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 wanted to investigate whether cisplatin interferes with the IL-2, IL-2 receptor (IL-2R), interferon (IFN)-gamma, and TNF-alpha expression in phytohemagglutinin-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. Furthermore, T cell subsets and IL-2R surface expression were analyzed by means of flow cytometry. A maximum stimulatory effect on IL-2 production (1.8-fold increase) was observed with cisplatin at 5-10 microM while IFN-gamma and TNF-alpha synthesis and IL-2R density were unaffected. However, cisplatin-treated cells displayed enhanced IL-2, IL-2R, IFN-gamma and TNF-alpha mRNA levels 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 microM). Bleomycin, carboplatin, doxorubicin, novobiocin or etoposide, which were included for comparison, did not interfere with IL-2 expression. Our data imply that cisplatin most likely stimulated cytokine transcription via a putative stress-induced signaling pathway.