The ‘danger’ sensors that STOP the immune response: the A2 adenosine receptors?

Sitkovsky, Michail V.; Ohta, Akio

doi:10.1016/j.it.2005.04.004

Cited by 245 publications

(256 citation statements)

References 47 publications

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“…The high expression levels of adenosine A 2A receptors in native PBL and their upregulation after stimulation of the cells have previously been reported [40,41]. These results underscore the importance of this receptor subtype as a mediator of antiinflammatory effects triggering the emergency downregulation of overactive immune cells [43]. On the other hand, the relatively high expression levels of adenosine A 2B receptors in cells of the malignant Jurkat T cell line compared to non-malignant PBL cells further indicate an important role of this subtype in malignant cell lines, as previously described [29,32].…”

Section: Discussionsupporting

confidence: 66%

Antiproliferative effects of selective adenosine receptor agonists and antagonists on human lymphocytes: evidence for receptor-independent mechanisms

Schiedel

Lacher

Linnemann

et al. 2013

Purinergic Signalling

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The effects of standard adenosine receptor (AR) agonists and antagonists on the proliferation of human T lymphocytes, unstimulated and phytohemagglutininstimulated human peripheral blood lymphocytes (PBL), and Jurkat T cells were investigated. Real-time PCR measurements confirmed the presence of all four AR subtypes on the investigated cells, although at different expression levels. A 2A ARs were predominantly expressed in PBL and further upregulated upon stimulation, while malignant Jurkat T cells showed high expression levels of A 1 , A 2A , and A 2B ARs. Cell proliferation was measured by [ 3 H]-thymidine incorporation assays. Several ligands, including the subtype-selective agonists CPA (A 1 ), BAY60-6583 (A 2B ), and IB-MECA (A 3 ), and the antagonists PSB-36 (A 1 ), MSX-2 (A 2A ), and PSB-10 (A 3 ) significantly inhibited cell proliferation at micromolar concentrations, which were about three orders of magnitude higher than their AR affinities. In contrast, further investigated AR ligands, including the agonists NECA (nonselective) and CGS21680 (A 2A ), and the antagonists preladenant (SCH-420814, A 2A ), PSB-1115 (A 2B ), and PSB-603 (A 2B ) showed no or only minor effects on lymphocyte proliferation. The anti-proliferative effects of the AR agonists could not be blocked by the corresponding antagonists. The non-selective AR antagonist caffeine stimulated phytohemagglutinin-activated PBL with an EC 50 value of 104 μM. This is the first study to compare a complete set of commonly used AR ligands for all subtypes on lymphocyte proliferation. Our results strongly suggest that these compounds induce an inhibition of lymphocyte proliferation and cell death through AR-independent mechanisms.

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Section: Discussionsupporting

confidence: 66%

Antiproliferative effects of selective adenosine receptor agonists and antagonists on human lymphocytes: evidence for receptor-independent mechanisms

Schiedel

Lacher

Linnemann

et al. 2013

Purinergic Signalling

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“…This profile stems from a handful of changes spanning pathways (i.e. Gnb1, Nfat2c, Acta1, Prkar2b, Map3k2 and Pde3b), supporting effects of A 2A R activity on G protein and cAMP/PKA signalling downstream of the receptor [5,8,60]. Deletion of the A 2A R has been shown to reduce cAMP and PKA activation in other cell types [61], consistent with impacts of KO here ( Table 3).…”

Section: Discussionsupporting

confidence: 77%

“…myocardial injury [1,2] is not only fundamentally important but also reveals targets for manipulating outcomes. In this regard, adenosine 2A receptors (A 2A Rs) may fulfil a broadly suppressive role to limit inflammatory injury in multiple tissues [3][4][5][6] and enhance myocardial resistance to ischaemic/hypoxic insult, presenting a potentially useful therapeutic target [3,7]. In heart, this G protein-coupled receptor (GPCR) influences coronary tone and angiogenesis, cardiac contractility, fibroblast growth and fibrosis and may mediate protection via ischaemic pre-and postconditioning [8][9][10].…”

Section: J Ashton and Melissa E Reichelt Denotes Equal First Authormentioning

confidence: 99%

Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium

Ashton

Reichelt

Mustafa

et al. 2016

Purinergic Signalling

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Influences of adenosine 2A receptor (A 2A R) activity on the cardiac transcriptome and genesis of endotoxemic myocarditis are unclear. We applied transcriptomic profiling (39 K Affymetrix arrays) to identify A 2A R-sensitive molecules, revealed by receptor knockout (KO), in healthy and endotoxemic hearts. Baseline cardiac function was unaltered and only 37 A 2A R-sensitive genes modified by A 2A R KO (≥1.2-fold change, <5 % FDR); the five most induced are Mtr, Ppbp, Chac1, Ctsk and Cnpy2 and the five most repressed are Hp, Yipf4, Acta1, Cidec and Map3k2. Few canonical paths were impacted, with altered Gnb1, Prkar2b, Pde3b and Map3k2 (among others) implicating modified G protein/cAMP/PKA and cGMP/NOS signalling. Lipopolysaccharide (LPS; 20 mg/kg) challenge for 24 h modified >4100 transcripts in wild-type (WT) myocardium (≥1.5-fold change, FDR < 1 %); the most induced are Lcn2 (+590); Saa3 (+516); Serpina3n (+122); Cxcl9 (+101) and Cxcl1 (+89) and the most repressed are Car3 (−38); Adipoq (−17); Atgrl1/Aplnr (−14); H19 (−11) and Itga8 (−8). Canonical responses centred on inflammation, immunity, cell death and remodelling, with pronounced amplification of tolllike receptor (TLR) and underlying JAK-STAT, NFκB and MAPK pathways, and a 'cardio-depressant' profile encompassing suppressed ß-adrenergic, PKA and Ca 2+ signalling, electromechanical and mitochondrial function (and major shifts in transcripts impacting function/injury including Lcn2, S100a8/S100a9, Icam1/Vcam and Nox2 induction, and Adipoq, Igf1 and Aplnr repression). Endotoxemic responses were selectively modified by A 2A R KO, supporting inflammatory suppression via A 2A R sensitive shifts in regulators of NFκB and JAK-STAT signalling (IκBζ, IκBα, STAT1, CDKN1a and RRAS2) without impacting the cardio-depressant gene profile. Data indicate A 2A Rs exert minor effects in un-stressed myocardium and selectively suppress NFκB and JAK-STATsignalling and cardiac injury without influencing cardiac depression in endotoxemia.

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“…Understanding how FOXP3 ϩ Treg cells respond to and integrate diverse cytokine signals that occur during inflammation (such as IL-6 plus TGF-␤) is clearly needed. Furthermore, it is also critical to elucidate how proinflammatory cytokine signals themselves are tightly regulated, such as by cAMP-elevating immunosuppressive G-protein-coupled receptors, which are now firmly implicated as one of the major regulators of immunosuppression (41,42). Moreover, the fact that HDACis modulate part of these signaling events at the chromatin level may provide insight into how they function to alter immune processes (9).…”

Section: Discussionmentioning

confidence: 99%

TGF-β and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3

Samanta

Li²,

Song³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

143

119

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The ‘danger’ sensors that STOP the immune response: the A2 adenosine receptors?

Cited by 245 publications

References 47 publications

Antiproliferative effects of selective adenosine receptor agonists and antagonists on human lymphocytes: evidence for receptor-independent mechanisms

Antiproliferative effects of selective adenosine receptor agonists and antagonists on human lymphocytes: evidence for receptor-independent mechanisms

Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium

TGF-β and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3

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