LIPOPOLYSACCHARIDE ANTAGONISTS BLOCK TAXOL-INDUCED SIGNALING IN MURINE MACROPHAGES

Taxol is the prototype of a new class of microtubule stabilizing agent s with promising anticancer activity. Several studies show that taxol mimics the actions of lipopolysaccharide (LPS) on murine macrophages. To investigate the mechanism of taxol-induced macrophage stimulation, we evaluated the ability of Rhodobacter sphaeroides diphosphoryl lipid A (RsDPLA) and SDZ 880.431 to block taxol-induced effects. RsDPLA and SDZ 880.431 are lipid A analogues that lack LPS-like activity, but in hibit the actions of LPS, presumably by blocking critical cellular bin ding sites. We report that RsDPLA and SDZ 880.431 potently inhibited t axol-induced TNF secretion, gene activation, and protein-tyrosine phos phorylation. The role of microtubules in taxol signaling was investiga ted. Taxol-induced microtubule bundling in primary and transformed RAW 264.7 macrophages was not blocked by RsDPLA or SDZ 880.431. Taxotere, a semisynthetic taxoid, was more potent than taxol as an inducer of m icrotubule bundling, but did not induce tumor necrosis factor alpha se cretion and gene activation. These data dissociate the microtubule eff ects of taxol from macrophage stimulation and suggest that taxol stimu lates macrophages through an LPS receptor-dependent mechanism. The res ults underscore the potential of taxol as a tool for studying LPS rece ptor activation and provide insights into possible therapeutic actions of this new class of drugs.