Role of cyclic AMP in mitogen induced transformation of human peripheral leukocytes

Abstract

Phytohemagglutinin (PHA) causes a stimulation of the adenyl cyclase activity of human peripheral leukocytes within 15 min of incubation of cells with the mitogen. An increase in the intracellular content of cyclic 3',5'-adenosine monophosphate (cAMP) was also observed in purified lymphocyte preparations. The blast transformation and the stimulation of the adenyl cyclase by PHA are dose dependent; excessive concentration of the mitogen is inhibitory for both effects. A variety of pharmacological agents (propranolol; chlorpromazine and imidazole) that interfere with the PHA induced activation of adenyl cyclase or that lower the intracellular levels of cAMP at the early stages inhibit also the blast transformation as measured by the incorporation of ³H-thymidine into DNA on the day of peak response. cAMP however does not simulate fully the mitogenic action of PHA. When added to the medium, a maximal stimulation of about 2- to 3-fold over the basal control value is obtained which is far lower than the transformation with PHA (450-fold). Dibutyryl cAMP, cyclic 3',5'-guanosine monophosphate and cyclic 3',5'-cytidine monophosphate were ineffective in the induction of transformation. Moreover, another potent mitogen, concanavalin A, gives only a marginal activation of adenyl cyclase and a moderate increase in intracellular cAMP levels in the initial phases. It is concluded that activation of adenyl cyclase and a rise in intracellular content of cAMP in the early phase are possibly a part (but not all) of the initial effects of PHA on human leukocytes.