Mediation of the antiproliferative effect of cyclosporine on human lymphocytes by blockade of interleukin 2 biosynthesis.

Normal human peripheral blood mononuclear cells (PBMC) were cultured with phytohemagglutinin-P (PHAP) and cyclosporine (CsA) to investigate the mode of action of CsA on cellular proliferation. CsA at 1 microgram/ml exerted a marked inhibitory effect on PBMC responsiveness to PHAP. An antiproliferative effect of CsA was observed at the inductive phase of the cell cycle, but the drug was ineffective when it was added to cultures 24 hr after stimulation. In parallel with this inhibitory effect interleukin 2 (IL-2) production was inhibited. In contrast, IL-2 receptor was expressed on the CsA-treated cells, and the antiproliferative influence of the drug was completely reversed by addition of highly purified human IL-2 to the CsA-treated cells. Exogenous IL-2, however, did not restore cellular capacity to produce IL-2. This study suggests that CsA acts by inhibiting IL-2 production (via blockade of IL-2 gene expression) rather than by preventing the expression of the IL-2 receptor.