INDUCED ILLNESS IN INTERLEUKIN-6 (IL-6) KNOCK-OUT MICE - A CAUSAL ROLE OF IL-6 IN THE DEVELOPMENT OF THE LOW 3,5,3'-TRIIODOTHYRONINE SYNDROME

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 T- 3 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 T-3 syndrome. The aim of the present study was to evaluate the role of IL-6 in the development of the sick euthy roid syndrome in IL-6 knock-out (IL-6(-/-)) mice compared to that in w ild-type mice (IL-G(+/+)). Illness was induced in IL-6(-/-) and IL-G(- /+) mice by 1) administration of bacterial endotoxin (LPS), 2) infecti on with Listeria monocytogenes, and 3) turpentine injection in both hi nd limbs. Food intake was kept similar in both groups in all three exp eriments. Serial measurements were made of serum IL-6, tumor necrosis factor-alpha, T-3, T-4, 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-a lpha was induced by LPS in both groups to a similar extent, but did no t rise after L. nonocytogenes or turpentine administration. Serum T-3 and T-4 decreased after all three stimuli. The decrease in serum T-4 i n IL-6(-/-) was similar to that in IL-6(+/+) mice. The decrease in ser um T-3, however, was smaller in the IL-6(-/-) mice than in the IL-6(+/ +) mice; T-3 levels were 1.56 +/- 0.29 and 0.99 +/- 0.15 nmol/liter, r espectively, 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 turpentin e treatment (P < 0.05). The smaller fall in serum T-3 in IL-6(-/-) mic e could not be attributed to differences in the severity of the induce d illness, food intake, or corticosterone response, which were all sim ilar in IL-6(-/-) mice and IL-6(-/+) mice. Liver 5'-deiodinase mRNA de creased after all three stimuli; the decrease after LPS and L. monocyt ogenes infection was smaller in the IL-6(-/-) mice, but the difference in IL-6(+/+) mice just failed to reached statistical significance. Li ver 5'-deiodinase activity after turpentine injection administration d ecreased in the wild-type animals by 36%, but did not change in the kn ock-out mice. In conclusion, acutely induced illness generates the low T-3 Syndrome, which is less marked in IL-6 knock-out mice than in wil d-type mice. The data suggest a causal role of IL-6 in the development of the low T-3 syndrome.