We investigated the reciprocal effects of interleukin-6 (IL-6), glucocorticoid and zinc (Zn) on metallothionein (MT) synthesis in rats. MT synthesis in the liver, which is a key responsible organ in acute phase responses, was induced by IL-6 or dexamethasone (Dex), and in an additive manner by a combination of IL-6 and Dex 18 h after injection. MT synthesis in the lung and heart was evaluated by immunoassay using a specific antibody to MT-1, because of its low concentration in these tissues. Heart concentrations of MT-1 were significantly increased by IL-6, and were further increased by the combination of IL-6 and Dex, although Dex by itself had no effect. This suggests a synergistic effect of IL-6 and Dex on MT-I synthesis in the heart. A similar synergism was observed in the lung. To study the effect of Zn on the induction of MT and acute phase proteins, Zn, IL-6 and Dex were administered in various concentrations. The increase in liver MT induced by the combination of IL-6 and Dex with Zn (130 micrograms MT/g of liver) was greater than the sum of the increases induced by (IL-6 + Zn) and by (Dex + Zn) (103 micrograms MT/g), suggesting a synergistic increase. The data indicate that the maximal increase in the induction of MT by a combination of IL-6 and Dex depends on an adequate liver Zn content. Thus, the in vivo synergistic induction of acute phase proteins by IL-6, glucocorticoid and Zn may be required for the maximal and rapid response, not only in liver but also in other tissues including heart and lung. This suggests that the synergistic reaction may be important for an enhancement of the radical scavenging ability of tissues in acute phase responses.