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 antineo plastic activity against various tumors. In addition, it has been show n that taxol resembles bacterial lipopolysaccharide in its ability to activate macrophages. Recently we have shown that lipopolysaccharide i nduces 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 test ed 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 M1 2.4.1. In unstimulated cells, no GM-CSF mRNA was detected, whereas in taxol-stimulated cells at a concentration of 30 mu M, GM-CSF mRNA was induced 4-8 h after stimulation. This induction of GM-CSF mRNA was dow n-regulated by 10 ng/ml of interleukin 4. Actinomycin D chase experime nts revealed that interleukin 4 did not affect the half-life of the ta xol-induced GM-CSF cytoplasmic mRNA, nor did it alter GM-CSF gene tran scription. Polymerase chain reaction analysis of nuclear RNA, utilizin g probes specific for sequences in the first intron of GM-CSF, indicat ed that taxol enhances accumulation of nuclear precursor RNA and that interleukin 4 decreases this accumulation. The present study shows a n ovel activity of taxol in inducing the release of the hematopoietic gr owth factor GM-CSF from B-cells. Since GM-CSF is known to recruit macr ophages and enhance their cytotoxicity against tumor cells, our observ ations 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.