Purinergic Signalling

, Volume 11, Issue 1, pp 79–85 | Cite as

Enhanced survival of lethally irradiated adenosine A3 receptor knockout mice. A role for hematopoietic growth factors?

  • Michal Hofer
  • Milan Pospíšil
  • Ladislav Dušek
  • Zuzana Hoferová
  • Denisa Komůrková
Original Article
  • 114 Downloads

Abstract

Adenosine A3 receptor knockout (A3AR KO) mice and their wild-type (WT) counterparts were compared from the point of view of their abilities to survive exposures to lethal doses of γ-radiation belonging to the range of radiation doses inducing the bone marrow acute radiation syndrome. Parameters of cumulative 30-day survival (experiment using a midlethal radiation dose) or cumulative 11-day survival (experiment using an absolutely lethal radiation dose), and of mean survival time were evaluated. The values of A3AR KO mice always reflected their higher survival in comparison with WT ones, the P values being above the limit for statistical significance after the midlethal radiation dose and standing for statistical significance after the absolutely lethal radiation dose. This finding was considered surprising, taking into account the previously obtained findings on defects in numbers and functional properties of peripheral blood cells in A3AR KO mice. Therefore, previous hematological analyses of A3AR KO mice were supplemented in the present studies with determination of serum levels of the granulocyte colony-stimulating factor, erythropoietin, and thrombopoietin. Though distinct differences in these parameters were observed between A3AR KO and WT mice, none of them could explain the relatively high postirradiation survival of A3AR KO mice. Further studies on these mice comprising also those on other than hemopoietic tissues and organs can help to clarify their relative radioresistance.

Keywords

Adenosine A3 receptor Postirradiation survival Hematopoiesis Granulocyte colony-stimulating factor Erythropoietin Thrombopoietin 

Notes

Acknowledgments

The authors thank the Merck Research Laboratories (West Point, PA, USA) for providing us with A3AR KO mice. This work was supported by the Grant Agency of the Czech Republic (Grant No. P303/11/0128).

Conflicts of interests

The authors declare that there are no conflicts of interests.

References

  1. 1.
    Abbracchio MP (1996) P1 and P2 receptors in cell growth and differentiation. Drug Dev Res 39:393–406CrossRefGoogle Scholar
  2. 2.
    Neary JT, Burnstock G (1996) Purinoceptors in the regulation of cell growth and differentiation. Drug Dev Res 39:407–412CrossRefGoogle Scholar
  3. 3.
    Jacobson KA, Hoffman C, Cattabeni F, Abbracchio MP (1999) Adenosine-induced cell death: evidence for receptor-mediated signalling. Apoptosis 4:197–211CrossRefPubMedGoogle Scholar
  4. 4.
    Schulte G, Fredholm BB (2003) Signalling from adenosine receptor to nitrogen-activated protein kinases. Cell Signal 15:813–827CrossRefPubMedGoogle Scholar
  5. 5.
    Olah ME, Stiles GL (1995) Adenosine receptor subtypes: characterization and therapeutic regulation. Annu Rev Pharmacol Toxicol 35:581–606CrossRefPubMedGoogle Scholar
  6. 6.
    Hofer M, Pospisil M, Weiterova L, Hoferova Z (2011) The role of adenosine receptor agonists in regulation of hematopoiesis. Molecules 16:675–685CrossRefPubMedGoogle Scholar
  7. 7.
    Hofer M, Pospíšil M, Hoferová Z, Komůrková D, Pápar P, Savvulidi F, Šefc L (2013) The pharmacological activation of adenosine A1 and A3 receptors does not modulate the long- or short-term repopulating ability of hematopoietic stem and multipotent progenitor cells in mice. Purinergic Signal 9:207–214CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Fishman P, Bar-Yehuda S (2003) Pharmacology and therapeutical applications of A3 receptor subtype. Curr Top Med Chem 3:463–469CrossRefPubMedGoogle Scholar
  9. 9.
    Wu WP, Hao JX, Halldner-Henriksson L, Xu XJ, Jacobson MA, Wiesenfeld-Hallin Z, Fredholm BB (2002) Decreased inflammatory pain due to reduced carrageenan-induced inflammation in mice lacking adenosine A3 receptors. Neuroscience 14:523–527CrossRefGoogle Scholar
  10. 10.
    Fedorova IM, Jacobson MA, Basile A, Jacobson KA (2003) Behavioral characterization of mice lacking the adenosine A3 receptor: sensitivity to hypoxic neurodegeneration. Cell Mol Neurobiol 23:431–447CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Björklund O, Halldner-Henriksson L, Yang J, Eriksson TM, Jacobson MA, Daré E, Fredholm BB (2008) Decreased behavioral activation following caffeine, amphetamine and darkness in A3 adenosine receptor knock-out mice. Physiol Behav 95:668–676CrossRefPubMedGoogle Scholar
  12. 12.
    Yang J, Wang Y, Garcia-Roves PM, Bjornholm M, Fredholm BB (2010) Adenosine A3 receptors regulate heart rate, motor activity and body temperature. Acta Physiol 199:221–230CrossRefGoogle Scholar
  13. 13.
    Shen H, Luo Y, Yu S-J, Wang Y (2011) Enhanced neurodegeneration after a high dose of methamphetamine in adenosine A3 receptor null mutant mice. Neuroscience 194:170–180CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Hofer M, Pospíšil M, Dušek L, Hoferová Z, Weiterová L, Komůrková D (2013) Erythropoiesis- and thrombopoiesis-characterizing parameters in adenosine A3 knock-out mice. Physiol Res 62:305–311PubMedGoogle Scholar
  15. 15.
    Hofer M, Pospíšil M, Dušek L, Hoferová Z, Komůrková D (2014) Evidence for compensatory mechanisms in the hematopoietic system of irradiated and non-irradiated mice lacking adenosine A3 receptors. Purinergic Signal 10:509–514CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Hofer M, Pospíšil M, Dušek L, Hoferová Z, Komůrková D (2014) Hematopoiesis in 5-fluorouracil-treated adenosine A3 receptor knock-out mice. Physiol Res, in press 2015Google Scholar
  17. 17.
    Salvatore CA, Tilley SL, Latour AM, Fletcher DS, Koller BH, Jacobson MA (2000) Disruption of the A3 adenosine receptor gene in mice and its effect on stimulated inflammatory cells. J Biol Chem 275:4429–4434CrossRefPubMedGoogle Scholar
  18. 18.
    Bond VP, Fliedner TM, Archambeau JO (1965) The radiation syndromes. In: Bond VP, Fliedner TM, Archambeau JO (eds) Mammalian radiation lethality. Academic Press, New York, pp 101–114Google Scholar
  19. 19.
    Fishman P, Bar-Yehuda S, Farbstein T, Barer F, Ohana G (2000) Adenosine acts as a chemoprotective agent by stimulating G-CSF production. A role for A1 and A3 adenosine receptors. J Cell Physiol 183:393–398CrossRefPubMedGoogle Scholar
  20. 20.
    Fishman P, Bar-Yehuda S, Barer F, Madi L, Multani AS, Pathak S (2001) The A3 adenosine receptor as a new target for cancer therapy and chemoprotection. Exp Cell Res 269:230–236CrossRefPubMedGoogle Scholar
  21. 21.
    Bar-Yehuda S, Madi L, Barak D, Mittelman M, Ardon E, Ochaion A, Cohn S, Fishman P (2002) Agonists to the A3 adenosine receptor induce G-CSF production via NF-kappaB activation: a new class of myeloprotective agents. Exp Hematol 30:1390–1398CrossRefPubMedGoogle Scholar
  22. 22.
    Fishman P, Bar-Yehuda S, Madi L, Cohn I (2002) A3 adenosine receptor as a target for cancer therapy. Anticancer Drugs 13:437–443CrossRefPubMedGoogle Scholar
  23. 23.
    Hofer M, Pospíšil M, Šefc L, Dušek L, Vacek A, Holá J, Hoferová Z, Štreitová D (2010) Activation of adenosine A3 receptors supports hematopoiesis-stimulating effects of granulocyte colony-stimulating factor in sublethally irradiated mice. Int J Radiat Biol 86:649–656CrossRefPubMedGoogle Scholar
  24. 24.
    Hofer M, Vacek A, Pospíšil M, Holá J, Štreitová D, Znojil V (2009) Activation of adenosine A3 receptors potentiates stimulatory effects of IL-3, SCF, and GM-CSF on mouse granulocyte-macrophage hematopoietic progenitor cells. Physiol Res 58:247–252PubMedGoogle Scholar
  25. 25.
    Štreitová D, Šefc L, Savvulidi F, Pospíšil M, Holá J, Hofer M (2010) Adenosine A1, A2a, A2b, and A3 receptors in hematopoiesis: 1. Expression of receptor mRNA in four mouse hematopoietic precursor cells. Physiol Res 59:133–137PubMedGoogle Scholar
  26. 26.
    Pospíšil M, Hofer M, Vacek A, Znojil V, Pipalová I (2004) Effects of stable adenosine receptor agonists on bone marrow haematopoietic cells as inferred from the cytotoxic action of 5-fluorouracil. Physiol Res 53:549–556PubMedGoogle Scholar
  27. 27.
    Bhanu NV, Aerbajinai W, Gantt NM, Jackson EK, Goh SH, Lee YT, Miller JL (2007) Cl-IB-MECA inhibits human erythropoiesis. Br J Haematol 137:233–236CrossRefPubMedGoogle Scholar
  28. 28.
    Goodman JW, Smith LH (1961) Erythrocyte life span in normal mice and in radiation bone marrow chimeras. Am J Physiol 200:764–770PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Michal Hofer
    • 1
  • Milan Pospíšil
    • 1
  • Ladislav Dušek
    • 2
  • Zuzana Hoferová
    • 1
  • Denisa Komůrková
    • 1
  1. 1.Department of Molecular Cytology and CytometryInstitute of Biophysics, v.v.i., Academy of Sciences of the Czech RepublicBrnoCzech Republic
  2. 2.Institute of Biostatistics and Analyses, Faculty of MedicineMasaryk UniversityBrnoCzech Republic

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