Jakobs Tatjana C, Mentrup Birgit, Schmutzler Cornelia, Dreher Ingeborg, Köhrle Josef
Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 021114, USA.
Eur J Endocrinol. 2002 Apr;146(4):559-66. doi: 10.1530/eje.0.1460559.
The sick euthyroid syndrome in critically ill patients without primary disease of the thyroid gland is characterised by low serum total triiodothyronine (T3), normal to elevated thyroxine (T4), elevated reverse T3 (rT3) and normal TSH levels. The aim of this work was to clarify if impaired T4 and rT3 5'-deiodination is an underlying mechanism.
We analysed the effect of the human recombinant proinflammatory cytokines interleukin (IL)-6 and IL-1beta, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on human type I 5'-iodothyronine deiodinase (5'DI) enzyme activity in the human hepatocarcinoma cell line HepG2, i.e. in a homologous human system. Furthermore, we analysed transcriptional effects of the cytokines by transient transfection assays using the luciferase or chloramphenicol acetyltransferase (CAT) reporter genes under the control of 1480 nucleotides of the human 5'DI promoter.
IL-6 at 500 pg/ml and TNF-alpha at 25 ng/ml had no significant effect, whereas 100 ng/ml IFN-gamma or 10 ng/ml IL-1beta reduced 5'DI enzyme activity to 77.9 and 59.5% of control values. IFN-gamma did not alter, IL-6 and TNF-alpha moderately decreased (in the case of IL-6 only in the CAT system), and IL-1beta (0.01-10 ng/ml) dose-dependently inhibited 5'DI promoter activity to a minimum of 38.1%.
IL-1beta inhibited both 5'DI enzyme and promoter activity and, thus, may exert its effect on thyroid hormone metabolism at least partially through direct inhibition of hepatic 5'DI gene transcription.
无原发性甲状腺疾病的危重症患者的低甲状腺素综合征的特征是血清总三碘甲状腺原氨酸（T3）降低、甲状腺素（T4）正常或升高、反三碘甲状腺原氨酸（rT3）升高以及促甲状腺激素（TSH）水平正常。本研究的目的是阐明T4和rT3 5'-脱碘受损是否为潜在机制。
我们分析了重组人促炎细胞因子白细胞介素（IL）-6、IL-1β、肿瘤坏死因子-α（TNF-α）和干扰素-γ（IFN-γ）对人肝癌细胞系HepG2中I型5'-碘甲状腺原氨酸脱碘酶（5'DI）酶活性的影响，即在同源人类系统中进行分析。此外，我们通过瞬时转染试验分析了细胞因子对荧光素酶或氯霉素乙酰转移酶（CAT）报告基因转录的影响，该报告基因受人类5'DI启动子1480个核苷酸的控制。
500 pg/ml的IL-6和25 ng/ml的TNF-α无显著影响，而100 ng/ml的IFN-γ或10 ng/ml的IL-1β将5'DI酶活性降低至对照值的77.9%和59.5%。IFN-γ未改变，IL-6和TNF-α适度降低（仅IL-6在CAT系统中），且IL-1β（0.01 - 10 ng/ml）剂量依赖性地抑制5'DI启动子活性，最低至38.1%。
IL-1β抑制5'DI酶和启动子活性，因此，其可能至少部分通过直接抑制肝脏5'DI基因转录对甲状腺激素代谢产生影响。
