Inhibition of Phorbol Ester-mediated lnterleukin-2 Production by Cellular Differentiating Agents1

Lymphocyte proliferation induced by the tumor promoter 12O-tetradecanoylphorbol-13-acetate (TPA) is inhibited by agents known to induce differentiation in murine erythroleukemia cells and other cell lines. In the present study, we determined the cellular targets for the action of TPA among murine thymocyte subpopulations, the phase of blastogenesis that is activated by the tumor promoter, and the phase that is inhibited by the differentiating agents. Mouse thymocytes were fractionated into populations bearing receptors for peanut agglutinin (PNA; PNApositive cells) and populations lacking such receptors (PNAnegative cells). TPA is comitogenic for lectin-treated, unfractionated thymocytes and PNA-negative thymocytes but not for PNApositive thymocytes. PNA-negative cells, a minor population in unfractionated thymocytes, are therefore the cellular targets for the comitogenic activity of TPA. TPA induces the production of interteukin-2 (IL-2) in lectin-treated PNA-negative populations but not in PNA-positive cells. The differentiating agents inhibit TPAmediated proliferation of unfractionated and PNA-negative, lec tin-treated thymocytes. In contrast, IL-2-mediated proliferation of lectin-treated thymocyte subpopulations is resistant to inhibi tion by these agents. Inhibition appears to be related to de creased production of IL-2, since the differentiating agents inhibit IL-2 production by both PNA-negative thymocytes and by a human leukemic cell line.