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 NKcell 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 Ca 2+ and chemokinesis. Moreover, ATP, but not uridine triphosphate, inhibited NK chemotaxis in response to CX 3CL1, whereas chemotaxis to CXCL12 was increased. CX 3CL1 elicited killing of human umbilical vein ECs and human coronary artery ECs by NK cells. However, in the presence of ATP, CX 3CL1 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 11R, and correlated with increased intracellular cyclic adenosine monophosphate concentrations induced by ATP or other P2Y 11R agonists, including NAD +. Extracellular ATP regulates NK-cell cytotoxicity via P2Y 11R activation, protecting ECs from CX 3CL1-elicited NK cell-mediated killing. These findings point out the P2Y 11R as a potential target for pharmacologic intervention aimed at reducing NK-mediated vascular injury.
|Titolo:||ATP secreted by endothelial cells blocks CX₃CL 1-elicited natural killer cell chemotaxis and cytotoxicity via P2Y₁₁ receptor activation|
|Parole Chiave:||Chemotaxis ; Adenosine Triphosphate ; Calcium ; Cell Line ; Chemokine CX3CL1 ; Cyclic AMP ; Endothelial Cells ; Gene Expression ; Humans ; Killer Cells, Natural ; RNA, Messenger ; Receptors, Purinergic P2 ; Receptors, Purinergic P2X ; Receptors, Purinergic P2Y|
|Settore Scientifico Disciplinare:||Settore MED/46 - Scienze Tecniche di Medicina di Laboratorio|
Settore MED/04 - Patologia Generale
|Data di pubblicazione:||25-nov-2010|
|Digital Object Identifier (DOI):||10.1182/blood-2009-12-260828|
|Appare nelle tipologie:||01 - Articolo su periodico|