Abstract
Thyroid hormone (TH; 3,3',5-triiodothyronine, T3) is required for the normal function of most tissues, with major effects on O(2) consumption and metabolic rate. These are due to transcriptional activation of respiratory genes through the interaction of T3-liganded TH receptors with TH response elements or the activation of intermediate factors, with the consequent higher production of reactive O(2) species (ROS) and antioxidant depletion. T3-induced oxidative stress in the liver triggers the redox upregulation of the expression of cytokines (tumor necrosis factor-alpha [TNF-alpha], interleukin-10), enzymes (inducible nitric oxide synthase, manganese superoxide dismutase), and anti-apoptotic proteins (Bcl-2), via a cascade initiated by TNF-alpha produced by Kupffer cells, involving inhibitor of kappaB phosphorylation and nuclear factor-kappaB activation. Thus, TH calorigenesis triggers an expression pattern that may represent an adaptive mechanism to re-establish redox homeostasis and promote cell survival under conditions of ROS toxicity secondary to TH-induced oxidative stress. Mechanisms of expression of respiratory and redox-sensitive genes may be functionally integrated, which could be of importance to understand the complexities of TH action and the outcome of thyroid gland dysfunction.
Highlights
Thyroid hormones (TH) are required for the normal function of most tissues of the body, playing essential roles in growth, development, differentiation, and metabolism, with major effects on O2 consumption (QO2) and metabolic rate (Videla, 2000)
Recent data suggest that T3 elicits the redox upregulation of gene expression as a secondary mechanism of reactive O2 species (ROS) produced by TH calorigenesis, which is triggered by redox-independent (i) direct T3-liganded
Upregulation of cytokine-encoding genes in Kupffer cells leads to a T3-induced TNF-α response, with concomitant inhibitor of κB-α (IκB-α) phosphorylation suggesting the activation of the IκB kinase complex, the participation of other signaling kinases cannot be discarded
Summary
Thyroid hormones (TH) are required for the normal function of most tissues of the body, playing essential roles in growth, development, differentiation, and metabolism, with major effects on O2 consumption (QO2) and metabolic rate (Videla, 2000). Studies by Fernández et al (2005a; 2005b) highlighted a novel nongenomic mechanism by which TH achieve the redox regulation of gene expression through activation of redox-sensitive transcription factors, as an adaptive response to re-establish redox homeostasis (Fig. 1).
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