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

被引:30
作者
Schiedel, Anke C. [1 ]
Lacher, Svenja K. [1 ]
Linnemann, Carsten [2 ]
Knolle, Percy A. [2 ]
Mueller, Christa E. [1 ]
机构
[1] Univ Bonn, PharmaCtr Bonn, Inst Pharmaceut, D-53121 Bonn, Germany
[2] Univ Bonn, Fac Med, Inst Mol Med & Expt Immunol, D-53121 Bonn, Germany
关键词
Adenosine receptors; Real-time PCR; Human lymphocytes; Jurkat Tcells; Proliferation; H-3] Thymidine incorporation; Receptor-independent mechanisms; CELL-CYCLE PROGRESSION; INTERNATIONAL UNION; IN-VITRO; T-CELLS; ACTIVATION; APOPTOSIS; GROWTH; PROLIFERATION; INHIBITION; DEATH;
D O I
10.1007/s11302-013-9354-7
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The effects of standard adenosine receptor (AR) agonists and antagonists on the proliferation of human T lymphocytes, unstimulated and phytohemagglutinin-stimulated 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 [H-3]-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 EC50 value of 104 mu M. 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.
引用
收藏
页码:351 / 365
页数:15
相关论文
共 52 条
[1]  
Abbracchio MP, 1996, DRUG DEVELOP RES, V39, P393, DOI 10.1002/(SICI)1098-2299(199611/12)39:3/4<393::AID-DDR21>3.0.CO
[2]  
2-1
[3]   The extracellular versus intracellular mechanisms of inhibition of TCR-triggered activation in thymocytes by adenosine under conditions of inhibited adenosine deaminase [J].
Apasov, SG ;
Sitkovsky, MV .
INTERNATIONAL IMMUNOLOGY, 1999, 11 (02) :179-189
[4]   Apoptosis by 2-chloro-2′-deoxy-adenosine and 2-chloro-adenosine in human peripheral blood mononuclear cells [J].
Barbieri, D ;
Abbracchio, MP ;
Salvioli, S ;
Monti, D ;
Cossarizza, A ;
Ceruti, S ;
Brambilla, R ;
Cattabeni, F ;
Jacobson, KA ;
Franceschi, C .
NEUROCHEMISTRY INTERNATIONAL, 1998, 32 (5-6) :493-504
[5]   Putative role of the adenosine A3 receptor in the antiproliferative action of N 6-(2-isopentenyl)adenosine [J].
Blad, Clara C. ;
Kunzel, Jacobien K. von Frijtag Drabbe ;
de Vries, Henk ;
Mulder-Krieger, Thea ;
Bar-Yehuda, Sara ;
Fishman, Pnina ;
IJzerman, Adriaan P. .
PURINERGIC SIGNALLING, 2011, 7 (04) :453-462
[6]   Inhibition of DNA repair by Pentoxifylline and related methylxanthine derivatives [J].
Böhm, L ;
Roos, WP ;
Serafin, AM .
TOXICOLOGY, 2003, 193 (1-2) :153-160
[7]  
Boyum A, 1968, Scand J Clin Lab Invest Suppl, V97, P7
[8]   Activation of the A3 adenosine receptor affects cell cycle progression and cell growth [J].
Brambilla, R ;
Cattabeni, F ;
Ceruti, S ;
Barbieri, D ;
Franceschi, C ;
Kim, YC ;
Jacobson, KA ;
Klotz, KN ;
Lohse, MJ ;
Abbracchio, MP .
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 2000, 361 (03) :225-234
[9]   Purinergic Signaling in the Airways [J].
Burnstock, Geoffrey ;
Brouns, Inge ;
Adriaensen, Dirk ;
Timmermans, Jean-Pierre .
PHARMACOLOGICAL REVIEWS, 2012, 64 (04) :834-868
[10]  
Ceruti S, 2000, J NEUROSCI RES, V60, P388, DOI 10.1002/(SICI)1097-4547(20000501)60:3<388::AID-JNR14>3.3.CO