ENHANCING AND PRIMING OF MACROPHAGES FOR SUPEROXIDE ANION PRODUCTION BY TAXOL

Taxol, an anticancer drug, has been known not only to block cell divis ion by stabilizing microtubules but also to activate murine macrophage s to express TNF-alpha, interleukin-l, and to produce nitric oxide (NO ). We therefore reasoned that taxol could activate murine macrophages to generate reactive oxygen intermediates, such as superoxide anion (O -2(-)), which are responsible for intracellular killing of pathogenic microbes. Treatment of RAW264.7 cells, murine macrophage cell line, wi th taxol increased phorbol ester-induced O-2(-) production in a dose d ependent manner (similar to 2 fold). In addition, taxol rapidly (<1 hr ) primed RAW264.7 cells to enhance O-2(-) release stimulated with PMA. Taxol also enhanced stimulation of O-2(-) production by FMLP, but not by Con A. This effect was abolished by prior treatment with both supe roxide dismutase (SOD) and N-acetyl-L-cystein, a free radical scavenge r. To investigate the mechanism of taxol-induced macrophage stimulatio n, we evaluated the ability of colchicine, a drug that inhibit tubulin polymerization, and cAMP analogues, which is known to depolymerize mi crotubule. Taxol-induced O-2(-) production was inhibited by the treatm ent with both colchicine and DB-cAMP. Taken together, these results de monstrated that taxol provides two signals, ''priming'' and ''enhancin g'', to generate superoxide anion via the stabilization of microtubule s in murine RAW264.7 cells.