Proinflammatory cytokines inhibit the expression and function of human type I 5'-deiodinase in HepG2 hepatocarcinoma cells

Abstract

Objective: The sick euthyroid syndrome in critically ill patients without primary disease of the thyroid gland is characterised by low serum total triiodothyronine (T 3 ), normal to elevated thyroxine (T 4 ), elevated reverse T 3 (rT 3 ) and normal TSH levels. The aim of this work was to clarify if impaired T 4 and rT 3 5 0 -deiodination is an underlying mechanism. Design and Methods: We analysed the effect of the human recombinant proinflammatory cytokines interleukin (IL)-6 and IL-1b, tumour necrosis factor-a (TNF-a) and interferon-g (IFN-g) on human type I 5 0 -iodothyronine deiodinase (5 0 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 0 DI promoter. Results: IL-6 at 500 pg/ml and TNF-a at 25 ng/ml had no significant effect, whereas 100 ng/ml IFN-g or 10 ng/ml IL-1b reduced 5 0 DI enzyme activity to 77.9 and 59.5% of control values. IFN-g did not alter, IL-6 and TNF-a moderately decreased (in the case of IL-6 only in the CAT system), and IL-1b (0.01 -10 ng/ml) dose-dependently inhibited 5 0 DI promoter activity to a minimum of 38.1%. Conclusion: IL-1b inhibited both 5 0 DI enzyme and promoter activity and, thus, may exert its effect on thyroid hormone metabolism at least partially through direct inhibition of hepatic 5 0 DI gene transcription.

Interleukin-18, a proinflammatory cytokine, contributes to the pathogenesis of non-thyroidal illness mainly via the central part of the hypothalamus-pituitary-thyroid axis

“…It is known that LPS administration results in increased IL-12 and IL-18 expression, which subsequently synergistically enhances INFg mRNA transcription by activating Stat4 and AP-1. The enhanced IFNg mRNA expression might be responsible for decreased D1 activity in the pituitary after LPS administration, as confirmed by in vitro studies (14). Therefore, we also studied the effects of LPS on the pituitary of IFNgR 2/2 mice compared to their WT.…”

Interleukin-1β modulates endogenous thyroid hormone receptor α gene transcription in liver cells

“…This is probably because LPS administration induces a number of cytokines (Boelen et al 2004a) and therefore has more effect than IL-1b alone. Studies from Jakobs et al (2002) have shown that IL-1b is the most potent cytokine to induce decreased D1 mRNA Figure 3 Relative expression of TRa1 and TRa2 mRNA in HepG2 cells after 4-h incubation with medium and 10 ng/ml IL-1b with or without 30-min preincubation with (A) 5 mg/ml actinomycin D (ActD) and (B) 10 mg/ml cycloheximide (Chx). Mean valuesGS.E.M.…”

“…NTI, among others, is characterized by low serum T 3 levels and decreased liver deiodinase type 1 (D1) activity (Peeters et al 2003, Wiersinga 2005. It has been shown that proinflammatory cytokines are capable of decreasing liver D1 mRNA expression and activity (Yu & Koenig 2000, Jakobs et al 2002, via the activation of nuclear factor (NF)kB and activator protein (AP)-1 (Kwakkel et al 2006). Liver D1 is involved in the peripheral conversion of thyroxine into T 3 and decreased activity of liver D1 therefore contributes to low serum T 3 levels.…”

Is there a link between polycystic ovary syndrome and non-thyroidal illness syndrome?

“…It was suggested that, together, these modifications in deiodinase expression could be a major factor involved in causing the low T3 concentration that is associated with NTIS. The trigger for these changes in deiodinase expression has been attributed to an increase in proinflammatory cytokines, which often occurs in NTIS (35)(36)(37)(38)(39).…”