INHIBITION OF LPS-INDUCED TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION BY COLCHICINE AND OTHER MICROTUBULE DISRUPTING DRUGS

Colchicine has been shown to act as an antiinflammatory agent. In this study, we examined a whether colchicine and other microtubule-depolym erizing drugs affected the production of TNF-alpha. When rat peritonea l macrophages were stimulated by LPS, addition of colchicine, vincrist ine, vinblastine or nocodazole was found to inhibit TNF-alpha release in a concentration-dependent manner. Suppression of TNF-alpha release was not due to interference with secretion as the cytokine did not acc umulate intracellularly following colchicine treatment. Colchicine mar kedly enhanced PGE(2) release from LPS-stimulated macrophages. However , addition of the cyclooxygenase inhibitor indomethacin only partially reversed the suppressive effect of colchicine on TNF-alpha production . Colchicine caused a strong reduction of LPS-induced TNF-alpha mRNA a ccumulation, suggesting that a pretranslational effect may represent t he primary mechanism by which colchicine reduced TNF-alpha production. These observations could have clinical relevance in ameliorating unde sirable effects due to excessive TNF-alpha production, for example fol lowing LPS stimulation of monocytes/macrophages in gram-negative sepsi s. Furthermore, these drugs may provide useful tools to study the appa rent involvement of the microtubular system in cytokine gene expressio n and cytokine production.