TUMOR-PROMOTING AND NONPROMOTING PROINFLAMMATORY ESTERS ACT AS HUMAN-LYMPHOCYTE MITOGENS WITH DIFFERENT SENSITIVITIES TO INHIBITION BY CYCLOSPORIN-A

  • 1 January 1983
    • journal article
    • research article
    • Vol. 23  (3) , 703-708
Abstract
Ten closely related tumor-promoting and nonpromoting, proinflammatory phorbol derivatives were tested for stimulation of [3H]thymidine ([3H]TdR) incorporation into human mononuclear cells: co-mitogenic activity was assessed with maximally effective concentrations of phytohemagglutinin (PHA) or mixed-lymphocyte reactions (MLR) in the presence of phorbol esters. TPA, two 4-deoxyphorbol esters, and two 12-deoxyphorbol monoesters stimulated [3H]TdR incorporation in a dose-related manner. Two established nonpromoting 12-deoxyphorbol diesters were mitogenic, although less effective than TPA and produced lower maximal responses. TPA, the 4-deoxyphorbol esters, the 12-deoxyphorbol monoesters, and the nonpromoting diesters were able to increase MLR-induced incorporation to the same level. When conditions were used where PHA and phorbol esters were optimally mitogenic, inhibition resulted. With the exception of co-mitogenic activity of the nonpromoting diesters, the mitogenic, co-mitogenic, and PHA-inhibiting activities were correlatable. Phorbol, a 4.alpha.-deoxyphorbol ester, and resiniferatoxin had no effects. Mitogenic activity of the phorbol esters was inhibited by dexamethasone, chloroquine and p-bromophenacyl bromide. TPA, the 4-deoxyphorbol esters, and the 12-deoxyphorbol monoesters were resistant to inhibition of activity by cyclosporin A, whereas the noncorrelating diesters exhibited sensitivity to cyclosporin A inhibition comparable to that of PHA. MLR-induced [3H] TdR incorporation was susceptible to cyclosporin A, but the phorbol ester-enhanced responses were cyclosporin A-resistant.