Ligand-Activation of the Adenosine A2a Receptors Inhibits IL-12 Production by Human Monocytes

Link, Amrey A.; Kino, Tomoshige; Worth, James A.; McGuire, Jennifer L.; Crane, Marianna; Chrousos, George P.; Wilder, Ronald L.; Elenkov, Ilia J.

doi:10.4049/jimmunol.164.1.436

Cited by 221 publications

(155 citation statements)

References 35 publications

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“…Stimulation of adenosine receptors has been shown to result in an anti-inflammatory, deactivated macrophage phenotype (16,17). In LPS-stimulated monocytes/macrophages, adenosine receptor activation attenuates the production of several proinflammatory cytokines, including TNF-␣ (18 -24) and IL-12 (22,25,26). In contrast to the suppressive effect of adenosine on the production of these proinflammatory mediators, adenosine up-regulates IL-10 production by LPS-stimulated monocytes/macrophages (22,26).…”

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confidence: 76%

“…In LPS-stimulated monocytes/macrophages, adenosine receptor activation attenuates the production of several proinflammatory cytokines, including TNF-␣ (18 -24) and IL-12 (22,25,26). In contrast to the suppressive effect of adenosine on the production of these proinflammatory mediators, adenosine up-regulates IL-10 production by LPS-stimulated monocytes/macrophages (22,26). The mode of action of adenosine in up-regulating IL-10 production is unclear and so is the identity of receptors responsible for the adenosine enhancement of IL-10 production in LPS-activated macrophages.…”

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confidence: 99%

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Adenosine Augments IL-10 Production by Macrophages through an A2B Receptor-Mediated Posttranscriptional Mechanism

Németh¹,

Lutz²,

Csóka³

et al. 2005

The Journal of Immunology

244

161

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Adenosine receptor ligands have anti-inflammatory effects and modulate immune responses by up-regulating IL-10 production by immunostimulated macrophages. The adenosine receptor family comprises G protein-coupled heptahelical transmembrane receptors classified into four types: A1, A2A, A2B, and A3. Our understanding of the signaling mechanisms leading to enhanced IL-10 production following adenosine receptor occupancy on macrophages is limited. In this study, we demonstrate that adenosine receptor occupancy increases IL-10 production by LPS-stimulated macrophages without affecting IL-10 promoter activity and IL-10 mRNA levels, indicating a posttranscriptional mechanism. Transfection experiments with reporter constructs containing sequences corresponding to the AU-rich 3′-untranslated region (UTR) of IL-10 mRNA confirmed that adenosine receptor activation acts by relieving the translational repressive effect of the IL-10 3′-UTR. By contrast, adenosine receptor activation failed to liberate the translational arrest conferred by the 3′-UTR of TNF-α mRNA. The IL-10 3′-UTR formed specific complexes with proteins present in cytoplasmic extracts of RAW 264.7 cells. Adenosine enhanced binding of proteins to a region of the IL-10 3′-UTR containing the GUAUUUAUU nonamer. The stimulatory effect of adenosine on IL-10 production was mediated through the A2B receptor, because the order of potency of selective agonists was 5′-N-ethylcarboxamidoadenosine (NECA) > N6-(3-iodobenzyl)-adenosine-5′-N-methyluronamide (IB-MECA) > 2-chloro-N6-cyclopentyladenosine (CCPA) = 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethyl-carboxamidoadenosine (CGS-21680). Also, the selective A2B antagonist, alloxazine, prevented the effect of adenosine. Collectively, these studies identify a novel pathway in which activation of a G protein-coupled receptor augments translation of an anti-inflammatory gene.

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confidence: 76%

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confidence: 99%

Adenosine Augments IL-10 Production by Macrophages through an A2B Receptor-Mediated Posttranscriptional Mechanism

Németh¹,

Lutz²,

Csóka³

et al. 2005

The Journal of Immunology

244

161

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“…Activation of the A3AR, which inhibits adenylyl cyclase activity and decreases cAMP levels, may thus lead to the activation of NK cells. Link et al (2000) showed that a specific A2a receptor agonist inhibited the production of IL-12 in whole blood and monocyte cultures. In addition, in vivo studies by Hasko et al (1998) resulting in IL-12 downregulation, whereas low doses, as was used in this study, exclusively activate the A3AR and will results in IL-12 upregulation and potentiation of NK cell activity.…”

Section: A3 Adenosine Receptor Agonists Inhibit Colon Carcinoma G Ohamentioning

confidence: 99%

Inhibition of primary colon carcinoma growth and liver metastasis by the A3 adenosine receptor agonist CF101

et al. 2003

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Adenosine is a purine nucleoside that acts as a regulatory molecule by binding to specific G-protein-coupled A1, A 2A , A 2B , and A3 cell surface receptors. We have recently demonstrated that adenosine inhibits tumour cell growth and concomitantly stimulates bone marrow cell proliferation via activation of the A3 adenosine receptor (A3AR). In the present study, we show that a synthetic agonist to the A3AR, CF101, at the low nanomolar concentration range, inhibits HCT-116 human colon carcinoma cell growth. This effect was reversed by the selective A3AR antagonist MRS1523, demonstrating the specificity of the response. CF101 (given orally) was efficacious in inhibiting the development of primary tumours in xenograft and syngeneic models in which mice were inoculated subcutaneously with human HCT-116 or murine CT-26 colon carcinoma cells, respectively. Moreover, CF101 suppressed (50%, Po0.01) colon cancer liver metastases in syngeneic mice inoculated to the spleen with CT-26 cells. The mechanism of action entailed upregulation of interleukin-12 production in the CF101-treated groups and potentiation of NK cell activity. In the HCT-116 xenograft model in which a combined therapy of CF101 and 5-fluorouracyl (5-FU) was examined, an additive antitumour effect was demonstrated. Moreover, CF101 prevented the 5-FU-induced myelotoxicity, resulting in normal values of white blood cell and neutrophil counts. We conclude that the A3AR agonist CF101, a small orally bioavailable molecule, exerts systemic anticancer, antimetastatic, and myeloprotective effects in colon carcinoma-bearing mice, and may serve as an adjuvant treatment to enhance the chemotherapeutic index and prevent myelotoxicity.

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“…It has also been shown by other labs and us that LPS-induced IL-12 expression can be greatly downregulated by cAMP inducers [1], [13], [19], [20]. However there is little information about the mechanism for cAMP-signal-inhibitory effect on LPS-induced IL-12 expression in macrophages.…”

Section: Introductionmentioning

confidence: 99%

cAMP elevators inhibit LPS-induced IL-12 p40 expression by interfering with phosphorylation of p38 MAPK in Murine Peritoneal Macrophages

et al. 2002

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mediated signaling may play a suppressive role in immune response. We previously found that the cAMPelevators (CTx and 8-Br-cAMP) inhibited IL-12, IL-1a, IL-6 gene expression, but increased the transcriptional levels of IL-10 and IL-1Ra in LPS-treated murine peritoneal macrophages. The present study examined a possible molecular mechanism involved in cAMP elevators-induced inhibition of IL-12 p40 expression in response to LPS. Our data demonstrated that cAMP elevators downregulated IL-12 p40 mRNA expression and IL-12 p70 production in murine peritoneal macrophages. Subsequent studies revealed that cAMP-elevators blocked phosphorylation of p38 MAPK, but did not affect the activity of NF-B binding to . This is the first report that cAMP elevators inhibit LPS-induced IL-12 production by a mechanism that is associated, at least in part, with p38-dependent inhibition by cAMP signaling pathways.

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Ligand-Activation of the Adenosine A2a Receptors Inhibits IL-12 Production by Human Monocytes

Cited by 221 publications

References 35 publications

Adenosine Augments IL-10 Production by Macrophages through an A2B Receptor-Mediated Posttranscriptional Mechanism

Adenosine Augments IL-10 Production by Macrophages through an A2B Receptor-Mediated Posttranscriptional Mechanism

Inhibition of primary colon carcinoma growth and liver metastasis by the A3 adenosine receptor agonist CF101

cAMP elevators inhibit LPS-induced IL-12 p40 expression by interfering with phosphorylation of p38 MAPK in Murine Peritoneal Macrophages

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