The review summarizes data evaluating the role of adenosine receptor signaling in murine hematopoietic functions. The studies carried out utilized either non-selective activation of adenosine receptors induced by elevation of extracellular adenosine or by administration of synthetic adenosine analogs having various proportions of selectivity for a particular receptor. Numerous studies have described stimulatory effects of non-selective activation of adenosine receptors, manifested as enhancement of proliferation of cells at various levels of the hematopoietic hierarchy. Subsequent experimental approaches, considering the hematopoiesis-modulating action of adenosine receptor agonists with a high level of selectivity to individual adenosine receptor subtypes, have revealed differential effects of various adenosine analogs. Whereas selective activation of A₁ receptors has resulted in suppression of proliferation of hematopoietic progenitor and precursor cells, that of A₃ receptors has led to stimulated cell proliferation in these cell compartments. Thus, A₁ and A₃ receptors have been found to play a homeostatic role in suppressed and regenerating hematopoiesis. Selective activation of adenosine A₃ receptors has been found to act curatively under conditions of drug- and radiation-induced myelosuppression. The findings in these and further research areas will be summarized and mechanisms of hematopoiesis-modulating action of adenosine receptor agonists will be discussed.

Working Group of Experimental Hematology Institute of Biophysics v v i Academy of Sciences of the Czech Republic Královopolská 135 CZ 61265 Brno Czech Republic

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Drury A.N., Szent-Györgyi A. The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart. J. Physiol. (London) 1929;68:213–237. PubMed PMC

Abbracchio M.P. P1 and P2 receptors in cell growth and differentiation. Drug Dev. Res. 1996;39:393–406. doi: 10.1002/(SICI)1098-2299(199611/12)39:3/4<393::AID-DDR21>3.0.CO;2-1. DOI

Linden J. Molecular approach to adenosine receptors: Receptor-mediated mechanisms of tissue protection. Annu. Rev. Pharmacol. Toxicol. 2001;41:775–778. doi: 10.1146/annurev.pharmtox.41.1.775. PubMed DOI

Berne R.M. Cardiac nucleotides in hypoxia – possible role in regulation of coronary blood flow. Am. J. Physiol. 1963;204:317–322. PubMed

Newby A.C. Adenosine and the concept of ‘retaliatory metabolites’. Trends Biochem. Sci. 1984;9:42–44. doi: 10.1016/0968-0004(84)90176-2. DOI

Bruns R.F. Role of adenosine in energy supply/demand balance. Nucleos. Nucleot. 1991;10:931–943. doi: 10.1080/07328319108047231. DOI

Abbracchio M.P., Burnstock G. Purinergic signalling: Pathophysiological roles. Jap. J. Pharmacol. 1998;78:113–145. doi: 10.1254/jjp.78.113. PubMed DOI

Poulsen S.-A., Quinn R.J. Adenosine receptors: New opportunities for future drugs. Bioorgan. Med. Chem. 1998;6:619–641. doi: 10.1016/S0968-0896(98)00038-8. PubMed DOI

Olah M.E., Stiles G.L. Adenosine receptor subtypes: Characterization and therapeutic regulation. Annu. Rev. Pharmacol. Toxicol. 1995;35:581–606. doi: 10.1146/annurev.pa.35.040195.003053. PubMed DOI

Fredholm B.B., Arslan G., Halldner L., Kull B., Schulte G., Wasserman W. Structure and function of adenosine receptors and their genes. Naunyn-Schmied. Arch. Pharmacol. 2000;362:364–374. doi: 10.1007/s002100000313. PubMed DOI

Fredholm B.B., Arslan G., Halldner L, Kull B., Schulte G., Ådén U., Svenningsson P. Adenosine receptor signaling in vitro and in vivo. Drug Dev. Res. 2001;52:274–282. doi: 10.1002/ddr.1124. DOI

Klotz K.-N. Adenosine receptors and their ligands. Naunyn-Schmied. Arch. Pharmacol. 2000;362:382–391. doi: 10.1007/s002100000315. PubMed DOI

Cronstein B.N., Bouma M.G., Becker B.F. Purinergic mechanisms in inflammation. Drug Dev. Res. 1996;39:426–435. doi: 10.1002/(SICI)1098-2299(199611/12)39:3/4<426::AID-DDR24>3.0.CO;2-Y. DOI

Haskó G., Linden J., Cronstein B., Pacher P. Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat. Rev. Drug Dis. 2008;7:759–770. doi: 10.1038/nrd2638. PubMed DOI PMC

Plagemann P.G.W., Wohlhueter R.W., Woffendin C. Nucleoside and nucleobase transport in animal cells. Biochim. Biophy. Acta. 1988;947:405–443. doi: 10.1016/0304-4157(88)90002-0. PubMed DOI

Thorn J.A., Jarvis S.M. Adenosine transporters. Gen. Pharmacol. 1996;27:613–620. doi: 10.1016/0306-3623(95)02053-5. PubMed DOI

Brown J.R., Cornell K., Cook P.W. Adenosine- and adenine-nucleotide-mediated inhibition of normal and transformed keratinocyte proliferation is dependent upon dipyridamole-sensitive adenosine transport. J. Invest. Dermatol. 2000;115:849–859. doi: 10.1046/j.1523-1747.2000.00145.x. PubMed DOI

Schrier S.M., van Tilburg E.W., van der Meulen H., Ijzerman A.P., Mulder G.J., Nagelkerke J.F. Extracellular adenosine-induced apoptosis in mouse neuroblastoma cells-studies on involvement of adenosine receptors and adenosine uptake. Biochem. Pharmacol. 2001;61:417–425. PubMed

Nucciarelli F., Mearini E., Minelli A. Effects of adenosine on prostate adenocarcinoma PC-3 and bladder carcinoma J82 cells lines. Drug Dev. Res. 2003;58:390–395. doi: 10.1002/ddr.10183. DOI

Hofer M., Hoferová Z., Pospíšil M, Znojil V., Chramostová K. Effects of adenosine on the growth of murine G:5:113 fibrosarcoma cells in vitro. FoliaBiologica (Praha) 2003;49:207–210. PubMed

Gordon E.L., Pearson J.D., Dickinson E.S., Moreau D., Slakey L.L. The hydrolysis of extracellular adenine nucleotides by arterial smooth muscle cells - Regulation of adenosine production at the cell-surface. J. Biol. Chem. 1989;264:18986–18992. PubMed

Pospíšil M., Hofer M., Znojil V., Vácha J., Netíková J., Holá J. Synergistic effect of granulocyte colony-stimulating factor and drugs elevating extracellular adenosine on neutrophil production in mice. Blood. 1995;86:3692–3697. PubMed

Pospíšil M., Hofer M., Netíková J., Viklická Š., Pipalová I., Bartoníčková A. Effect of dipyridamole and adenosine monophosphate on cell proliferation in the hemopoietic tissue of normal and gamma-irradiated mice. Experientia. 1992;48:253–257. doi: 10.1007/BF01930468. PubMed DOI

Hošek B., Boháček J., Šikulová J., Pospíšil M., Vacek A. Protection of early cellular damage in 1 Gy-irradiated mice by the elevation of extracellular adenosine. Radiat. Environ. Biophys. 1992;31:289–297. doi: 10.1007/BF01210209. PubMed DOI

Boháček J., Hošek B., Pospíšil M. Postirradiation administration of adenosine monophosphate with dipyridamole reduces early cellular damage in mice. Life Sci. 1993;53:1317–1324. doi: 10.1016/0024-3205(93)90577-P. PubMed DOI

Hofer M., Mazur L., Pospíšil M., Weiterová L., Znojil V. Radioprotective action of extracellular adenosine on bone marrow cells in mice exposed to gamma rays as assayed by the micronucleus test. Radiat. Res. 2000;154:217–221. doi: 10.1667/0033-7587(2000)154[0217:RAOEAO]2.0.CO;2. PubMed DOI

Pospíšil M., Hofer M., Netíková J., Pipalová I., Vacek A., Bartoníčková A., Volenec K. Elevation of extracellular adenosine induces radioprotective effects in mice. Radiat. Res. 1993;134:323–330. doi: 10.2307/3578192. PubMed DOI

Pospíšil M., Hofer M., Vacek A., Netíková J., Pipalová I., Viklická Š. Noradrenaline reduces cardiovascular effects of the combined dipyridamole and AMP administration but preserves radioprotective effects of these drugs on hematopoiesis in mice. Physiol. Res. 1993;42:333–340. PubMed

Hofer M., Pospíšil M., Netíková J., Znojil V., Vácha J. Enhancement of haemopoietic spleen colony formation by drugs elevating extracellular adenosine: Effects of repeated in vivo treatment. Physiol. Res. 1997;46:285–290. PubMed

Pospíšil M., Hofer M., Znojil V., Vácha J., Netíková J., Holá J. Radioprotection of mouse hemopoiesis by dipyridamole and adenosine monophosphate in fractionated treatment. Radiat. Res. 1995;142:16–22. doi: 10.2307/3578962. PubMed DOI

Hofer M., Pospíšil M., Netíková J., Znojil V., Vácha J., Holá J. Radioprotective efficacy of dipyridamole and AMP combination in fractionated radiation regimen, and its dependence on the time of administration of the drugs prior to irradiation. Physiol. Res. 1995;44:93–98. PubMed

Pospíšil M., Hofer M., Vacek A., Netíková J., Holá J., Znojil V., Weiterová L. Drugs elevating extracellular adenosine enhance cell-cycling of hematopoietic progenitor cells as inferred from the cytotoxic effects of 5-fluorouracil. Exp. Hematol. 2001;29:557–562. doi: 10.1016/S0301-472X(01)00622-1. PubMed DOI

Hofer M., Weiterová L., Vacek A., Znojil V., Pospíšil M., Vácha J. Elevation of of extracellular adenosine mobilizes haematopoietic progenitor cells into peripheral blood and enhances the mobilizing effects of granulocyte colony-stimulating factor. Eur. J. Haematol. 2003;71:204–210. doi: 10.1034/j.1600-0609.2003.00120.x. PubMed DOI

Pospíšil M., Hofer M., Znojil V., Netíková J., Vácha J., Holá J., Vacek A. Granulocyte colony-stimulating factor and drugs elevating extracellular adenosine synergize to enhance haematopoietic reconstitution in irradiated mice. Eur. J. Haematol. 1998;60:172–180. PubMed

Weiterová L., Hofer M., Pospíšil M., Znojil V., Vácha J., Vacek A., Pipalová I. Influence of the joint treatment with granulocyte colony-stimulating factor and drugs elevating extracellular adenosine on erythropoietic recovery following 5-fluorouracil-induced hematotoxicity in mice. Eur. J. Haematol. 2000;65:310–316. PubMed

Hofer M., Pospíšil M., Weiterová L., Znojil V., Vácha J., Holá J., Vacek A., Pipalová I. Combination of drugs elevating extracellular adenosine with granulocyte colony-stimulating factor promotes granulopoietic recovery in mouse bone marrow after 5-fluorouracil treatment. Physiol. Res. 2001;50:521–524. PubMed

Hofer M., Pospíšil M., Znojil V., Vacek A., Weiterová L., Holá J., Vácha J. Drugs elevating extracellular adenosine promote regeneration of haematopoietic progenitor cells in severely myelosuppressed mice: their comparison and joint effects with granulocyte colony-stimulating factor. Eur. J. Haematol. 2002;68:4–11. doi: 10.1034/j.1600-0609.2002.00564.x. PubMed DOI

Hofer M., Pospíšil M., Netíková J., Znojil V., Vácha J. Granulocyte colony-stimulating factor and drugs elevating extracellular adenosine act additively to enhance the hemopoietic spleen colony formation in irradiated mice. Physiol. Res. 1999;48:37–42. PubMed

Jacobson M.A. Adenosine receptor agonists. Expert Opin. Ther. Patents. 2002;12:489–501. doi: 10.1517/13543776.12.4.489. DOI

Tuovinen K., Tarjanen J. Clearance of cyclopentyladenosine and cyclohexyladenosine in rats following a single subcutaneous dose. Pharmacol. Res. 2004;50:329–334. doi: 10.1016/j.phrs.2004.02.007. PubMed DOI

Martin P.L., Barrett R.J., Sykes A., Droppleman D.A., Wright K.F., Mossem D. Pharmacology and toxicology of the A2A -adenosine receptor agonist 2-[(cyclohexylmethylene)hydrazino]adenosine (MRE-0470) in the rat. Drug Dev. Res. 1997;42:76–85. doi: 10.1002/(SICI)1098-2299(199710)42:2<76::AID-DDR4>3.0.CO;2-M. DOI

Pospíšil M., Hofer M., Vacek A., Znojil V., Pipalová I. Effects of stable adenosine receptor agonists on bone marrow hematopoietic cells as inferred from the cytotoxic action of 5-fluorouracil. Physiol. Res. 2004;53:549–556. PubMed

Fredholm B.B., Arslan G., Halldner L., Kull B., Schulte G., Wassermann G. Structure and function of adenosine receptors and their genes. Naunyn-Schmied. Arch. Pharmacol. 2000;362:364–374. doi: 10.1007/s002100000313. PubMed DOI

Parsons M., Young L., Lee J.E., Jacobson K.A., Liang B.T. Distinct cardioprotective effects of adenosine mediated by differential coupling of receptor subtypes to phospholipases C and D. FASEB J. 2000;14:1423–1431. doi: 10.1096/fj.14.10.1423. PubMed DOI PMC

Hofer M., Pospíšil M., Vacek A., Holá J., Znojil V., Weiterová L., Štreitová D. Effects of adenosine A3 receptor agonist on bone marrow granulocytic system in 5-fluorouracil-treated mice. Eur. J. Pharmacol. 2006;538:163–167. doi: 10.1016/j.ejphar.2006.03.042. PubMed DOI

Pospíšil M., Hofer M., Vacek A., Holá J., Pipalová I., Znojil V. N6-Cyclopentyladenosine inhibits proliferation of haematopoietic progenitor cells in vivo. Eur. J. Pharmacol. 2005;507:1–6. doi: 10.1016/j.ejphar.2004.11.027. PubMed DOI

Hofer M., Pospíšil M., Znojil V., Holá J., Vacek A., Štreitová D. Adenosine A3 receptor agonist acts as a homeostatic regulator of bone marrow hematopoiesis. Biomed. Pharmacother. 2007;61:356–359. doi: 10.1016/j.biopha.2007.02.010. PubMed DOI

Hofer M., Pospíšil M., Znojil V., Holá J., Štreitová D., Vacek A. Homeostatic action of adenosine A3 and A1 receptor agonists on proliferation of hematopoietic precursor cells. Exp. Biol. Med. 2008;233:897–900. doi: 10.3181/0802-RM-43. PubMed DOI

Merimsky O., Bar-Yehuda S., Madi L., Fishman P. Modulation of the A3 adenosine receptor by low agonist concentration induces antitumor and myelostimulatory effects. Drug Dev. Res. 2003;58:386–389. doi: 10.1002/ddr.10182. DOI

Fortin A., Harbour D., Fernandes M., Borgeat P., Bourgoin S. Differential expression of adenosine receptors in human neutrophils: up-regulation by specific Th1 cytokines and lipopolysaccharide. J. Leukocyte Biol. 2006;79:574–585. PubMed

Thiele A., Kronstein R., Wetzel A., Gerth A., Nieber K., Hauschildt S. Regulation of adenosine receptor subtypes during cultivation of human monocytes: Role of receptors in preventing lipopolysaccharide-triggered respiratory burst. Infec. Immunity. 2004;72:1349–1357. doi: 10.1128/IAI.72.3.1349-1357.2004. PubMed DOI PMC

Himer L., Csoka B., Selmeczy Z., Koscso B., Pocza T., Pacher P., Nemeth Z.H., Deitch E.A., Vizi E.S., Cronstein B.N., Hasko G. Adenosine A2a receptor activation protects CD4+ T lymphocytes against activation-induced cell death. FASEB J. 2010;24:2631–2640. PubMed PMC

Mirabet M., Herrera C., Cordero O.J., Mallol J., Lluis C., Franco R. Expression of A2B adenosine receptors in human lymphocytes: their role in T cell activation. J. Cell Sci. 1999;112:491–502. PubMed

Gessi S., Varani K., Merighi S., Cattabriga E., Avitabile A., Gavioli R., Fortini C., Leung E., Mac Lennan S., Borea P.A. Expression of adenosine A3 receptors in human lymphocytes: up-regulation in T-cell activation. Mol. Pharmacol. 2004;65:711–719. doi: 10.1124/mol.65.3.711. PubMed DOI

Štreitová D., Šefc L., Savvulidi F., Pospíšil M., Holá J., Hofer M. Adenosine A1, A2a, A2b, and A3 receptors in hematopoiesis. 1. Expression of receptor mRNA in four mouse hematopoietic precursor cells. Physiol. Res. 2010;59:133–137. PubMed

Hofer M., Vacek A., Lojek A., Holá J., Štreitová D. Ultrafiltered pig leukocyte extract (IMUNOR®) decreases nitric oxide formation and hematopoiesis-stimulating cytokine production in lipopolysaccharide-stimulated RAW 264.7 macrophages. Int. Immunopharmacol. 2007;7:1369–1374. doi: 10.1016/j.intimp.2007.06.003. PubMed DOI

Kamio N., Akifusa S., Yamaguchi N., Yamashita Y. Induction of granulocyte colony-stimulating factor by globular adiponectin via the MEK-ERK pathway. Mol. Cell. Endocrinol. 2008;292:20–25. doi: 10.1016/j.mce.2008.05.002. PubMed DOI

Murphree L.J., Sullivan G.W., Marshall M.A., Linden J. Lipopolysaccharide rapidly modifies adenosine receptor transcripts in murine and human macrophages: role of NF-κB in A2A adenosine receptor induction. Biochem. J. 2005;391:575–580. doi: 10.1042/BJ20050888. PubMed DOI PMC

Štreitová D., Hofer M., Holá J., Vacek A., Pospíšil M. Adenosine A1, A2a, A2b, and A3 receptors in hematopoiesis. 2. Expression of receptor mRNA in resting and lipopolysaccharide-activated mouse RAW 264.7 macrophages. Physiol. Res. 2010;59:139–144. PubMed

Katebi M., Fernandez P., Chan E.S., Cronstein B.N. Adenosine A2a receptor blockade or deletion diminishes fibrocyte accumulation in the skin in a murine model of scleroderma, bleomycin-induced fibrosis. Inflammation. 2008;31:299–303. doi: 10.1007/s10753-008-9078-y. PubMed DOI PMC

Katebi M., Soleimani M., Cronstein B.N. Adenosine A2a receptors play an active role in mouse bone marrow-derived mesenchymal stem cell development. J. Leukocyte Biol. 2009;85:438–444. PubMed PMC

Montesinos M.C., Shaw J.P., Yee H., Shamamian P., Cronstein B.N. Adenosine A2a receptor activation promotes wound neovascularization by stimulating angiogenesis and vasculogenesis. Am. J. Pathol. 2004;164:1887–1892. doi: 10.1016/S0002-9440(10)63749-2. PubMed DOI PMC

Weiterová L., Hofer M., Pospíšil M., Znojil V., Štreitová D. Drugs elevating extracellular adenosine administered in vivo induce serum colony forming activity and interleukin-6 in mice. Physiol. Res. 2007;56:463–473. PubMed

Bar-Yehuda S., Madi L., Barak D., Mittelman M., Ardon E., Ochaion A., Cohn S., Fishman P. Agonists to the A3 adenosine receptor induce G-CSF production via NF-κ B activation: A new class of myeloprotective agents. Exp. Hematol. 2002;30:1390–1398. doi: 10.1016/S0301-472X(02)00962-1. PubMed DOI

Hofer M., Vacek A., Pospíšil M., Weiterová L., Holá J., Štreitová D., Znojil V. Adenosine potentiates stimulatory effects on granulocyte-macrophage hematopoietic progenitor cells in vitro of IL-3 and SCF, but not those of G-CSF, GM-CSF and IL-11. Physiol. Res. 2006;55:591–596. PubMed

Hofer M., Pospíšil M., Šefc L., Dušek L., Vacek A., Holá J., Hoferová Z., Štreitová D. Activation of adenosine A3 receptors supports hematopoiesis-stimulating effects of granulocyte colony-stimulating factor in sublethally irradiated mice. Int. J. Radiat. Biol. 2010;86:649–656. doi: 10.3109/09553001003746075. PubMed DOI

Van Troostenburg A.-R., Clark E.V., Carey W.O.H., Warrington, Kerns W.D., Cohn I., Silverman M.H., Bar-Yehuda S., Fong K.-L.L., Fishman P. Tolerability, pharmacokinetics and concentration-dependent hemodynamic effects of oral CF 101, an A3 adenosine receptor agonist, in healthy young men. Int. J. Clin. Pharma. Therapeutics. 2004;42:534–542. PubMed

Fishman P., Bar-Yehuda S. Pharmacology and therapeutic applications of A3 receptor subtype. Curr. Top. Med. Chem. 2003;3:463–469. doi: 10.2174/1568026033392147. PubMed DOI

Silverman M.H., Strand V., Markovits D., Nahir M., Reitblat T., Molad Y., Rosner I., Rozenbaum M., Mader R., Adawi M., et al. Clinical evidence for utilization of the A3 adenosine receptor as a target to treat rheumatoid arthritis: Data from a Phase II clinical trial. J. Rheumatol. 2008;35:41–48. PubMed

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