THE PURINERGIC P-2Z RECEPTOR OF HUMAN MACROPHAGE CELLS - CHARACTERIZATION AND POSSIBLE PHYSIOLOGICAL-ROLE

We have investigated responses of human monocyte/macrophage cells to e xtracellular ATP (ATP(e)). Freshly isolated peripheral blood monocytes showed responses linked to P-2Y but not P-2Z purinergic receptors; ho wever, during in vitro macrophage differentiation, these cells also ex hibited responses suggestive of the presence of the membrane-permeabil izing P-2Z receptor. In fact, in human macrophages a brief (15-min) ex posure to ATP(e), but not other nucleotides, caused (1) a rapid and lo ng-lasting plasma membrane depolarization; (2) a large increase in int racellular Ca2+ concentration followed by efflux of the Ca2+ indicator ; (3) uptake of low molecular weight hydrophilic molecules such as Luc ifer yellow and ethidium bromide; and (4) cell rounding, swelling, and eventual release of the cytoplasmic enzyme lactate dehydrogenase. rIF N-gamma enhanced both membrane-permeabilizing and cytotoxic ATP(e) eff ects. Membrane permeabilization and cytotoxicity were fully blocked by pretreatment of the cells with oxidized ATP, a compound recently show n to block P-2Z receptors covalently in macrophages. Blocking of the P -2Z receptor by oxidized ATP also inhibited multinucleated giant cell generation stimulated by concanavalin A or rIFN-gamma without decreasi ng monocyte migration or membrane adhesion molecule expression. These data suggest that human macrophages express rIFN-gamma-modulated purin ergic P-2Z receptors in vitro and hint at a role for these plasma memb rane molecules in the generation of macrophage polykarions.