Adenosine Inhibits Tumor Necrosis Factor-α Release from Mouse Peritoneal Macrophages via A2Aand A2Bbut Not the A3Adenosine Receptor

Kreckler, Laura M.; Wan, Tina C.; Ge, Zhi‐Dong; Auchampach, John A.

doi:10.1124/jpet.105.096016

Cited by 183 publications

(178 citation statements)

References 32 publications

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“…We have demonstrated that this action of adenosine is mediated by the A 2B receptor and involves an increase in cAMP. The A 2B receptor has previously been found to exert an anti-inflammatory action on murine macrophages [28] and mast cells [33,34]. The importance of both A 2A and A 2B receptors in protection against inflammation is supported by the study of mice deficient in these receptors: A 2A -/- [18] and A 2B -/- [35] mice exhibit exacerbated responses in various models of inflammation.…”

Section: Discussionmentioning

confidence: 55%

Modulation of murine dendritic cell function by adenine nucleotides and adenosine: Involvement of the A_2B receptor

et al. 2008

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BelgiumAdenosine 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 0 -(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 0 -(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 downregulated. 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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Section: Discussionmentioning

confidence: 55%

Modulation of murine dendritic cell function by adenine nucleotides and adenosine: Involvement of the A_2B receptor

et al. 2008

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“…In addition, CGS 21680 potently decreased TNF-α production by A 2A WT macrophages but it failed to influence TNF-α release by KO cells (Hasko, Kuhel, Chen et al, 2000). On the other hand, A 3 receptors are not involved in the suppressive effect of adenosine, because adenosine inhibited TNF-α production with the same potency by macrophages isolated from A 3 receptor KO mice as by cells from WT mice (Kreckler et al, 2006). Moreover, the A 2A receptor-independent portion of the adenosine effect that we observed (Hasko, Kuhel, Chen et al, 2000) appears to be secondary to A 2B receptors, because MRS 1754 was able to completely antagonize this adenosine-induced A 2A -independent effect (Kreckler et al, 2006).…”

Section: Mouse Monocytes/macrophages-adenosine Is a Strong Inhibitor mentioning

confidence: 85%

“…On the other hand, A 3 receptors are not involved in the suppressive effect of adenosine, because adenosine inhibited TNF-α production with the same potency by macrophages isolated from A 3 receptor KO mice as by cells from WT mice (Kreckler et al, 2006). Moreover, the A 2A receptor-independent portion of the adenosine effect that we observed (Hasko, Kuhel, Chen et al, 2000) appears to be secondary to A 2B receptors, because MRS 1754 was able to completely antagonize this adenosine-induced A 2A -independent effect (Kreckler et al, 2006). In summary, TNF-α production by monocytes/macrophages can be subject to inhibition by A 1 , A 2A , and A 3 receptors and the receptor subtype involved depends on many factors, which include the source of cell, the species, and the inflammatory stimulus used.…”

Section: Mouse Monocytes/macrophages-adenosine Is a Strong Inhibitor mentioning

confidence: 99%

Shaping of monocyte and macrophage function by adenosine receptors

Haskó

Pacher

Deitch

et al. 2007

Pharmacology & Therapeutics

196

154

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Adenosine is an endogenous purine nucleoside that, following its release into the extracellular space, binds to specific adenosine receptors expressed on the cell surface. Adenosine appears in the extracellular space under metabolically stressful conditions, which are associated with ischemia, inflammation, and cell damage. There are 4 types of adenosine receptors (A 1 , A 2A , A 2B and A 3 ) and all adenosine receptors are members of the G protein-coupled family of receptors. Adenosine receptors are expressed on monocytes and macrophages and through these receptors adenosine modulates monocyte and macrophage function. Since monocytes and macrophages are activated by the same danger signals that cause accumulation of extracellular adenosine, adenosine receptors expressed on macrophages represent a sensor system that provide monocytes and macrophages with information about the stressful environment. Adenosine receptors, thus, allow monocytes and macrophages to fine-tune their responses to stressful stimuli. Here, we review the consequences of adenosine receptor activation on monocyte/macrophage function. We will detail the effect of stimulating the various adenosine receptor subtypes on macrophage differentiation/proliferation, phagocytosis, and tissue factor (TF) expression. We will also summarize our knowledge of how adenosine impacts the production of extracellular mediators secreted by monocytes and macrophages in response to toll-like receptor (TLR) ligands and other inflammatory stimuli. Specifically, we will delineate how adenosine affects the production of superoxide, nitric oxide (NO), tumor necrosis factor-α, interleukin (IL)-12, IL-10, and vascular endothelial growth factor (VEGF). A deeper insight into the regulation of monocyte and macrophage function by adenosine receptors should assist in developing new therapies for inflammatory diseases.

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“…Indeed these cytokines have a critical modulatory action in the acute pleural inflammatory reaction caused by carrageenan [55] promoting the recruitment of leukocytes and expression of adhesion molecules at the site of inflammation [56,57]. Accordingly, literature has also shown that adenosine A 2A receptor is the predominant receptor subtype responsible for inhibiting TNF-α production [58]. Regarding the quick metabolism of adenosine into inosine and it synergic effects showed here, we can hypothesize that in acute pleural inflammation the adenosine effects in reducing cytokine levels are due to adenosine conversion into inosine mediated via A 2A receptors.…”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory effects of purine nucleosides, adenosine and inosine, in a mouse model of pleurisy: evidence for the role of adenosine A2 receptors

Lapa

Silva

Cabrini

et al. 2012

Purinergic Signalling

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Adenosine and its metabolite, inosine, have been described as molecules that participate in regulation of inflammatory response. The aim of this study was to investigate the effect of adenosine and inosine in a mouse model of carrageenan-induced pleurisy as well as the participation of adenosine receptors in this response. Injection of carrageenan into the pleural cavity induced an acute inflammatory response characterized by leukocyte migration, pleural exudation, and increased release of interleukin-1β and tumor necrosis factor-α in pleural exudates. The treatment with adenosine (0.3-100 mg/kg, i.p.) and inosine (0.1-300 mg/ kg, i.p.) 30 min before carrageenan injection reduced significantly all these parameters analyzed. Our results also demonstrated that A 2A and A 2B receptors seem to mediate the adenosine and inosine effects observed, since pretreatment with selective antagonists of adenosine A 2A (ZM241385) and A 2B (alloxazine) receptors, reverted the inhibitory effects of adenosine and inosine in pleural inflammation. The involvement of A 2 receptors was reinforced with adenosine receptor agonist CGS21680 treatment, since its anti-inflammatory effects were reversed completely and partially with ZM241385 and alloxazine injection, respectively. Moreover, the combined treatment with subeffective dose of adenosine (0.3 mg/kg) and inosine (1.0 mg/kg) induced a synergistic anti-inflammatory effect. Thus, based on these findings, we propose that inosine contributes with adenosine to exert anti-inflammatory effects in pleural inflammation, reinforcing the notion that endogenous nucleosides play an important role in controlling inflammatory diseases. This effect is likely mediated by the activation of adenosine A 2 subtype receptors and inhibition of production or release of pro-inflammatory cytokines.

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Adenosine Inhibits Tumor Necrosis Factor-α Release from Mouse Peritoneal Macrophages via A_2Aand A_2Bbut Not the A₃Adenosine Receptor

Cited by 183 publications

References 32 publications

Modulation of murine dendritic cell function by adenine nucleotides and adenosine: Involvement of the A_2B receptor

Modulation of murine dendritic cell function by adenine nucleotides and adenosine: Involvement of the A_2B receptor

Shaping of monocyte and macrophage function by adenosine receptors

Anti-inflammatory effects of purine nucleosides, adenosine and inosine, in a mouse model of pleurisy: evidence for the role of adenosine A2 receptors

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Adenosine Inhibits Tumor Necrosis Factor-α Release from Mouse Peritoneal Macrophages via A2Aand A2Bbut Not the A3Adenosine Receptor

Cited by 183 publications

References 32 publications

Modulation of murine dendritic cell function by adenine nucleotides and adenosine: Involvement of the A2B receptor

Modulation of murine dendritic cell function by adenine nucleotides and adenosine: Involvement of the A2B receptor

Shaping of monocyte and macrophage function by adenosine receptors

Anti-inflammatory effects of purine nucleosides, adenosine and inosine, in a mouse model of pleurisy: evidence for the role of adenosine A2 receptors

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Adenosine Inhibits Tumor Necrosis Factor-α Release from Mouse Peritoneal Macrophages via A_2Aand A_2Bbut Not the A₃Adenosine Receptor

Modulation of murine dendritic cell function by adenine nucleotides and adenosine: Involvement of the A_2B receptor

Modulation of murine dendritic cell function by adenine nucleotides and adenosine: Involvement of the A_2B receptor