Journal
BLOOD
Volume 116, Issue 22, Pages 4492-4500Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-12-260828
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Funding
- Ricerca Finalizzata Ministero della Salute Terapia fisica da sola o combinata a terapie specifiche nel trattamento delle cardiovasculopatie
- Regione Emilia-Romagna (Progetti di Ricerca Universita-Regione Emilia Romagna, Progetto Medicina Rigenerativa)
- MIUR [PRIN 2006]
- National Research Council of Italy
- Italian Association for Cancer Research
- Italian Space Agency, Telethon of Italy
- University of Ferrara
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Endothelial cells (ECs) represent a major source of actively secreted adenosine triphosphate (ATP). Natural killer (NK) cells can mediate vascular injury in several pathologic conditions, including cytomegalovirus infection and vascular leak syndrome. We studied NK-cell expression of P2 receptors and the role of these nucleotide receptors in the regulation of endothelial-NK cell crosstalk. NK cells from healthy subjects expressed P2Y(1,2,4,6,11,12,13,14) and P2X(1,4,5,6,7) receptors. NK cells stimulated with ATP, but not uridine triphosphate, increased intracellular Ca2+ and chemokinesis. Moreover, ATP, but not uridine triphosphate, inhibited NK chemotaxis in response to CX(3)CL1, whereas chemotaxis to CXCL12 was increased. CX(3)CL1 elicited killing of human umbilical vein ECs and human coronary artery ECs by NK cells. However, in the presence of ATP, CX(3)CL1 failed to stimulate killing of ECs. Such inhibitory effect was lost on exogenous addition of the ATP-hydrolyzing enzyme apyrase or by pharmacologic inhibition of the P2Y(11)R, and correlated with increased intracellular cyclic adenosine monophosphate concentrations induced by ATP or other P2Y(11)R agonists, including NAD(+). Extracellular ATP regulates NK-cell cytotoxicity via P2Y(11)R activation, protecting ECs from CX(3)CL1-elicited NK cell-mediated killing. These findings point out the P2Y(11)R as a potential target for pharmacologic intervention aimed at reducing NK-mediated vascular injury. (Blood. 2010;116(22):4492-4500)
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