Inhibition of LPS-Induced Tumor Necrosis Factor-α Production by Colchicine and Other Microtubule Disrupting Drugs

• Published in: Immunobiology (1979) 1996-10, Vol.195 (4), p.624-639
• Main Authors: Li, Zhouya, Davis, Gerald S., Mohr, Carsten, Nain, Marianne, Gemsa, Diethard
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Cells, Cultured; Colchicine - pharmacology; Dinoprostone - biosynthesis; Extracellular Space - immunology; Extracellular Space - metabolism; Fibroblasts; Intracellular Fluid - immunology; Intracellular Fluid - metabolism; Lipopolysaccharides - pharmacology; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; Male; Microtubules - drug effects; Microtubules - metabolism; Nocodazole - pharmacology; Rats; Rats, Inbred F344; RNA, Messenger - drug effects; RNA, Messenger - metabolism; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - toxicity; Vinblastine - pharmacology; Vincristine - pharmacology
• ISSN: 0171-2985; 1878-3279
• DOI: 10.1016/S0171-2985(96)80027-1

Colchicine has been shown to act as an anti-inflammatory agent. In this study, we examined whether colchicine and other microtubule-depolymerizing drugs affected the production of TNF-α. When rat peritoneal macrophages were stimulated by LPS, addition of colchicine, vincristine, vinblastine or nocodazole was found to inhibit TNF-α release in a concentration-dependent manner. Suppression of TNF-α release was not due to interference with secretion as the cytokine did not accumulate intracellularly following colchicine treatment. Colchicine markedly 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-α production. Colchicine caused a strong reduction of LPS-induced TNF-α mRNA accumulation, suggesting that a pretranslational effect may represent the primary mechanism by which colchicine reduced TNF-α production. These observations could have clinical relevance in ameliorating undesirable effects due to excessive TNF-α production, for example following LPS stimulation of monocytes/macrophages in gram-negative sepsis. Furthermore, these drugs may provide useful tools to study the apparent involvement of the microtubular system in cytokine gene expression and cytokine production.