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Didier Communi - One of the best experts on this subject based on the ideXlab platform.
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modulation of murine dendritic cell function by Adenine Nucleotides and adenosine involvement of the a2b receptor
European Journal of Immunology, 2008Co-Authors: Abduelhakem Ben Addi, Jeanmarie Boeynaems, Didier Communi, Anne Lefort, Frederick Libert, Catherine Ledent, Pascale Macours, Stephen L Tilley, Bernard RobayeAbstract:Adenosine triphosphate has previously been shown to induce semi-mature human monocyte-derived dendritic cells (DC). These are characterized by the up-regulation of co-stimulatory molecules, the inhibition of IL-12 and the up-regulation of some genes involved in immune tolerance, such as thrombospondin-1 and indoleamine 2,3-dioxygenase. The actions of adenosine triphosphate are mediated by the P2Y(11) receptor; since there is no functional P2Y(11) gene in the murine genome, we investigated the action of Adenine Nucleotides on murine DC. Adenosine 5'-(3-thiotriphosphate) and adenosine inhibited the production of IL-12p70 by bone marrow-derived DC (BMDC). These inhibitions were relieved by 8-p-sulfophenyltheophylline, an adenosine receptor antagonist. The use of selective ligands and A(2B) (-/-) BMDC indicated the involvement of the A(2B) receptor. A microarray experiment, confirmed by quantitative PCR, showed that, in presence of LPS, 5'-(N-ethylcarboxamido) adenosine (NECA, the most potent A(2B) receptor agonist) regulated the expression of several genes: arginase I and II, thrombospondin-1 and vascular endothelial growth factor were up-regulated whereas CCL2 and CCL12 were down-regulated. We further showed that NECA, in combination with LPS, increased the arginase I enzymatic activity. In conclusion, the described actions of Adenine Nucleotides on BMDC are mediated by their degradation product, adenosine, acting on the A(2B) receptor, and will possibly lead to an impairment of Th1 response or tolerance.
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extracellular Adenine Nucleotides inhibit the release of major monocyte recruiters by human monocyte derived dendritic cells
FEBS Letters, 2006Co-Authors: Michael Horckmans, Brice Marcet, Frederic Marteau, Frederic Bulte, Arielle Maho, Marc Parmentier, Jeanmarie Boeynaems, Didier CommuniAbstract:Extracellular ATP is known to affect the maturation of monocyte-derived dendritic cells mainly by regulation of cytokines and costimulatory molecules. The present study describes the inhibition of MCP-1 (CCL2) and MIP-1alpha (CCL3) release by human monocyte-derived dendritic cells in response to Adenine Nucleotides. Our pharmacological data support the involvement of P2Y11 and P2Y1 purinergic receptors in the downregulation of these major monocyte recruiters. Migration assays have demonstrated that supernatants of dendritic cells treated with Adenine Nucleotides or anti-MCP-1/MIP-1alpha blocking antibodies display a strongly reduced capacity to attract monocytes and immature dendritic cells.
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extracellular Adenine Nucleotides inhibit the activation of human cd4 t lymphocytes
Journal of Immunology, 2002Co-Authors: Xavier Duhant, Jeanmarie Boeynaems, Liliane Schandene, Catherine Bruyns, Nathalie Suarez Gonzalez, Michel Goldman, Didier CommuniAbstract:ATP has been reported to inhibit or stimulate lymphoid cell proliferation, depending on the origin of the cells. Agents that increase cAMP, such as PGE 2 , inhibit human CD4 + T cell activation. We demonstrate that several ATP derivatives increase cAMP in both freshly purified and activated human peripheral blood CD4 + T cells. The rank order of potency of the various Nucleotides was: adenosine 5′- O -(3-thiotriphosphate) (ATPγS) ≈ 2′- and 3′- O -(4-benzoylbenzoyl) ATP (BzATP) > ATP > 2-methylthio-ATP ≫ dATP, 2-propylthio-β,γ-dichloromethylene-d-ATP, UDP, UTP. This effect did not involve the activation of A 2 Rs by adenosine or the synthesis of prostaglandins. ATPγS had no effect on cytosolic calcium, whereas BzATP induced an influx of extracellular calcium. ATPγS and BzATP inhibited secretion of IL-2, IL-5, IL-10, and IFN-γ; expression of CD25; and proliferation after activation of CD4 + T cells by immobilized anti-CD3 and soluble anti-CD28 Abs, without increasing cell death. Taken together, our results suggest that extracellular Adenine Nucleotides inhibit CD4 + T cell activation via an increase in cAMP mediated by an unidentified P2YR, which might thus constitute a new therapeutic target in immunosuppressive treatments.
Ursula Windscheif - One of the best experts on this subject based on the ideXlab platform.
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inhibitory action of ppads on relaxant responses to Adenine Nucleotides or electrical field stimulation in guinea pig taenia coli and rat duodenum
British Journal of Pharmacology, 1995Co-Authors: Ursula Windscheif, Otmar Pfaff, A U Ziganshin, Charles H V Hoyle, Hans G Baumert, E Mutschler, Geoffrey Burastock, Gunter LambrechtAbstract:1. The effect of pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) on the relaxant response to Adenine Nucleotides was examined in the carbachol-contracted guinea-pig taenia coli and rat duodenum, two tissues possessing P2y-purinoceptors. In addition, in the taenia coli PPADS was investigated for its effect on relaxations evoked by adenosine, noradrenaline and electrical field stimulation. In order to assess the selectivity of PPADS between P2-purinoceptor blockade and ectonucleotidase activity, its influence on ATP degradation was studied in guinea-pig taenia coli. 2. The resulting rank order of potency for the Adenine Nucleotides in guinea-pig taenia coli was: 2-methylthio ATP >> ATP > alpha,beta-methylene ATP with the respective pD2-values 7.96 +/- 0.08 (n = 23), 6.27 +/- 0.12 (n = 21) and 5.88 +/- 0.04 (n = 24). 3. In guinea-pig taenia coli, PPADS (10-100 microM) caused a consistent dextral shift of the concentration-response curve (CRC) of 2-methylthio ATP and ATP resulting in a biphasic Schild plot. A substantial shift was only observed at 100 microM PPADS, the respective pA2-values at this particular concentration were 5.26 +/- 0.16 (n = 5) and 5.15 +/- 0.13 (n = 6). Lower concentrations of PPADS (3-30 microM) antagonized the relaxant effects to alpha,beta-methylene ATP in a surmountable manner. An extensive shift of the CRC was produced only by 30 microM PPADS (pA2 = 5.97 +/- 0.08, n = 6), and the Schild plot was again biphasic.(ABSTRACT TRUNCATED AT 250 WORDS)
Elizabeth V. Menshikova - One of the best experts on this subject based on the ideXlab platform.
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Characterization of the N^6-etheno-bridge method to assess extracellular metabolism of Adenine Nucleotides: detection of a possible role for purine nucleoside phosphorylase in adenosine metabolism
Purinergic Signalling, 2020Co-Authors: Edwin K. Jackson, Delbert G. Gillespie, Dongmei Cheng, Zaichuan Mi, Elizabeth V. MenshikovaAbstract:The goal of this study was to determine the validity of using N^6-etheno-bridged Adenine Nucleotides to evaluate ecto-nucleotidase activity. We observed that the metabolism of N^6-etheno-ATP versus ATP was quantitatively similar when incubated with recombinant CD39, ENTPD2, ENTPD3, or ENPP-1, and the quantitative metabolism of N^6-etheno-AMP versus AMP was similar when incubated with recombinant CD73. This suggests that ecto-nucleotidases process N^6-etheno-bridged Adenine Nucleotides similarly to endogenous Adenine Nucleotides. Four cell types rapidly ( t _1/2, 0.21 to 0.66 h) metabolized N^6-etheno-ATP. Applied N^6-etheno-ATP was recovered in the medium as N^6-etheno-ADP, N^6-etheno-AMP, N^6-etheno-adenosine, and surprisingly N^6-etheno-Adenine; intracellular N^6-etheno compounds were undetectable. This suggests minimal cellular uptake, intracellular metabolism, or deamination of these compounds. N^6-etheno-ATP, N^6-etheno-ADP, N^6-etheno-AMP, N^6-etheno-adenosine, and N^6-etheno-Adenine had little affinity for recombinant A_1, A_2A, or A_2B receptors, for a subset of P2X receptors (^3H-α,β-methylene-ATP binding to rat bladder membranes), or for a subset of P2Y receptors (^35S-ATP-αS binding to rat brain membranes), suggesting minimal pharmacological activity. N^6-etheno-adenosine was partially converted to N^6-etheno-Adenine in four different cell types; this was blocked by purine nucleoside phosphorylase (PNPase) inhibition. Intravenous N^6-etheno-ATP was quickly metabolized, with N^6-etheno-Adenine being the main product in naïve rats, but not in rats pretreated with a PNPase inhibitor. PNPase inhibition reduced the urinary excretion of endogenous Adenine and attenuated the conversion of exogenous adenosine to Adenine in the renal cortex. The N^6-etheno-bridge method is a valid technique to assess extracellular metabolism of Adenine Nucleotides by ecto-nucleotidases. Also, rats express an enzyme with PNPase-like activity that metabolizes N^6-etheno-adenosine to N^6-etheno-Adenine.
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characterization of the n 6 etheno bridge method to assess extracellular metabolism of Adenine Nucleotides detection of a possible role for purine nucleoside phosphorylase in adenosine metabolism
Purinergic Signalling, 2020Co-Authors: Edwin K. Jackson, Delbert G. Gillespie, Dongmei Cheng, Zaichuan Mi, Elizabeth V. MenshikovaAbstract:The goal of this study was to determine the validity of using N(6)-etheno-bridged Adenine Nucleotides to evaluate ecto-nucleotidase activity. We observed that the metabolism of N(6)-etheno-ATP versus ATP was quantitatively similar when incubated with recombinant CD39, ENTPD2, ENTPD3, or ENPP-1, and the quantitative metabolism of N(6)-etheno-AMP versus AMP was similar when incubated with recombinant CD73. This suggests that ecto-nucleotidases process N(6)-etheno-bridged Adenine Nucleotides similarly to endogenous Adenine Nucleotides. Four cell types rapidly (t1/2, 0.21 to 0.66 h) metabolized N(6)-etheno-ATP. Applied N(6)-etheno-ATP was recovered in the medium as N(6)-etheno-ADP, N(6)-etheno-AMP, N(6)-etheno-adenosine, and surprisingly N(6)-etheno-Adenine; intracellular N(6)-etheno compounds were undetectable. This suggests minimal cellular uptake, intracellular metabolism, or deamination of these compounds. N(6)-etheno-ATP, N(6)-etheno-ADP, N(6)-etheno-AMP, N(6)-etheno-adenosine, and N(6)-etheno-Adenine had little affinity for recombinant A1, A2A, or A2B receptors, for a subset of P2X receptors ((3)H-alpha,beta-methylene-ATP binding to rat bladder membranes), or for a subset of P2Y receptors ((35)S-ATP-alphaS binding to rat brain membranes), suggesting minimal pharmacological activity. N(6)-etheno-adenosine was partially converted to N(6)-etheno-Adenine in four different cell types; this was blocked by purine nucleoside phosphorylase (PNPase) inhibition. Intravenous N(6)-etheno-ATP was quickly metabolized, with N(6)-etheno-Adenine being the main product in naive rats, but not in rats pretreated with a PNPase inhibitor. PNPase inhibition reduced the urinary excretion of endogenous Adenine and attenuated the conversion of exogenous adenosine to Adenine in the renal cortex. The N(6)-etheno-bridge method is a valid technique to assess extracellular metabolism of Adenine Nucleotides by ecto-nucleotidases. Also, rats express an enzyme with PNPase-like activity that metabolizes N(6)-etheno-adenosine to N(6)-etheno-Adenine.
Jeanmarie Boeynaems - One of the best experts on this subject based on the ideXlab platform.
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modulation of murine dendritic cell function by Adenine Nucleotides and adenosine involvement of the a2b receptor
European Journal of Immunology, 2008Co-Authors: Abduelhakem Ben Addi, Jeanmarie Boeynaems, Didier Communi, Anne Lefort, Frederick Libert, Catherine Ledent, Pascale Macours, Stephen L Tilley, Bernard RobayeAbstract:Adenosine triphosphate has previously been shown to induce semi-mature human monocyte-derived dendritic cells (DC). These are characterized by the up-regulation of co-stimulatory molecules, the inhibition of IL-12 and the up-regulation of some genes involved in immune tolerance, such as thrombospondin-1 and indoleamine 2,3-dioxygenase. The actions of adenosine triphosphate are mediated by the P2Y(11) receptor; since there is no functional P2Y(11) gene in the murine genome, we investigated the action of Adenine Nucleotides on murine DC. Adenosine 5'-(3-thiotriphosphate) and adenosine inhibited the production of IL-12p70 by bone marrow-derived DC (BMDC). These inhibitions were relieved by 8-p-sulfophenyltheophylline, an adenosine receptor antagonist. The use of selective ligands and A(2B) (-/-) BMDC indicated the involvement of the A(2B) receptor. A microarray experiment, confirmed by quantitative PCR, showed that, in presence of LPS, 5'-(N-ethylcarboxamido) adenosine (NECA, the most potent A(2B) receptor agonist) regulated the expression of several genes: arginase I and II, thrombospondin-1 and vascular endothelial growth factor were up-regulated whereas CCL2 and CCL12 were down-regulated. We further showed that NECA, in combination with LPS, increased the arginase I enzymatic activity. In conclusion, the described actions of Adenine Nucleotides on BMDC are mediated by their degradation product, adenosine, acting on the A(2B) receptor, and will possibly lead to an impairment of Th1 response or tolerance.
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extracellular Adenine Nucleotides inhibit the release of major monocyte recruiters by human monocyte derived dendritic cells
FEBS Letters, 2006Co-Authors: Michael Horckmans, Brice Marcet, Frederic Marteau, Frederic Bulte, Arielle Maho, Marc Parmentier, Jeanmarie Boeynaems, Didier CommuniAbstract:Extracellular ATP is known to affect the maturation of monocyte-derived dendritic cells mainly by regulation of cytokines and costimulatory molecules. The present study describes the inhibition of MCP-1 (CCL2) and MIP-1alpha (CCL3) release by human monocyte-derived dendritic cells in response to Adenine Nucleotides. Our pharmacological data support the involvement of P2Y11 and P2Y1 purinergic receptors in the downregulation of these major monocyte recruiters. Migration assays have demonstrated that supernatants of dendritic cells treated with Adenine Nucleotides or anti-MCP-1/MIP-1alpha blocking antibodies display a strongly reduced capacity to attract monocytes and immature dendritic cells.
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extracellular Adenine Nucleotides modulate cytokine production by human monocyte derived dendritic cells dual effect on il 12 and stimulation of il 10
European Journal of Immunology, 2002Co-Authors: Francoise Wilkin, Jeanmarie Boeynaems, Michel Goldman, Patrick Stordeur, Bernard RobayeAbstract:To clarify the functional consequences of Adenine Nucleotides action on human monocyte-derived dendritic cells (DC), we have systematically compared the effects of adenosine 5′-O-(3-thiotriphosphate) (ATPγS), an ATP analog active on the P2Y11 receptor, on the responses to three DC stimuli, TNF-α, LPS, sCD40L, tested at various concentrations, using two different IL-12 assays. We observed that ATPγS potentiated the IL-12p40 release induced by TNF-α, but also by lipopolysaccharides (LPS) and soluble CD40 ligand (sCD40L). This potentiation was observed as long as the IL-12p40 concentration under agonist stimulation remained below a threshold value close to 10 ng/ml; inhibition was observed above this value. The combinations ATPγS-TNF-α and ATPγS-sCD40L were unable to induce detectable bioactive IL-12p70 production and at concentrations of LPS that induced a significant stimulation of IL-12p70, the effect of ATPγS was purely inhibitory. Our results also show that ATPγS synergized with LPS and sCD40L, but not TNF-α, to stimulate IL-10 production. In conclusion, we have clarified the discrepancies in the literature concerningthe action of Adenine Nucleotides on DC and our study supports the concept that, like prostaglandin E2 and other agents increasing cyclic AMP, they favor either a Th2 response or tolerance.
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extracellular Adenine Nucleotides inhibit the activation of human cd4 t lymphocytes
Journal of Immunology, 2002Co-Authors: Xavier Duhant, Jeanmarie Boeynaems, Liliane Schandene, Catherine Bruyns, Nathalie Suarez Gonzalez, Michel Goldman, Didier CommuniAbstract:ATP has been reported to inhibit or stimulate lymphoid cell proliferation, depending on the origin of the cells. Agents that increase cAMP, such as PGE 2 , inhibit human CD4 + T cell activation. We demonstrate that several ATP derivatives increase cAMP in both freshly purified and activated human peripheral blood CD4 + T cells. The rank order of potency of the various Nucleotides was: adenosine 5′- O -(3-thiotriphosphate) (ATPγS) ≈ 2′- and 3′- O -(4-benzoylbenzoyl) ATP (BzATP) > ATP > 2-methylthio-ATP ≫ dATP, 2-propylthio-β,γ-dichloromethylene-d-ATP, UDP, UTP. This effect did not involve the activation of A 2 Rs by adenosine or the synthesis of prostaglandins. ATPγS had no effect on cytosolic calcium, whereas BzATP induced an influx of extracellular calcium. ATPγS and BzATP inhibited secretion of IL-2, IL-5, IL-10, and IFN-γ; expression of CD25; and proliferation after activation of CD4 + T cells by immobilized anti-CD3 and soluble anti-CD28 Abs, without increasing cell death. Taken together, our results suggest that extracellular Adenine Nucleotides inhibit CD4 + T cell activation via an increase in cAMP mediated by an unidentified P2YR, which might thus constitute a new therapeutic target in immunosuppressive treatments.
Gunter Lambrecht - One of the best experts on this subject based on the ideXlab platform.
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inhibitory action of ppads on relaxant responses to Adenine Nucleotides or electrical field stimulation in guinea pig taenia coli and rat duodenum
British Journal of Pharmacology, 1995Co-Authors: Ursula Windscheif, Otmar Pfaff, A U Ziganshin, Charles H V Hoyle, Hans G Baumert, E Mutschler, Geoffrey Burastock, Gunter LambrechtAbstract:1. The effect of pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) on the relaxant response to Adenine Nucleotides was examined in the carbachol-contracted guinea-pig taenia coli and rat duodenum, two tissues possessing P2y-purinoceptors. In addition, in the taenia coli PPADS was investigated for its effect on relaxations evoked by adenosine, noradrenaline and electrical field stimulation. In order to assess the selectivity of PPADS between P2-purinoceptor blockade and ectonucleotidase activity, its influence on ATP degradation was studied in guinea-pig taenia coli. 2. The resulting rank order of potency for the Adenine Nucleotides in guinea-pig taenia coli was: 2-methylthio ATP >> ATP > alpha,beta-methylene ATP with the respective pD2-values 7.96 +/- 0.08 (n = 23), 6.27 +/- 0.12 (n = 21) and 5.88 +/- 0.04 (n = 24). 3. In guinea-pig taenia coli, PPADS (10-100 microM) caused a consistent dextral shift of the concentration-response curve (CRC) of 2-methylthio ATP and ATP resulting in a biphasic Schild plot. A substantial shift was only observed at 100 microM PPADS, the respective pA2-values at this particular concentration were 5.26 +/- 0.16 (n = 5) and 5.15 +/- 0.13 (n = 6). Lower concentrations of PPADS (3-30 microM) antagonized the relaxant effects to alpha,beta-methylene ATP in a surmountable manner. An extensive shift of the CRC was produced only by 30 microM PPADS (pA2 = 5.97 +/- 0.08, n = 6), and the Schild plot was again biphasic.(ABSTRACT TRUNCATED AT 250 WORDS)