We examined the effect of interleukin-6 (IL-6) on the expression of transglutaminase in human hepatoblastoma HepG2 cells. Treatment of cells with IL-6 increased their transglutaminase activity in a time- and dose-dependent way. Dexamethasone strengthened the stimulation by IL-6. Half-maximum stimulation of transglutaminase activity in the cells occurred at a dose of 40 pM IL-6 regardless of the presence of dexamethasone. Based on its immunoreactivity, the transglutaminase induced was identified as tissue-type transglutaminase. Immunoblot analysis showed that the increase in transglutaminase activity was related to an increase in the amount of transglutaminase protein. Northern blot analysis with a cDNA probe specific for human tissue-type transglutaminase showed that exposure of HepG2 cells to IL-6 increased the mRNA level of the enzyme, and the increase was detectable 3 h after IL-6 was added. Induction of the mRNA was maximum between 10 and 14 h. The increase in the mRNA level was not blocked by the presence of cycloheximide, suggesting that the increase was independent of protein synthesis. Injections into mice of substances that induce inflammation such as turpentine and lipopolysaccharides increased the liver transglutaminase activity. These results indicated that transglutaminase may be involved in some biological processes in hepatocytes regulated by IL-6 signaling.