Fall in oxygen tension of culture medium stimulates the adenosinergic signalling of a human T cell line

By, Youlet; Jacquin, Laurent; Franceschi, Frédéric; Durand‐Gorde, Josée‐Martine; Condo, Jocelyne; Michelet, Pierre; Guieu, Régis; Ruf, Jean

doi:10.1007/s11302-012-9295-6

Cited by 11 publications

(10 citation statements)

References 33 publications

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“…We conducted four experimental conditions in culture medium supplemented with PMA + PHA: the control situation, hypoxia, hypoxia and hyperhomocysteinaemia, and hypoxia and hyperhomocysteinaemia in the presence of PPG. We previously reported using the same CEM cell line that hypoxia stimulates adenosinergic signalling and that A 2A R stimulation decreases lymphocyte viability . Here, we confirmed these previous data and detailed the metabolic pathways of HCy and adenosine that are interdependent and involved in the control of lymphocyte viability (see Fig.…”

Section: Discussionsupporting

confidence: 90%

High homocysteine levels prevent via H₂S the CoCl₂‐induced alteration of lymphocyte viability

Bruzzese

Fenouillet

Fromonot

et al. 2016

J Cellular Molecular Medi

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High homocysteine (HCy) levels are associated with lymphocyte‐mediated inflammatory responses that are sometimes in turn related to hypoxia. Because adenosine is a potent lymphocyte suppressor produced in hypoxic conditions and shares metabolic pathways with HCy, we addressed the influence of high HCy levels on the hypoxia‐induced, adenosine‐mediated, alteration of lymphocyte viability. We treated mitogen‐stimulated human lymphocytes isolated from healthy individuals and the human lymphoma T‐cell line CEM with cobalt chloride (CoCl2)to reproduce hypoxia. We found that CoCl2‐altered cell viability was dose‐dependently reversed using HCy. In turn, the HCy effect was inhibited using DL‐propargylglycine, a specific inhibitor of the hydrogen sulphide (H2S)‐synthesizing enzyme cystathionine‐γ‐lyase involved in HCy catabolism. We then addressed the intracellular metabolic pathway of adenosine and HCy, and the role of the adenosine A2A receptor (A2 AR). We observed that: (i) hypoxic conditions lowered the intracellular concentration of HCy by increasing adenosine production, which resulted in high A2 AR expression and 3′, 5′‐cyclic adenosine monophosphate production; (ii) increasing intracellular HCy concentration reversed the hypoxia‐induced adenosinergic signalling despite high adenosine concentration by promoting both S‐adenosylhomocysteine and H2S production; (iii) DL‐propargylglycine that inhibits H2S production abolished the HCy effect. Together, these data suggest that high HCy levels prevent, via H2S production and the resulting down‐regulation of A2 AR expression, the hypoxia‐induced adenosinergic alteration of lymphocyte viability. We point out the relevance of these mechanisms in the pathophysiology of cardiovascular diseases.

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Section: Discussionsupporting

confidence: 90%

High homocysteine levels prevent via H₂S the CoCl₂‐induced alteration of lymphocyte viability

Bruzzese

Fenouillet

Fromonot

et al. 2016

J Cellular Molecular Medi

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“…In this respect, it is worthwhile to note here that 1) the hyperoxic conditions achieved in our experiments mimic conditions that are used in human, inasmuch as 1-bar O 2 is a common treatment of CO poisoning and 2-bar O 2 is used notably by combat divers (31), suggesting that the effects we observed here can be found in humans; 2) the way hyperoxia regulates the adenosine response, as shown here, contributes to explain how and why hyperoxia promotes vasoconstriction (24); 3) our data are consistent with the observation that a low oxygen level induces adenosine release and high A 2A R expression, in particular in peripheral blood mononuclear cells (13,22,35,56,63).…”

Section: Discussionsupporting

confidence: 88%

“…A2AR expression was assessed using a semiquantitative Western blot procedure (13). Frozen brains or Chem-3 cells were quickly thawed and treated using a 4% SDS aqueous solution supplemented with a protease inhibitor cocktail (Sigma-Aldrich) and a 15-min sonication treatment at 47 kHz.…”

Section: Methodsmentioning

confidence: 99%

“…The A 2A receptor (A 2A R) is of particular interest because it is expressed in the brain, where it inhibits dopaminergic pathways of the basal ganglia, and in the cardiovascular system, where it controls the heart rate and the blood pressure by its vasodilator capacity (18,23,39,55,63,64). It is known that A 2A R expression increases in hypoxic conditions (11,13,22,37). Regarding hyperoxia, the adenosinergic response has been already addressed in the lung, and the supplemental use of high oxygen levels to treat the acute respiratory distress syndrome was found to weaken the local tissue hypoxia-driven and adenosine-mediated anti-inflammatory mechanism, hence further exacerbating lung injury (16,48,61).…”

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confidence: 99%

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Effect of hyperoxic and hyperbaric conditions on the adenosinergic pathway and CD26 expression in rat

Bruzzese

Rostain

Nee

et al. 2015

Journal of Applied Physiology

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The nucleoside adenosine acts on the nervous and cardiovascular systems via the A2A receptor (A2AR). In response to oxygen level in tissues, adenosine plasma concentration is regulated in particular via its synthesis by CD73 and via its degradation by adenosine deaminase (ADA). The cell-surface endopeptidase CD26 controls the concentration of vasoactive and antioxidant peptides and hence regulates the oxygen supply to tissues and oxidative stress response. Although overexpression of adenosine, CD73, ADA, A2AR, and CD26 in response to hypoxia is well documented, the effects of hyperoxic and hyperbaric conditions on these elements deserve further consideration. Rats and a murine Chem-3 cell line that expresses A2AR were exposed to 0.21 bar O2, 0.79 bar N2 (terrestrial conditions; normoxia); 1 bar O2 (hyperoxia); 2 bar O2 (hyperbaric hyperoxia); 0.21 bar O2, 1.79 bar N2 (hyperbaria). Adenosine plasma concentration, CD73, ADA, A2AR expression, and CD26 activity were addressed in vivo, and cAMP production was addressed in cellulo. For in vivo conditions, 1) hyperoxia decreased adenosine plasma level and T cell surface CD26 activity, whereas it increased CD73 expression and ADA level; 2) hyperbaric hyperoxia tended to amplify the trend; and 3) hyperbaria alone lacked significant influence on these parameters. In the brain and in cellulo, 1) hyperoxia decreased A2AR expression; 2) hyperbaric hyperoxia amplified the trend; and 3) hyperbaria alone exhibited the strongest effect. We found a similar pattern regarding both A2AR mRNA synthesis in the brain and cAMP production in Chem-3 cells. Thus a high oxygen level tended to downregulate the adenosinergic pathway and CD26 activity. Hyperbaria alone affected only A2AR expression and cAMP production. We discuss how such mechanisms triggered by hyperoxygenation can limit, through vasoconstriction, the oxygen supply to tissues and the production of reactive oxygen species.

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“…In the acute setting it is known that the upregulated expression of A2AR on T cells is driven through NFAT/ NFκB which are activated downstream of the TCR or HIF1α in the context of hypoxia [130,134]. Maximal upregulation is seen rapidly (~4-6 hours post activation) suggesting that activated cells within the hypoxic tumor microenvironment may be immediately sensitized to ADO [135]. Rapid upregulation of the A2AR is a physiological mechanism to reduce inflammatory tissue damage in multiple organs [136,137], but this pathway is also utilised by tumors to suppress anti-tumor immunity, with increased expression of the A2AR being observed on tumorinfiltrating CD8 + T cells relative to those isolated from the draining lymph node [131].…”

Section: Effect Of Adenosine On T Cell Responsesmentioning

confidence: 99%

Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

Sek¹,

Mølck²,

Stewart³

et al. 2018

Preprint

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The immune system plays a major role in the surveillance and control of malignant cells, with the presence of tumor infiltrating lymphocytes (TILs) correlating with better patient prognosis in multiple tumor types. The development of ‘checkpoint blockade’ and adoptive cellular therapy has revolutionized the landscape of cancer treatment and highlights the potential of utilizing the patient’s own immune system to eradicate cancer. One mechanism of tumor-mediated immunosuppression that has gained attention as a potential therapeutic target is the purinergic signaling axis, whereby the production of the purine nucleoside adenosine in the tumor microenvironment can potently suppress T and NK cell function. The production of extracellular adenosine is mediated by the cell surface ectoenzymes CD73, CD39 and CD38 and therapeutic agents have been developed to target these as well as the downstream adenosine receptors (A1R, A2AR, A2BR, A3R) to enhance anti-tumor immune responses. This review will discuss the role of adenosine and adenosine receptor signaling in tumor and immune cells with a focus on their cell-specific function and their potential as targets in cancer immunotherapy.

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Fall in oxygen tension of culture medium stimulates the adenosinergic signalling of a human T cell line

Cited by 11 publications

References 33 publications

High homocysteine levels prevent via H₂S the CoCl₂‐induced alteration of lymphocyte viability

High homocysteine levels prevent via H₂S the CoCl₂‐induced alteration of lymphocyte viability

Effect of hyperoxic and hyperbaric conditions on the adenosinergic pathway and CD26 expression in rat

Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

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Fall in oxygen tension of culture medium stimulates the adenosinergic signalling of a human T cell line

Cited by 11 publications

References 33 publications

High homocysteine levels prevent via H2S the CoCl2‐induced alteration of lymphocyte viability

High homocysteine levels prevent via H2S the CoCl2‐induced alteration of lymphocyte viability

Effect of hyperoxic and hyperbaric conditions on the adenosinergic pathway and CD26 expression in rat

Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

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High homocysteine levels prevent via H₂S the CoCl₂‐induced alteration of lymphocyte viability

High homocysteine levels prevent via H₂S the CoCl₂‐induced alteration of lymphocyte viability