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-1β, tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) 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-α at 25 ng/ml had no significant effect, whereas 100 ng/ml IFN-γ or 10 ng/ml IL-1β reduced 5′DI enzyme activity to 77.9 and 59.5% of control values. IFN-γ did not alter, IL-6 and TNF-α moderately decreased (in the case of IL-6 only in the CAT system), and IL-1β (0.01–10 ng/ml) dose-dependently inhibited 5′DI promoter activity to a minimum of 38.1%.

IL-1β 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.