Vinca alkaloids induce granulocyte-macrophage colony stimulating factor inhuman peripheral blood mononuclear cells

Several anti-cancer drugs are known to have proliferation-related effects o n various cells, such as art activation of some transcription factors and a n induction of some cytokines. We examined the effect of anti-cancer drugs on granulocyte-macrophage colony stimulating factor (GMCSF) induction in hu man peripheral blood mononuclear cells (PBMC). Increase of GM-CSF protein a nd mRNA were observed in PBMC after exposure to vindesine sulfate (VDS). In duction of GM-CSF protein was dose-dependent and detectable at VDS concentr ations of 0.1 mu g/ml. This effect was also observed in response to treatme nt with other microtuble-depolymerizing agents, vincristine sulfate and vin orelbine ditartrate, but nor with cisplatin, etoposide, or paclitaxel. In o rder to elucidate the mechanism of this phenomenon, we examined the effects of cyclohexamide and actinomycin D on the expression of CM-CSF mRNA. Both of these drugs completely inhibited GM-CSF mRNA expression. after VDS expos ure, implying that VDS induces de novo CM-CSF synthesis in an indirect mann er. As a candidate for the initial signaling, we next examined the role of the IL-1 beta autocrine or paracrine pathways in CM-CSF induction by VDS. I L-1 beta protein and mRNA expression were induced after VDS exposure more r apidly (from 4 hours) than expression of GMCSF (protein from 12 hours and m RNA from 8 hours). Addition of anti-IL-1 beta antibody partially inhibited induction of GM-CSF by VDS. These results suggest that GM-CSF induction by VDS is partially mediated through the initial generation of lL-1 beta in PB MC.