Phorbol esters of different biological activities may preferentially act as mitogens of human suppressor T-cells and are equi-effective mitogens of IL-2 dependent cells.
The actions of tetradecanoylphorbolacetate (TPA) and 12-deoxyphorbolphenylacetate-20-acetate (DPPAA) together with a phytohaemagglutinin (PHA) have been examined on the proliferative responses of human mononuclear cells (MNC) depleted of specific cell subsets by the use of monoclonal antibodies. PHA-induced proliferation was found to be reduced when monocytes/macrophages and T-helper cells were depleted from MNC, but enhanced compared with MNC responses when T-suppressor cells were depleted. In contrast, TPA- and DPPAA-induced proliferation was unchanged or slightly enhanced following macrophage/monocyte depletion, and whereas TPA-induced proliferation was largely independent of subtype constitution, the non-tumour promoting DPPAA appeared to selectively enhance proliferation of the T8+ suppressor subset. Indomethacin increased the proliferative MNC responses of phorbol esters whilst having little effect upon the PHA response, an effect antagonized by addition of PGE2. The addition of interleukin-2 (IL-2) increased the proliferative response, as well as resistance to inhibition induced by cyclosporin A and dexamethasone and partially abolished the selective actions of DPPAA and PHA. In IL-2 dependent cultures PHA induced stimulation was more sensitive to inhibition by cyclosporin than were the phorbol esters. The results suggest that, although induction of lymphocyte proliferation by phorbol esters is not a correlate for tumour promotion itself, non-promoting phorbol esters may have a more restricted ability to induce proliferation than TPA.
Edwards
M C
MC
Department of Pharmacognosy, School of Pharmacy, University of London, UK.
Evans
A T
AT
Evans
F J
FJ
D000911:Antibodies, Monoclonal / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007376:Interleukin-2 / Q000502:physiology*; D008934:Mitogens; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D010703:Phorbol Esters / Q000494:pharmacology*; D010835:Phytohemagglutinins / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*
D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D008934:Mitogens; D010703:Phorbol Esters; D010835:Phytohemagglutinins; D007213:Indomethacin