Adenosine A(2A) receptor activation protects CD4(+) T lymphocytes against activation-induced cell death

Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
The FASEB Journal (Impact Factor: 5.04). 04/2010; 24(8):2631-40. DOI: 10.1096/fj.10-155192
Source: PubMed


Activation-induced cell death (AICD) is initiated by T-cell receptor (TCR) restimulation of already activated and expanded peripheral T cells and is mediated through Fas/Fas ligand (FasL) interactions. Adenosine is a purine nucleoside signaling molecule, and its immunomodulatory effects are mediated by 4 G-protein-coupled receptors: A(1), A(2A), A(2B), and A(3). In this study, we investigated the role of A(2A) receptors in regulating CD4(+) T lymphocyte AICD. Our results showed that the selective A(2A) receptor agonist CGS21680 (EC(50)=15.2-32.6 nM) rescued mouse CD4(+) hybridomas and human Jurkat cells from AICD and that this effect was reversed by the selective A(2A) receptor antagonist ZM241385 (EC(50)=2.3 nM). CGS21680 decreased phosphatidylserine exposure on the membrane, as well as the cleavage of caspase-3, caspase-8 and poly(ADP-ribose) polymerase indicating that A(2A) receptor stimulation blocks the extrinsic apoptotic pathway. In addition, CGS21680 attenuated both Fas and FasL mRNA expression. This decrease in FasL expression was associated with decreased activation of the transcription factor systems NF-kappaB, NF-ATp, early growth response (Egr)-1, and Egr-3. The antiapoptotic effect of A(2A) receptor stimulation was mediated by protein kinase A. Together, these results demonstrate that A(2A) receptor activation suppresses the AICD of peripheral T cells.

Download full-text


Available from: Pal Pacher
  • Source
    • "These effects of MK-801 may be in relation to its mitigative influence on the LPS-evoked increase in absence epileptic activity (Fig. 4D), which suggests the interaction between proinflammatory cytokines and glutamatergic system in modulation of absence epileptic activity and the crucial role of cortical excitability in LPS-evoked increase in absence epileptic activity in WAG/Rij rats (Kovács et al., 2006, 2014a; Van Luijtelaar et al., 2012). It was demonstrated that LPS may increase the level of Ado A 2A receptors (A 2A Rs) in microglial cells (Saura et al., 2005) and activation of A 2A Rs may have crucial role in inflammatory processes (Abbracchio and Ceruti, 2007; Csóka et al., 2007, 2008; Haskó et al., 2005; Himer et al., 2010). LPS-evoked increase in IL-1 may generate release of Ado in the CNS (Sperlágh et al., 2004) and A 2A R activation may inhibit LPS-induced cytokine production in microglial cells (Van der Putten et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: We showed previously that the number of spike-wave discharges (SWDs) was increased after intraperitoneal (i.p.) injection of lipopolysaccharide (LPS), inosine (Ino) and muscimol alone whereas i.p. guanosine (Guo), uridine (Urd), bicuculline, theophylline and (+)-5-methyl-10,11-dihydro-5H-dibenzo (a,d) cyclohepten-5,10-imine maleate (MK-801) alone decreased the SWD number in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. These drugs may exert their effects on absence epileptic activity mainly via proinflammatory cytokines-evoked increase in cortical excitability (such as LPS), GABAergic system (LPS, Ino, Urd, muscimol and bicuculline), glutamatergic system (LPS, Guo and MK-801) and adenosinergic system (LPS, Ino, Guo, Urd and theophylline). Both GABAergic system and glutamatergic system are involved in the pathomechanism of absence epilepsy, the LPS-evoked increase in absence epileptic activity and the pro- or antiepileptic effects of non-adenosine (non-Ado) nucleosides Ino, Guo and Urd. Moreover, Ino, Guo and Urd have modulatory effects on inflammatory processes. Thus, we investigated whether Ino, Guo and Urd have also modulatory influence on LPS-evoked increase in SWD number using two different concentrations of each nucleoside in WAG/Rij rats. We demonstrated that Ino dose-dependently aggravated whereas Guo and Urd attenuated the LPS-evoked increase in SWD number. Our results suggest that different nucleosides have diverse effects on LPS-induced changes in absence epileptic activity.
    Full-text · Article · Sep 2015 · Brain research bulletin
    • "Moreover, A2A activation has both apoptotic and anti-apoptotic effects. A2A activation reduces activation-induced cell death in mouse CD4+ hybridomas and human Jurkat cells (Himer et al., 2010) and this activation also affects activation-induced cell death by interfering with the production of factors that stimulate T cell activation, IL-2, and downstream expression of the co-stimulatory molecules CD2 and CD28 (Butler et al., 2003). In contrast, other studies have suggested that adenosine and its analogues induce apoptosis through A2A or A3 receptors in a variety of cell types including lymphoid cells (Barbieri et al., 1998, Jacobson et al., 1999). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Regulatory T cells have various mechanisms to suppress the inflammatory response, among these, the modulation of the microenvironment through adenosine and with the participation of CD39, CD73 and A2A. The aim of this study was to assess the expression of CD73 and A2A in immune cells and the effect of activation of A2A by an adenosine analogue on apoptosis in patients with obesity and type 2 diabetes mellitus (T2D). CD73 and A2A expression were analyzed by flow cytometry in lymphocyte subpopulations from patients with obesity (n=22), T2D (n=22), and healthy subjects (n=20). Lymphocytes were treated with the selective A2A antagonist (ZM241385) or the selective A2A agonist (CGS21680), and apoptotic cells were detected by Annexin V. We found an increased expression of CD39 coupled to a decrease in CD73 in the patient groups with obesity and T2D compared to the control group in the different studied lymphocyte subpopulations. A2A expression was found to be increased in different subpopulations of lymphocytes from T2D patients. We also detected positive correlations between CD39+ cells and age and BMI. Meanwhile, CD73+ cells showed negative correlations with age, WHR, BMI, FPG, HbAc1, triglycerides and cholesterol. Moreover, an increase in the percentage of apoptotic cells from T2D patients with regard to the groups with obesity and control was observed. In addition, the CD8+ T cells of patients with T2D exhibited decreased apoptosis when treated with the A2A agonist. In conclusion, our data suggest a possible role for CD73 and A2A in inflammation observed in patients with T2D and obesity mediated via apoptosis. Copyright © 2015 Elsevier GmbH. All rights reserved.
    No preview · Article · Feb 2015 · Immunobiology
  • Source
    • "Activation of the A 2A R on CD4 + Tcells prevents myocardial ischemia–reperfusion injury by inhibiting the lymphocyte accumulation and activation in the reperfused heart [26]. A 2A R can also prevent Th1/Th2 development [27] as well as Tcell apoptosis [28]. Finally, it was reported that adenosine produced by regulatory T-cells mediates immune suppression activity through Abbreviations: A2AR, adenosine A2A receptors; Emax, maximal ligand response; Bmax, maximal occupation of the receptors; EC50, half-maximal effective concentration; KD, dissociation constant; NMS, neurally-mediated syncope; APC, adenosine plasma concentration ; PBMC, peripheral blood mononuclear cells; AU, arbitrary units * Corresponding author. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Some ligand-receptor couples involve spare receptors, which are apparent when a maximal response is achieved with only a small fraction of the receptor population occupied. This situation favours cross-reactions with low-affinity ligands, which may be detrimental for cell signaling. In the case of the adenosine A2A receptors (A2AR), which have an immunosuppressive effect on lymphocytes through cAMP production, the presence of spare A2AR remains to be established. We examined the situation using patients over-expressing lymphocyte A2AR and an agonist-like mAb to A2AR. We found that maximal mAb binding and functional response varied among the patients whereas the dissociation constant and half-maximal effective concentration had similar mean values (0.19 and 0.18 μM, respectively). Lymphocyte A2AR expression was correlated to plasma adenosine level and A2AR occupation but not to A2AR response. These results are consistent with a lack of a reserve of functional A2AR on human lymphocytes as a general rule and suggest that the amount and functional state of the expressed A2AR determine the maximal level of the lymphocyte response to adenosine.
    Full-text · Article · Dec 2013 · FEBS Open Bio
Show more