Effect of zinc on the proliferative response of human lymphocytes: mechanism of its mitogenic action.

To study the effect of Zn on the proliferative response of normal human lymphocytes, ZnCl2 at a final concentration of 10(-4) M was added to cultures of peripheral blood mononuclear cells (PBMC) stimulated with concanavalin A (Con A) and to autologous mixed lymphocyte cultures of responder T lymphocytes and irradiated autologous non-T cells. Addition of Zn increased by about 50% the synthesis of DNA in cultures stimulated with either 10 or 20 micrograms/ml of Con A and markedly enhanced the autologous mixed lymphocyte reaction, which increased about 5-fold in the presence of Zn. In a narrow dose range, Zn induced per se the incorporation of [3H]thymidine by PBMC, with maximal effects in cultures stimulated with 10(-4) M ZnCl2. The percentage of cells expressing receptors for IL-2 and transferrin as assessed by immunofluorescence with the monoclonal antibodies (mAb) anti-Tac and OKT9, respectively, significantly increased when PBMC were stimulated with 10(-4) M ZnCl2 alone. Maximal [3H]thymidine incorporation and maximal percentage of cells bearing those activation markers were observed on day 6 of culture. Thus, the increase in the uptake of [3H]thymidine induced by Zn is not artifactual but due to progression in the cell cycle. Incubation with the mAb anti-Tac significantly inhibited the proliferative response to Zn, indicating that this requires binding of IL-2 to its receptor. However, addition of human recombinant IL-2 did not increase [3H]thymidine incorporation by PBMC cultured in the presence of ZnCl2.