Lymphocyte mitogenesis and CD4 modulation induced by different phorbol esters: comparative studies.

Phorbol 12-myristate 13-acetate (PMA) can stimulate T-cells via its binding to protein kinase C (PKC). Such a phenomenon occurs when a threshold of concentration as low as 1 nM of PMA is reached. Other phorbol esters possess the ability to stimulate lymphocytes but at higher thresholds of concentration. We show here that the different phorbol ester concentrations needed to induce stimulation and proliferation, estimated by both interleukin-2 receptor (IL-2R) expression and DNA synthesis, correspond very closely to those inducing the modulation of CD4 antigen, confirming a direct relationship between CD4 down-regulation and cellular activation. We estimated the structural features of these different phorbol derivatives in relation to lymphocyte activation and CD4 modulation, and confirm that the ester side chains which give to the phorbol ester derivatives their lipophilic character, discriminate, according to their length, the ability of the different compounds to reach their receptor inside the cell membrane; we also brought some evidence that the polar phorbol nucleus of these compounds is probably responsible for their interaction with the membrane receptor mainly through the hydroxyl group in the C4 position.