of human lymphocytes to PHA, PWM, and bacterial LPS. Inosine (a substrate of purine nucleoside phosphorylase) and hypoxanthine (a substrate of xanthine oxidase) showed no or only a small effect on blastogenic responses of human lymphocytes. These results suggest that adenosine deaminase activity is associated with the T-cell response but not with the B-cell response and that the impaired T-cell response in adenosine deaminase deficiency is the result of intracellular retention of adenosine in T cells. The results also suggest that purine nucleoside phosphorylase or xanthine oxidase activity is associated with both T- and B-cell responses.
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PMID:Purine metabolic enzymes in lymphocytes. IV. Effects of enzyme inhibitors and enzyme substrates on the blastogenic responses of human lymphocytes. 392 75

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

1. Engagement of adenosine A2 receptors suppresses several leukocyte functions. In the present study, we examined the effect of adenosine on the inhibition of leukotriene B4 (LTB4) synthesis in heparinized human whole blood, pretreated with lipopolysaccharide (LPS) and tumour necrosis factor alpha (TNF-alpha) and stimulated with the chemotactic peptide, N-formyl-Met-Leu-Phe (FMLP). 2. The FMLP-induced synthesis of LTB4 in whole blood pretreated with LPS and TNF-alpha was dose-dependently inhibited by adenosine analogues in the following order of potency; 5'(N-ethyl)carboxamidoadenosine (NECA) approximately equal to CGS 21680 > 2-Cl-adenosine > N6-cyclopentyladenosine (CPA), indicating the involvement of the adenosine A2 receptor subtype. The IC50 values for NECA, CGS 21680, 2-Cl-adenosine, and CPA were 6 nM, 9 nM, 180 nM, and 990 nM, respectively. 3. Dipyridamole, an agent that blocks the cellular uptake of adenosine by red cells and causes its accumulation in plasma, also inhibited the synthesis of LTB4 in LPS and TNF-alpha-treated whole blood stimulated by FMLP; moreover, this inhibition was reversed upon addition of adenosine deaminase. 4. A highly selective antagonist of the adenosine A2 receptor, 8-(3-chlorostyryl)caffeine (CSC), reversed the inhibition of LTB4 synthesis by 2-Cl-adenosine and dipyridamole in LPS and TNF-alpha-treated whole blood, stimulated by FMLP. 5. LTB4 synthesis in whole blood originates predominantly from neutrophils and to a lesser extent from monocytes. 2-Cl-adenosine also inhibited the synthesis of LTB4 induced by FMLP in these isolated LPS and TNF-alpha-treated cells; however, 2-Cl-adenosine was a more potent inhibitor of LTB4 synthesis in neutrophils than monocytes. 6. The present data demonstrate that adenosine, acting through A2 receptors, exerts a potent inhibitory effect on the synthesis of LTB4 and thus contribute to the understanding of its anti-inflammatory properties.
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PMID:Adenosine A2 receptor-induced inhibition of leukotriene B4 synthesis in whole blood ex vivo. 873 71

Monophosphoryl lipid A (MLA), a derivative of the minimal substructure of lipopolysaccharide (lipid A) possesses immunomodulatory activity of the parent lipid A yet enjoys reduced toxicity. It has previously been reported that pretreatment with MLA reduces myocardial infarct size and stunning in dogs following ischemia and reperfusion. The aim of this study was to evaluate the ability of monophosphoryl lipid A (MLA) to preserve global cardiac function and peripheral hemodynamics in a rabbit model of prolonged regional ischemia (90 min), and reperfusion (6 h). An evaluation of potential mechanisms by which MLA may preserve cardiac function was also undertaken. Single dose pretreatment with MLA (35 micrograms/kg i.v.) 24 h prior to ischemia resulted in significant improvement in left ventricular developed pressure, dP/dt, rate-pressure product and mean arterial pressure during reperfusion (P < 0.05 v control). Although in this model of prolonged ischemia MLA pretreatment did not reduce infarct size (54.5 +/- 11.4% in control v 63.3 +/- 8.3% in MLA, P = N.S.), evaluation of myocardial adenylate and adenosine catabolite pools at the end of ischemia indicated a preservation of ATP and ADP and a decreased production of downstream adenosine catabolites including inosine, xanthine and uric acid. Adenosine kinase, but not 5'-nucleotidase (5'-NTase) or adenosine deaminase activity determined following reperfusion was 76% and 60% higher (P < 0.05) in non-risk and post-ischemic myocardium of MLA pretreated rabbits compared with controls. Although there was a trend toward lower tissue myeloperoxidase activity in post-ischemic myocardium from treated rabbits, the results were not significantly different from control animals. These results suggest that a 24-h pretreatment with MLA, without further treatment during ischemia or reperfusion was associated with: (1) preservation of global myocardial function during reperfusion; (2) preservation of myocardial high energy adenylates and reduced formation of adenosine catabolites during ischemia; (3) elevated myocardial adenosine kinase activity. Increased recycling of adenosine to phosphorylated nucleotides may result from MLA's affect on adenosine kinase, which could explain the drugs effect on adenylate and adenosine metabolite pools.
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PMID:Preservation of global cardiac function in the rabbit following protracted ischemia/reperfusion using monophosphoryl lipid A (MLA). 874 27

Immune cell activation releases ATP into the extracellular space. ATP-sensitive P2 purinergic receptors are expressed on immune cells and activation of these receptors alters immune cell function. Furthermore, ATP is metabolized by ectonucleotidases to adenosine, which has also been shown to alter cytokine production. In the present study, we investigated how extracellular ATP affects interleukin (IL)-12 and tumour necrosis factor (TNF)-alpha production in bacterial lipopolysaccharide (LPS)-treated murine peritoneal macrophages and we also examined whether extracellular ATP alters the production of the T helper 1 cytokine interferon (IFN)-gamma. Pretreatment of the peritoneal macrophages with ATP or various ATP analogues decreased both IL-12 and TNF-alpha production induced by LPS (10 microgram ml(-1)). The effect of ATP was partially reversed by cotreatment with adenosine deaminase (0.1 - 1 u ml(-1)), suggesting that the suppressive effect of ATP on cytokine production is, in part, due to its degradation products. Immunoneutralization with an anti-IL-10 antibody demonstrated that although ATP increases IL-10 production, the inhibition of IL-12 and TNF-alpha production is independent of the increased IL-10. The effect of ATP was pretranslational, as it suppressed steady state levels of mRNAs for IL-12 (both p35 and p40). In spleen cells stimulated with either LPS (10 microgram ml(-1)) or anti-CD3 (2 microgram ml(-1)) antibody, ATP suppressed, in a concentration-dependent manner, the production of IFN-gamma. These results suggest that extracellular ATP has multiple anti-inflammatory effects and that release of ATP into the extracellular space may play a role in blunting the overactive immune response in autoimmune diseases.
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PMID:ATP suppression of interleukin-12 and tumour necrosis factor-alpha release from macrophages. 1069 89

The purpose of this study was to investigate in vivo the effects of modulating the adenosine system on endotoxin-induced release of cytokines and changes in heart performance and neurohumoral status in early, profound endotoxemia in rats. Time/pressure variables of heart performance and blood pressure were recorded continuously, and plasma levels of tumor necrosis factor alpha (TNFalpha), interleukin 1-beta (IL-1beta), plasma renin activity (PRA), and catecholamines were determined before and 90 min after administration of endotoxin (30 mg/kg of lipopolysaccharide, i.v.). Erythro-9[2-hydroxyl-3-nonyl] adenine (EHNA; an adenosine deaminase inhibitor) had no effects on measured time-pressure variables of heart performance under baseline conditions and during endotoxemia, yet significantly attenuated endotoxin-induced release of cytokines and PRA. Pretreatment with the non-selective adenosine receptor antagonist DPSPX not only prevented the effects of EHNA but also increased the basal release of cytokines and augmented PRA. At baseline, caffeine (a non-selective adenosine receptor antagonist) increased HR, +dP/dtmax, heart rate x ventricular pressure product (HR x VPSP) and +dP/dtmax normalized by pressure (+dP/dtmax/VPSP), and these changes persisted during endotoxemia. Caffeine attenuated endotoxin-induced release of cytokines and augmented endotoxin-induced increases in plasma catecholamines and PRA. Pretreatment with propranolol abolished the effects of caffeine on heart performance and neurohumoral activation during the early phase of endotoxemia. 6N-cyclopentyladenosine (CPA; selective A1 adenosine receptor agonist) induced bradicardia and negative inotropic effects, reduced work load (i.e., decreased HR, VPSP, +dP/dtmax, +dP/dtmax/VPSP and HR x VPSP) and inhibited endotoxin-induced tachycardia and renin release. CGS 21680 (selective A2A adenosine receptor agonist) decreased blood pressure under basal condition but did not potentiate decreases in blood pressure during endotoxemia. CGS 21680 completely inhibited endotoxin-induced release of TNFalpha, augmented sympathetic activity and PRA, and increased +dP/dtmax and +dP/dtmax/VPSP in the absence and presence of endotoxin. The present study provides strong evidence that inhibition of adenosine deaminase reduces cytokine release in vivo without producing significant hemodynamic and cardiac effects during the early phase of profound endotoxemia in rats. The augmented neurohumoral activation induced by caffeine is associated with decreased cytokine release induced by endotoxin. Further studies are warranted to determine the impact of these effects on cardiac function and hemodynamics in the late phase of endotoxemia.
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PMID:Inhibition of adenosine deaminase attenuates endotoxin-induced release of cytokines in vivo in rats. 1153 Oct 21


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