A. Boelen et al., 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, Endocrinology, 137(12), 1996, pp. 5250-5254
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.