Since liver is the major site of T 4 to T 3 conversion, we examined the effect of activated NF-κB on T 3-dependent 5′-DI induction in a human hepatoma cell line, HepG2, which retains differentiated function ( 21). Since 5′-DI gene expression is upregulated by T 3-TR signaling, we speculated that the T 3-dependent induction of 5′-DI might be interfered with by the TNF-α–mediated NF-κB activation, culminating in euthyroid sick syndrome. It was reported that NF-κB was induced in PBMCs of septic patients ( 20). NF-κB plays a pivotal role in immune and inflammatory responses by controlling gene expression of a number of cytokines. Upon stimulation of cells with TNF-α, NF-κB is translocated from the cytoplasm to the nucleus through the signal-induced degradation of its inhibitory proteins, IκBs ( 19). TNF-α exerts its biological activities through the activation of the transcription factor NF-κB. We thus focused this study on how TNF-α causes euthyroid sick syndrome. The relevance of TNF-α in this syndrome is supported by the following observations: (a) injection of TNF-α into healthy volunteers resulted in reduced serum T 3 levels ( 16) (b) serum T 3 levels were lower in nursing home patients with detectable serum TNF-α than those with undetectable levels ( 17) and (c) the single injection of TNF-α into rats resulted in decreased serum T 3 levels with repressed 5′-DI activity in liver ( 18). As for low serum T 3 levels in this syndrome, one important cause is decreased conversion of T 4 to T 3 ( 8) due to decreased 5′-DI activity in the liver ( 11).Īlthough there are conflicting data ( 12– 15), TNF-α is suggested to be one of the candidates for causing euthyroid sick syndrome. The changes in serum T 4 levels in euthyroid sick syndrome have been attributed to a decreased T 4 production rate ( 8), increased metabolic clearance of T 4 from serum ( 9), and diminished hypothalamic and pituitary function ( 10). The prognosis of the underlying disease is correlated with the degree of low T 3 ( 5, 6) and with that of low T 4 ( 7). With increasing severity of illness, serum T 4 levels are also decreased ( 4). This syndrome is usually associated with the terminal stage of sepsis, malignancy, AIDS, myocardial infarction, and starvation ( 4). Expression of the 5′-DI gene is upregulated through liganded thyroid hormone receptor (TR), which binds to a thyroid-hormone responsive element (TRE) in the promoter region of the 5′-DI gene ( 1).Įuthyroid sick syndrome ( 2, 3), also called low-T 3 syndrome or nonthyroidal illness, is characterized by low serum T 3 levels. Most of the serum T 3 is derived from this conversion, which is catalyzed by type I 5′-deiodinase (5′-DI). The thyroid gland secretes mainly L-thyroxine (T 4) into the circulation where it is converted to 3,5,3′-triiodothyronine (T 3) in liver and kidney. Thyroid hormone is one of the critical hormones in mammals and plays an indispensable role in development as well as in lipid and carbohydrate metabolism and energy generation. 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 T 3 levels and thus ameliorate euthyroid sick syndrome. Furthermore, we show that an inhibitor of NF-κB activation, clarithromycin (CAM), can inhibit TNF-α–induced activation of NF-κB and restore T 3-dependent induction of 5′-DI mRNA and enzyme activity. Inhibition of NF-κB action by a dominant-negative NF-κB reversed this effect and allowed T 3 induction of 5′-DI. Here we demonstrate that the activation of NF-κB by TNF-α interferes with thyroid-hormone action as demonstrated by impairment of T 3-dependent induction of 5′-DI gene expression in HepG2 cells. 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. The degree of low T 3 in circulation has been shown to correlate with the severity of the underlying disorders and with the prognosis. 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.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |