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To elucidate the mechanism by which low T3 and low T4 syndrome occurs in patients with acute or chronic infection or malignancy, recombinant human tumor necrosis factor-alpha (TNF-alpha)/cachectin (TNF) was administered ip to mice and thyroid hormone metabolism was studied. Since administration of TNF caused a decrease in food intake and body weight, all experiments were performed using pair-fed control (PFC) mice. Administration of TNF at a dose of 1-100 micrograms/day for 3 days decreased serum T4, T3, and rT3 concentrations in a dose-dependent manner. In PFC mice, serum T4 and T3 also decreased, but rT3 was significantly increased. T3/T4 ratio was greater in TNF-treated mice than in PFC mice. Type I iodothyronine-5'-deiodinating activity in the liver was significantly decreased in PFC mice but not in TNF-treated mice. The effect of TNF was reversible and could be abolished by boiling the cytokine. Furthermore, T3 and T4 response to TSH was greatly diminished in TNF-treated mice in comparison with PFC mice. These findings suggest that TNF directly inhibited the effect of TSH on the thyroid gland and decreased the serum concentrations of T4 and T3. Although TNF decreased food intake and body weight in TNF-treated mice, it did not decrease type I 5'-deiodinating activity in the liver, resulting in a greater T3/T4 ratio and lower serum rT3 concentration than those in PFC mice. We speculate that TNF is at least partly involved in the altered thyroid hormone metabolism (decreased serum T4, T3, and rT3 concentrations) caused by infections in mice.