IDENTIFICATION AND CHARACTERIZATION OF SURFACE-RECEPTORS FOR HISTAMINE IN THE HUMAN PROMYELOCYTIC LEUKEMIA-CELL LINE HL-60 - COMPARISON WITH HUMAN PERIPHERAL NEUTROPHILS

Abstract

The magnitude, potency, duration and specificity of histamine-induced cAMP formation were compared in human promyelocytic leukemic HL-60 cells and in human peripheral neutrophils. In HL-60 cells incubated at 37.degree. in the absence of phosphodiesterase inhibitor, histamine caused a 20-fold stimulation of basal cAMP levels, with an EC50 [media effective concentration] of 5 .times. 10-6 M. Typical H2 receptors were involved as shown by the relative potencies of the H1-selective agonists, 2-(2-pyridyl)ethylamine (PEA) and 2-(2-amino-ethyl)thiazole (AET), and the H2-selective agonists, impromidine and 4-(methyl)histamine(4-MH), impromidine > histamine > 4-MH > AET > PEA. Impromidine had mixed agonist-antagonist properties as shown by the rightward shift of the concentration-response curve of histamine (EC50 = 2 .times. 10-3 M histamine in the presence of 10-4 M impromidine). Histamine stimulation was competitively inhibited by the furane derivative ranitidine (Ki [inhibition constant] = 0.16 .times. 10-6 M) and by the imidazole analogs oxmetidine (Ki = 0.48 .times. 10-6 M) and cimetidine (Ki = 0.65 .times. 10-6 M); however, the H1 antagonist diphenhydramine inhibited histamine action at about 100-300 times higher concentrations (Ki = 51 .times. 10-6 M). Prostaglandin E1 (PGE1) also stimulated cAMP levels (50-fold increase) in HL-60 cells; half-maximal activation by PGE1 occurred at 3.2 .times. 10-6 M. Prostaglandin and histamine H2 receptors are evidently present and functional at an early stage during myeloid differentiation, and there is no substantial difference between the pharmacological properties of the histamine H2 receptors in HL-60 cells and in mature human peripheral neutrophils. The remarkable capacity for cAMP formation noted in HL-60 leukemic cells after cell surface interaction by histamine or prostaglandin suggests that cAMP and agents which increase its formation may have a role in the regulation of proliferation and/or differentiation of human myeloid progenitor cells.