Cisplatin at clinically relevant concentrations enhances interleukin-2 synthesis by human primary blood lymphocytes

Cytotoxic drugs influence the expression of certain genes in cancer cells. Cisplatin has recently been shown to modulate interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha production in macrophages. In this study, we wa nted to investigate whether cisplatin interferes with the IL-2, IL-2 recept or (IL-2R), interferon (IFN)-gamma, and TNF-alpha expression in phytohemagg lutinin-stimulated human peripheral blood lymphocytes. IL-2 was analyzed in a bioassay, while IFN-gamma and TNF-alpha were measured by ELISA. Northern blots were performed to quantify steady-state cytokine mRNA levels. Furthe rmore, T cell subsets and IL-2R surface expression were analyzed by means o f flow cytometry. A maximum stimulatory effect on IL-2 production (1.8-fold increase) was observed with cisplatin at 5-10 mu M while IFN-gamma and TNF -alpha synthesis and IL-2R density were unaffected. However, cisplatin-trea ted cells displayed enhanced IL-2, IL-2R, IFN-gamma and TNF-alpha mRNA leve ls compared to drug-free controls. Cisplatin did not prolong cytokine mRNA half-life as revealed with the transcriptional inhibitor actinomycin D. In contrast to an inhibited growth of CD4(+) T lymphocytes, CD3(+)CD8(+) cell density was unaffected at intermediate cisplatin concentrations (10 mu M). Bleomycin, carboplatin, doxorubicin, novobiocin or etoposide, which were in cluded for comparison, did not interfere with IL-2 expression. Our data imp ly that cisplatin most likely stimulated cytokine transcription via a putat ive stress-induced signaling pathway. [(C) 1999 Lippincott Williams & Wilki ns.].