Boelen A, Platvoet-ter Schiphorst M C, Wiersinga W M
Department of Endocrinology, Academic Medical Center, University of Amsterdam, The Netherlands.
J Endocrinol. 1997 Apr;153(1):115-22. doi: 10.1677/joe.0.1530115.
The sick euthyroid syndrome is a state of altered thyroid hormone metabolism which occurs during illness. The pathogenesis is incompletely understood but recent studies indicate a role of cytokines. It is unknown if cytokines released during illness are directly responsible for the changes in thyroid hormone metabolism. Therefore we studied if previous immunoneutralization of cytokines can prevent endotoxin (lipopolysaccharide LPS), induced sick euthyroid syndrome. LPS administration resulted in systemic illness, an increase in serum tumor necrosis factor (TNF alpha) and interleukin (IL)-6 and a decrease in serum triiodothyronine (T3) and thyroxine (T4). Immunoneutralization of the effects of cytokines was accomplished by administration of monoclonal antibodies against mouse IL-1 type-1 receptor (IL-1R), TNF alpha, IL-6 or interferon (IFN gamma) prior to LPS. The LPS-induced release of cytokines was affected by previous immunoneutralization as compared with control experiments with normal immunoglobulin (IgG): anti-IL-1R did not affect serum TNF alpha but decreased serum IL-6, anti-TNF alpha decreased serum TNF alpha but not IL-6, anti-IL-6 did not affect serum TNF alpha but hugely increased IL-6 and anti-IFN gamma decreased both serum TNF alpha and IL-6. Specific immunoneutralization of IL-1, TNF alpha or IFN gamma did not prevent the LPS-induced decrease in serum T3, T4 and liver 5'-deiodinase mRNA. However, immunoneutralization of IL-6, although not preventing the fall in serum T3 and T4, did mitigate the LPS-induced decrease in liver 5'-deiodinase mRNA. In view of possible non-specific effects of the huge dose of immunoglobulins (1 mg), used only in the immunoneutralization of IL-6, we repeated the experiment with F(ab')2 fragments of anti-IL-6 antibodies. Compared with F(ab')2 fragments of control IgG, anti-IL-6 F(ab')2 did not affect the LPS-induced rise in serum TNF alpha or the decrease in serum T3 and T4 and liver 5'-deiodinase mRNA. Serum IL-6 levels induced by LPS were, however, cleared more rapidly from the circulation when anti-IL-6 F(ab')2 fragments rather than intact anti-IL-6 were administered. In conclusion, immunoneutralization of IL-1, TNF alpha or IFN gamma did not prevent the LPS-induced sick euthyroid syndrome in mice; immunoneutralization of IL-6, however, transiently inhibits the LPS-induced decrease of liver 5'-deiodinase mRNA.
低甲状腺素病态综合征是疾病期间发生的甲状腺激素代谢改变状态。其发病机制尚未完全明了，但最近的研究表明细胞因子起了一定作用。尚不清楚疾病期间释放的细胞因子是否直接导致甲状腺激素代谢的变化。因此，我们研究了预先对细胞因子进行免疫中和是否能预防内毒素（脂多糖LPS）诱导的低甲状腺素病态综合征。给予LPS导致全身疾病、血清肿瘤坏死因子（TNFα）和白细胞介素（IL）-6升高以及血清三碘甲状腺原氨酸（T3）和甲状腺素（T4）降低。在给予LPS之前，通过给予抗小鼠IL-1Ⅰ型受体（IL-1R）、TNFα、IL-6或干扰素（IFNγ）的单克隆抗体来实现对细胞因子作用的免疫中和。与用正常免疫球蛋白（IgG）进行的对照实验相比，预先进行的免疫中和影响了LPS诱导的细胞因子释放：抗IL-1R不影响血清TNFα但降低血清IL-6，抗TNFα降低血清TNFα但不影响IL-6，抗IL-6不影响血清TNFα但大幅增加IL-6，抗IFNγ降低血清TNFα和IL-6。对IL-1、TNFα或IFNγ进行特异性免疫中和并不能预防LPS诱导的血清T3、T4和肝脏5'-脱碘酶mRNA降低。然而，对IL-6进行免疫中和虽然不能防止血清T3和T4下降，但确实减轻了LPS诱导的肝脏5'-脱碘酶mRNA降低。鉴于仅在对IL-6进行免疫中和时使用的大剂量免疫球蛋白（1mg）可能存在非特异性作用，我们用抗IL-6抗体的F(ab')2片段重复了实验。与对照IgG的F(ab')2片段相比，抗IL-6 F(ab')2不影响LPS诱导的血清TNFα升高或血清T3、T4以及肝脏5'-脱碘酶mRNA降低。然而，当给予抗IL-6 F(ab')2片段而非完整的抗IL-6时，LPS诱导的血清IL-6水平从循环中清除得更快。总之，对IL-1、TNFα或IFNγ进行免疫中和不能预防LPS诱导的小鼠低甲状腺素病态综合征；然而，对IL-6进行免疫中和可短暂抑制LPS诱导的肝脏5'-脱碘酶mRNA降低。
