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

Euthyroid sick syndrome, characterized by low serum 3,5,3'-triiodothyronine (T-3) With normal L-thyroxine levels, is associated with a wide variety of disorders including sepsis, malignancy, and AIDS. The degree of low T-3 in circulation has been shown to correlate with the severity of the underlyin g disorders and with the prognosis, Elevated TNF-alpha levels, which accomp any severe illness, are associated with decreased activity of type I 5'-dei odinase (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-kappa-D by TNF-alpha interferes with thyroid-hormone actio n as demonstrated by impairment of T-3-dependent induction of 5'-DI gene ex pression in HepG2 cells. Inhibition of NF-kappa B action by a dominant-nega tive NF-kappa B reversed this effect and allowed T-3 induction of 5'-DI. Fu rthermore, we show that an inhibitor of NF-kappa B activation, clarithromyc in (CAM), can inhibit TNF-alpha-induced activation of NF-kappa B and restor e T-3-dependent induction of 5'-DI mRNA and enzyme activity. These results suggest that NF-kappa B activation by TNF-alpha is involved in the pathogen esis of euthyroid sick syndrome and that CAM could help prevent a decrease in serum T-3 levels and thus ameliorate euthyroid sick syndrome.