Interleukin-6 (IL-6) administration to human subjects or experimental animals induces changes in thyroid hormone metabolism resembling those in the sick euthyroid syndrome. Furthermore, the decrease in serum T3 during illness is significantly related to serum IL-6 concentrations. These findings suggest, but do not prove, a causal role for IL-6 in the development of the low T3 syndrome. The aim of the present study was to evaluate the role of IL-6 in the development of the sick euthyroid syndrome in IL-6 knock-out (IL-6(-/-)) mice compared to that in wild-type mice (IL-6(+/+)). Illness was induced in IL-6(-/-) and IL-6(+/+) mice by 1) administration of bacterial endotoxin (LPS), 2) infection with Listeria monocytogenes, and 3) turpentine injection in both hind limbs. Food intake was kept similar in both groups in all three experiments. Serial measurements were made of serum IL-6, tumor necrosis factor-alpha, T3, T4, corticosterone, and liver 5'-deiodinase (5'-DI) messenger RNA (mRNA) for 24 h (LPS), 96 h (L. monocytogenes), and 48 h (turpentine). Serum IL-6 increased in response to all stimuli in IL-6(+/+) mice, but not in IL-6(-/-) mice. Serum tumor necrosis factor-alpha was induced by LPS in both groups to a similar extent, but did not rise after L. monocytogenes or turpentine administration. Serum T3 and T4 decreased after all three stimuli. The decrease in serum T4 in IL-6(-/-) was similar to that in IL-6(+/+) mice. The decrease in serum T3, however, was smaller in the IL-6(-/-) mice than in the IL-6(+/+) mice; T3 levels were 1.56 +/- 0.29 and 0.99 +/- 0.15 nmol/liter, respectively, 24 h after LPS treatment (P < 0.01), 2.39 +/- 0.17 and 1.75 +/- 0.24 nmol/liter 96 h after L. monocytogenes treatment (P < 0.01), and 1.46 +/- 0.18 and 1.10 +/- 0.25 nmol/liter 48 h after turpentine treatment (P < 0.05). The smaller fall in serum T3 in IL-6(-/-) mice could not be attributed to differences in the severity of the induced illness, food intake, or corticosterone response, which were all similar in IL-6(-/-) mice and IL-6(+/+) mice. Liver 5'-deiodinase mRNA decreased after all three stimuli; the decrease after LPS and L. monocytogenes infection was smaller in the IL-6(-/-) mice, but the difference in IL-6(+/+) mice just failed to reached statistical significance. Liver 5'-deiodinase activity after turpentine injection administration decreased in the wild-type animals by 36%, but did not change in the knock-out mice. In conclusion, acutely induced illness generates the low T3 syndrome, which is less marked in IL-6 knock-out mice than in wild-type mice. The data suggest a causal role of IL-6 in the development of the low T3 syndrome.