Role of P2Y(11) receptors in hematopoiesis

The HL-60 cell line are human promyelocytic leukocytes. They are induced to differentiate into neutrophil-like cells by various agents including retin oic acid (RA), dimethylsulfoxide, granulocyte-colony stimulating factor, an d cell-permeable forms of cyclic AMP (cAMP) such as N-6,2'-O-dibutyryl cAMP . More recently, extracellular ATP has been reported to induce the differen tiation of HL-60 cells into granulocytes through an increase in the intrace llular cAMP concentration. Our Northern blotting experiments have shown tha t P2Y(11) messengers were upregulated, rapidly (1 h) and independently from protein synthesis, after treatment with all the agents inducing granulocyt ic differentiation. Our pharmacological characterization of the recombinant human P2Y(11) receptor has shown that it is the receptor coupled to the cA MP pathway in the HL-60 cells. The P2Y(11) receptor is potently activated b y adenosine 5'-O-(3-thiotriphosphate), 2'- & 3'-O-(4-benzoyl-benzoyl)adenos ine 5'-triphosphate, and the ATP derivative AR-C67085 (2-propylthio-beta, g amma -dichloromethylene-D-ATP), which is a potent inhibitor of ADP-induced platelet aggregation. The P2Y(11) receptor is antagonized by suramin and th ioderivatives such as adenosine 5'-O-(2-thiodiphosphate). These data suppor t the conclusion that the effect of ATP on HL-60 cells differentiation is m ediated by the P2Y(11) receptor and suggest that this receptor plays an imp ortant role in neutrophil maturation. Knock-out experiments are in progress to evaluate the physiological role of the P2Y(11) receptor in murine granu lopoiesis. Drug Dev. Res. 52:156-163, 2001. (C) 2001 Wiley-Liss, Inc.