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E uthyroid 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.