A potential role of activated NF-κB in the pathogenesis of euthyroid sick syndrome
Takashi Nagaya, … , Takashi Okamoto, Hisao Seo
Takashi Nagaya, … , Takashi Okamoto, Hisao Seo
Published August 1, 2000
Citation Information: J Clin Invest. 2000;106(3):393-402. https://doi.org/10.1172/JCI7771.
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Article

A potential role of activated NF-κB in the pathogenesis of euthyroid sick syndrome

Abstract

Euthyroid sick syndrome, characterized by low serum 3,5,3′-triiodothyronine (T3) with normal L-thyroxine levels, is associated with a wide variety of disorders including sepsis, malignancy, and AIDS. The degree of low T3 in circulation has been shown to correlate with the severity of the underlying disorders and with the prognosis. Elevated TNF-α levels, which accompany severe illness, are associated with decreased activity of type I 5′-deiodinase (5′-DI) in liver, leading us to speculate that high levels of this factor contribute to euthyroid sick syndrome. Here we demonstrate that the activation of NF-κB by TNF-α interferes with thyroid-hormone action as demonstrated by impairment of T3-dependent induction of 5′-DI gene expression in HepG2 cells. Inhibition of NF-κB action by a dominant-negative NF-κB reversed this effect and allowed T3 induction of 5′-DI. Furthermore, we show that an inhibitor of NF-κB activation, clarithromycin (CAM), can inhibit TNF-α–induced activation of NF-κB and restore T3-dependent induction of 5′-DI mRNA and enzyme activity. These results suggest that NF-κB activation by TNF-α is involved in the pathogenesis of euthyroid sick syndrome and that CAM could help prevent a decrease in serum T3 levels and thus ameliorate euthyroid sick syndrome.

Authors

Takashi Nagaya, Miyuki Fujieda, Goro Otsuka, Jian-Ping Yang, Takashi Okamoto, Hisao Seo

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NF-κB induced by TNF-α inhibits reporter-gene expression positively regu...
NF-κB induced by TNF-α inhibits reporter-gene expression positively regulated by T3 but not the expression of TSH-α Luc, which is negatively regulated by T3. (a and b) T3-dependent activation of 3xPal TK Luc activity was inhibited by NF-κB induced with TNF-α. T3-dependent activation of 3xPal TK Luc was also inhibited by transfection of the plasmid expressing p65 and weakly by that expressing p50. This inhibition was reversed by transfection of p65 DN expressing plasmid. (a) The values of 3xPal TK Luc/β-gal activity. AP < 0.001, BP < 0.0001 vs. TR, T3 (+); CP < 0.0001, TR, T3 (+), TNF-α vs. TR, T3 (+), TNF-α, p65 DN. (b) Fold induction by T3. DP < 0.001, EP < 0.0001, TR + TNF-α vs. TR + TNF-α + p65 DN. (c and d) JEG-3 cells were transfected with TSH-α Luc gene, and the effect of T3 and/or TNF-α was studied. T3-dependent repression of TSH-α Luc gene was not inhibited by NF-κB induced with TNF-α. (c) The values of TSH-α Luc/β-gal activity. (d) Percentage relative T3 Luc activity by T3. FP < 0.0001 vs. TR(–). All the data were expressed as mean ± SD.