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.