Toxicological Significances of Metallothionein: Induction by Inflammation

Abstract

The biological roles of metallothionein (MT) in connection with defense systcins have been previously proposed. Some compounds in which toxicity is reduced by pre-synthesis of MT (e.g. some heavy metals and radical-producing compounds) can induce MT synthesis. Inflammation-producing compounds induce MT synthesis specific to the liver, rcduccd hy preadministration of glucocorticoid, and accompanied by the elevation of fibrinogen and ceruloplasmin in the plasma. MT inducing factor(s) for culturing hepatoma cells was detected in the serum of LPS-treated mice, and the presence of glucocorticoid at the physiological level was necessary for its MT-inducing activih. MT synthesis hy serum MT-inducing factor in cultured cells, and that by n-hexane administration in the liver were inhibited by the addition or preadministration of anti interleukin (IL)-6 antibody. In IL-6-transgenic micc. a high concentration of MT was observed specifically in the liver. These results show that MT synthesis by inflammation-producing compounds is mediated by IL-6. and MT is considered to be a kind of acute phase protein produced by inflammation. From the studies at promoter gene level, both the type 2 IL-6 responsive element and glucocorticoid responsive element are required for the synergistic activation by IL-6 and glucocorticoid. Furthermore, this synergistic activation may require not only the binding of signal transducers and activators 3 (Stat3) and the glucocorticoid receptor (GR) to their responsive element, but also the interaction of Stat3 and GR with each other.