Boelen A, Maas M A, Lowik C W, Platvoet M C, Wiersinga W M
Department of Endocrinology, Academic Medical Center, University of Amsterdam, The Netherlands.
Endocrinology. 1996 Dec;137(12):5250-4. doi: 10.1210/endo.137.12.8940342.
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.
对人类受试者或实验动物施用白细胞介素-6（IL-6）会引起甲状腺激素代谢变化，类似于病态正常甲状腺综合征中的变化。此外，疾病期间血清T3的降低与血清IL-6浓度显著相关。这些发现提示但未证明IL-6在低T3综合征发生中起因果作用。本研究的目的是评估与野生型小鼠（IL-6(+/+)）相比，IL-6基因敲除（IL-6(-/-)）小鼠中IL-6在病态正常甲状腺综合征发生中的作用。通过以下方式在IL-6(-/-)和IL-6(+/+)小鼠中诱导疾病：1）施用细菌内毒素（LPS），2）感染单核细胞增生李斯特菌，3）双侧后肢注射松节油。在所有三个实验中，两组的食物摄入量保持相似。连续24小时（LPS）、96小时（单核细胞增生李斯特菌）和48小时（松节油）测量血清IL-6、肿瘤坏死因子-α、T3、T4、皮质酮和肝脏5'-脱碘酶（5'-DI）信使核糖核酸（mRNA）。IL-6(+/+)小鼠中，血清IL-6对所有刺激均有升高反应，但IL-6(-/-)小鼠中无此反应。两组中LPS均诱导血清肿瘤坏死因子-α至相似程度，但单核细胞增生李斯特菌或松节油施用后未升高。所有三种刺激后血清T3和T4均降低。IL-6(-/-)小鼠血清T4的降低与IL-6(+/+)小鼠相似。然而，IL-6(-/-)小鼠血清T3的降低幅度小于IL-6(+/+)小鼠；LPS处理24小时后，T3水平分别为1.56±0.29和0.99±0.15nmol/升（P<0.01），单核细胞增生李斯特菌处理96小时后为2.39±0.17和1.75±0.24nmol/升（P<0.01），松节油处理48小时后为1.46±0.18和1.10±0.25nmol/升（P<0.05）。IL-6(-/-)小鼠血清T3下降幅度较小不能归因于诱导疾病的严重程度、食物摄入量或皮质酮反应的差异，这些在IL-6(-/-)小鼠和IL-6(+/+)小鼠中均相似。所有三种刺激后肝脏5'-脱碘酶mRNA均降低；LPS和单核细胞增生李斯特菌感染后IL-6(-/-)小鼠的降低幅度较小，但IL-6(+/+)小鼠中的差异刚未达到统计学显著性。松节油注射后野生型动物肝脏5'-脱碘酶活性降低36%，但基因敲除小鼠中未变化。总之，急性诱导的疾病会产生低T3综合征，在IL-6基因敲除小鼠中比野生型小鼠中表现较轻。数据提示IL-6在低T3综合征发生中起因果作用。
