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