DOWN-REGULATION OF INTERLEUKIN-2 AND ALPHA-CHAIN INTERLEUKIN-2 RECEPTOR BIOSYNTHESIS BY CISPLATIN IN HUMAN PERIPHERAL LYMPHOCYTES

To further investigate the mechanisms by which the antineoplastic agen t cisplatin interferes with immune function, we studied its effect on the biosynthesis of interleukin-2 (IL-2) and its alpha-chain receptor (IL-2R alpha). Normal human peripheral blood lymphocytes (PBL) were ac tivated in vitro with phytohemagglutinin (PHA), and anti-CD3 antibody in the presence of various concentrations of cisplatin. Purified T cel ls were also cultured with anti-CD3 antibody and costimulated by CD80 (B7-1, B7/BB1)-transfected P815 mastocytoma cells in the presence of c isplatin. Tritiated thymidine incorporation assays, an enzyme-linked i mmunosorbent assay for soluble IL-2R(alpha determination, and RNA dot- blot analysis and hybridization with IL-2- and IL-2R alpha-specific pr obes were used. PHA-induced and anti-CD3 antibody-induced proliferatio n of PBL were significantly inhibited by cisplatin at concentrations a ttainable in vivo. This inhibition was not due to direct cell death as shown by the absence of trypan blue uptake in the presence of high co ncentrations of cisplatin. Therapeutic concentrations of cisplatin (1 mu g/ml) also inhibited the IL-2-dependent proliferation of purified T cells, mediated via the CD28-CD80 costimulatory pathway. In addition, the amount of soluble IL-2R alpha released in the T cell culture supe rnatants was decreased by cisplatin in a dose-dependent fashion, sugge sting that inhibition of cell proliferation was associated with a para llel decrease in IL-2R alpha production. These effects correlated with a specific cisplatin-induced downregulation of both IL-2 and IL-2R al pha messenger RNA accumulation in PHA-stimulated PBL that was dependen t on the concentration of the drug. These findings suggest that the im munomodullatory effects of cisplatin may result in part from its capac ity to directly downregulate the IL-2/IL-2R system in activated lympho cytes. (C) 1996 Academic Press, Inc.