Colchicine-induced elevation of tissue metallothionein contents is mediated by inflammation-independent serum factor

Subcutaneous injection of colchicine caused dose-dependent and time-dependent induction of hepatic MT in mice. Other than colchicine, similar MT induction was observed in vincristine- or vinblastine-injected mice, but not in beta-lumicolchicine-injected mice. MT contents were also elevated in the kidney, spleen, lung and heart by colchicine injection. Isoforms of colchicine-induced MT in the liver were identified to be MT-I and II by immunoblot analysis. Unlike turpentine-induced MT synthesis, dexamethasone, an anti-inflammatory agent, could not block the MT-inducing activity of colchicine. Therefore, the MT-inducing activity of colchicine does not appear to be due to inflammation. Mouse serum, obtained at 4-24 h after colchicine treatment, stimulated MT induction in rat hepatoma H4IIEC3 cells. The MT-inducing activity in the serum from colchicine-treated mice was determined to be highest at 12 h after colchicine injection. The MT-inducing activity from sera of colchicine-treated mice was completely blocked by glucocorticoid antagonist, RU38486, similar to such activity in the serum from lipopolysaccharide-treated mice. The ability of sera to induce MT was abolished by heat treatment (56 degrees C, 30 min). The molecular weight of the MT-inducing factor estimated by gel filtration was approximately 20 000 Da. Thus, colchicine-induced stimulation of MT production is mediated by some humoral factor. The production of the MT-inducing factor was not blocked by dexamethasone. We conclude that the mediator is not an inflammatory cytokine or a glucocorticoid and suspect that the disruption of microtubule triggers production or release of such humoral mediator which stimulates MT induction.