Microtubule-active agents mimic lipopolysaccharides in priming macrophages for enhanced arachidonic acid metabolism.
Macrophages play a crucial role in inflammation and host defense, in part, by secreting metabolites of arachidonic acid (20:4). Bacterial lipopolysaccharides (LPS) are poor agonists of the 20:4 cascade, but do have the capacity to prime macrophages for greatly increased 20:4 metabolism upon subsequent stimulation with activators of protein kinase C (PKC). The microtubule-stabilizing agent, taxol, mimics many of the effects of LPS in macrophages. We demonstrate in this study that taxol, like LPS, primes murine peritoneal macrophages for an enhanced release of 20:4 in response to both phorbol 12-myristate 13-acetate (PMA) and zymosan. Taxol and LPS, when used at maximum concentrations, acted additively to prime macrophages for PMA-stimulated release of 20:4, suggesting that the two agents signal through different pathways. Interestingly, agents that stimulate the depolymerization of microtubules, colchicine and nocodazole, also primed macrophages for an enhanced release of 20:4 in response to PMA, however, they did not prime when zymosan was the stimulus. We conclude that agents that disrupt the microtubule network prime resident peritoneal macrophages for enhanced release of 20:4.
Veis
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Laboratory of Signal Transduction, Rockefeller University, New York, NY 10021, USA.
Rosen
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Aderem
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D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002478:Cells, Cultured; D003078:Colchicine / Q000494:pharmacology; D005260:Female; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008813:Mice, Inbred ICR; D008870:Microtubules / Q000187:drug effects*; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015054:Zymosan / Q000494:pharmacology
D008070:Lipopolysaccharides; D016718:Arachidonic Acid; D015054:Zymosan; D013755:Tetradecanoylphorbol Acetate; D017239:Paclitaxel; D015739:Nocodazole; D003078:Colchicine