Down-Regulation of Interleukin-2 Receptor Gene Activation and Protein Expression by Dideoxynucleoside Analogs

The in vitro effect of single or combined doses of zidovudine (AZT) and dideoxycytidine (ddC) on the production and utilization of interleukin-2 (IL-2) by normal human peripheral blood mononuclear cells (PBMC) was evaluated by measuring IL-2 concentrations in supernatants from PHA-stimulated PBMC cultures. Drugs were added at the beginning of the culture period and left throughout. Whereas AZT alone (1 and 10 μM) caused only a slight increase, ddC alone (1 and 10 μM) and combined AZT/ddC (1 + 1 and 10 + 10 μM) caused a considerable increase. IL-2 gene expression in the drug-treated PBMC did not increase. This finding suggested that the increased supernatant IL-2 accumulations might be caused by a drug-induced down-regulation of the IL-2 receptor a (IL-2Rα, CD25). AZT decreased IL-2Rα expression, but only slightly. In contrast, ddC alone and combined AZT/ddC decreased the CD25 molecules in a marked and dose-dependent manner. They also markedly reduced IL-2Rα gene expression. These findings show that the dideoxynucleoside drugs tested left PHA-induced IL-2 gene activation unchanged but decreased IL-2Rα gene activation, thus down-regulating IL-2Rα cell-surface protein expression.