REINFORCEMENT EFFECT OF HISTAMINE ON THE DIFFERENTIATION OF MURINE MYELOBLASTS AND PROMYELOCYTES - EXTERNALIZATION OF GRANULOCYTE-COLONY-STIMULATING FACTOR RECEPTORS INDUCED BY HISTAMINE

Histamine and recombinant granulocyte colony-stimulating factor (rG-CS F) stimulated the differentiation of murine myeloblasts and promyelocy tes to mature neutrophils. In connection with this, myeloperoxidase ac tivity of these progenitor cells was decreased by either histamine or rG-CSF treatment. After pretreatment with histamine at 1 mu M, both di fferentiation and the decrease in myeloperoxidase activity of myelobla sts and promyelocytes induced by rG-CSF were significantly augmented. Binding assays using I-125-labeled rG-CSF showed that the number of rG -CSF binding sites on the surface of neutrophil progenitor cells incre ased after histamine treatment. The histamine-induced increase in rG-C SF binding appeared to be definitely through H-2 receptors. Furthermor e, the increase in rG-CSF binding sites due to histamine treatment see med to take place in association with the externalization of G-CSF rec eptors, because 1) the binding increase was observed in the presence o f cycloheximide, 2) no concomitant increase in [H-3]leucine uptake was elicited, and 3) colchicine and cytochalasin D effectively prevented the increase in rG-CSF binding due to histamine. In neutrophil progeni tors, cAMP contents increased very rapidly and significantly after eit her histamine or rG-CSF treatment. Moreover, dibutyryl-cAMP increased rG-CSF binding to neutrophil progenitor cells in a dose-dependent fash ion. However, when progenitor cells were pretreated with protein kinas e A inhibitors, the histamine-induced increase in rG-CSF binding was r emarkably decreased. This result seems to indicate that the stimulator y effects of histamine on rG-CSF binding to progenitor cells are intim ately related to the cAMP-protein kinase A system in neutrophil progen itors. Moreover, c-myc mRNA expression in neutrophil progenitors was m arkedly reduced by either histamine or rG-CSF treatment. It was conclu ded that rG-CSF-induced differentiation of murine neutrophil progenito rs was augmented by histamine pretreatment mainly due to an increase i n rG-CSF receptors on these cells and this increase might be related t o the externalization of rG-CSF receptors.