title: Cisplatin at clinically relevant concentrations enhances interleukin-2 synthesis by human primary blood lymphocytes.
abstract: 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.
authors.affiliation: Department of Medical Microbiology, Malmö University Hospital, Lund University, Sweden. kristian.riesbeck@mikrobiol.mas.lu.se
authors.forename: K
authors.initials: K
authors.lastname: Riesbeck
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage*; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007371:Interferon-gamma / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D010835:Phytohemagglutinins / Q000494:pharmacology; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007376:Interleukin-2; D010835:Phytohemagglutinins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D004247:DNA; D002945:Cisplatin