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

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. The thyroid gland secretes mainly L-thyroxine (T4) into the circulation where it is converted to 3,5,3′-triiodothyronine (T3) in liver and kidney. Most of the serum T3 is derived from this conversion, which is catalyzed by type I 5′-deiodinase (5′DI). 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). Euthyroid sick syndrome (2, 3), also called low-T3 syndrome or nonthyroidal illness, is characterized by low serum T3 levels. This syndrome is usually associated with the terminal stage of sepsis, malignancy, AIDS, myocardial infarction, and starvation (4). With increasing severity of illness, serum T4 levels are also decreased (4). The prognosis of the underlying disease is correlated with the degree of low T3 (5, 6) and with that of low T4 (7). The changes in serum T4 levels in euthyroid sick syndrome have been attributed to a decreased T4 production rate (8), increased metabolic clearance of T4 from serum (9), and diminished hypothalamic and pituitary function (10). As for low serum T3 levels in this syndrome, one important cause is decreased conversion of T4 to T3 (8) due to decreased 5′-DI activity in the liver (11). Although there are conflicting data (12–15), TNF-α is suggested to be one of the candidates for causing 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 T3 levels (16); (b) serum T3 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 T3 levels with repressed 5′-DI activity in liver (18). We thus focused this study on how TNF-α causes euthyroid sick syndrome. TNF-α exerts its biological activities through the activation of the transcription factor NF-κB. Upon stimulation of cells with TNF-α, NF-κB is translocated from the cytoplasm to the nucleus through the signalinduced degradation of its inhibitory proteins, IκBs (19). NF-κB plays a pivotal role in immune and inflammatory responses by controlling gene expression of a number of cytokines. It was reported that NF-κB was induced in PBMCs of septic patients (20). Since 5′-DI gene expression is upregulated by T3-TR signaling, we speculated that the T3-dependent induction of 5′-DI