Taxol induces the hematopoietic growth factor granulocyte-macrophage colony-stimulating factor in murine B-cells by stabilization of granulocyte-macrophage colony-stimulating factor nuclear RNA.
Taxol, a microtubule-stabilizing agent, has been shown to have antineoplastic activity against various tumors. In addition, it has been shown that taxol resembles bacterial lipopolysaccharide in its ability to activate macrophages. Recently we have shown that lipopolysaccharide induces the expression of the granulocyte-macrophage colony-stimulating factor (GM-CSF) in murine B-cell lines. In light of the similarity of taxol and lipopolysaccharide in their effects on macrophages, we tested whether taxol could also induce the expression of GM-CSF in B-cell lines. In the present study we used the murine B-lymphoma cell line M12.4.1. In unstimulated cells, no GM-CSF mRNA was detected, whereas in taxol-stimulated stimulated cells at a concentration of 30 microM, GM-CSF mRNA was induced 4-8 h after stimulation. This induction of GM-CSF mRNA was down-regulated by 10 ng/ml of interleukin 4. Actinomycin D chase experiments revealed that interleukin 4 did not affect the half-life of the taxol-induced GM-CSF cytoplasmic mRNA, nor did it alter GM-CSF gene transcription. Polymerase chain reaction analysis of nuclear RNA, utilizing probes specific for sequences in the first intron of GM-CSF, indicated that taxol enhances accumulation of nuclear precursor RNA and that interleukin 4 decreases this accumulation. The present study shows a novel activity of taxol in inducing the release of the hematopoietic growth factor GM-CSF from B-cells. Since GM-CSF is known to recruit macrophages and enhance their cytotoxicity against tumor cells, our observations suggest that part of the known antitumor activity of taxol may be due to synergistic effects of GM-CSF activity together with direct cytotoxic actions through microtubule stabilization.
Pluznik
D H
DH
Division of Hematologic Products, Food and Drug Administration, Bethesda, Maryland 20892.
Lee
N S
NS
Sawada
T
T
D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D006207:Half-Life; D015847:Interleukin-4 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D016393:Lymphoma, B-Cell / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D017239:Paclitaxel / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017239:Paclitaxel