Role of cyclic nucleotides in the proliferation of committed granulocyte-macrophage progenitor cells.

Abstract

The proliferative response of murine hemopoietic progenitor cells to the stimulatory actions of colony-stimulating factor can be antagonized by agents that elevate cyclic adenosine 3′:5′-monophosphate and can be potentiated by agents associated with increases in cyclic guanosine 3′:5′-monophosphate. The granulocyte-macrophage progenitor cell is profoundly inhibited by the E-series prostaglandins, whereas its proliferative ability can be augmented by low concentrations of prostaglandin F2α. The existence of different receptors for prostaglandins E and F, determined with the prostaglandin antagonist, SC-19220, correlates with the differential effects of the two prostaglandin subclasses on colony-stimulating factor action. A role of cyclic adenosine 3′:5′-monophosphate in the mediation of prostaglandin E action is indicated by the capacity of theophylline, a phosphodiesterase inhibitor, to potentiate significantly prostaglandin E inhibition while having little effect by itself. Similarly, imidazole, an activator of cyclic adenosine 3′:5′-monophosphate phosphodiesterase and an inhibitor of cyclic guanosine 3′:5′-monophosphate phosphodiesterase, reduces the inhibition of granulocyte-macrophage progenitor cell proliferation by prostaglandin E. Imidazole, prostaglandin F2α, and carbamylcholine, three agents that are known to increase intracellular cyclic guanosine 3′,5′-monophosphate levels, augment the stimulatory action of colony-stimulating factor on the hemopoietic progenitor cell. The ability of atropine to reverse the potentiating effects of carbamylcholine indicates the presence of a muscarinic receptor on the progenitor cell. An opposing role of the cyclic nucleotides in the clonal proliferation of the committed granulocyte-macrophage progenitor cells is therefore indicated.