Attention has focused on the cytokine interleukin 6 (IL-6) as a major mediator of acute-phase protein synthesis in hepatocytes in response to infection and tissue injury. We have evaluated the effects of IL-6 and IL-1 alpha as well as extracellular zinc and glucocorticoid hormone on metallothionein gene expression and cellular zinc accumulation in rat hepatocyte monolayer cultures. Further, we have evaluated the teleological basis for cytokine mediation by examining cytoprotection from CCl4-induced damage. Incubation of hepatocytes with IL-6 led to concentration-dependent and time-dependent increases in metallothionein-1 and -2 mRNA and metallothionein protein. The level of each was increased within 3 hr after the addition of IL-6 at 10 ng/ml (10 hepatocyte-stimulating factor units/ml). Maximal increases in metallothionein mRNA and metallothionein protein were achieved after 12 hr and 36 hr, respectively. In contrast, IL-1 alpha concentrations as high as 20 ng/ml (1000 lymphocyte-activating factor units/ml) had no effect. Concomitant with the up-regulation of metallothionein gene expression, IL-6 also increased cellular zinc. Responses to IL-6 required the synthetic glucocorticoid hormone dexamethasone and were optimized by increased extracellular zinc. In addition, IL-6 with dexamethasone, dexamethasone alone, and increased extracellular zinc each reversed, in decreasing potency, the deleterious effects of CCl4 on hepatocyte viability as measured by cell protein and lactate dehydrogenase activity of the medium. Thus, IL-6 is a major cytokine mediator of metallothionein gene expression and zinc metabolism in hepatocytes and provides cytoprotection from CCl4-induced hepatotoxicity via a mode consistent with dependence upon increased cellular metallothionein synthesis and zinc accumulation.