611 VARELA ET AL. Biol Res 39, 2006, 611-617 The role of thyroid hormone calorigenesis in the redox regulation of gene expression PATRICIA VARELA 1 , GLADYS TAPIA 2 , VIRGINIA FERNÁNDEZ 2 and LUIS A VIDELA 2 1 Cellular and Molecular Biology Program and 2 Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile ABSTRACT Thyroid hormone (TH; 3,3 , ,5-triiodothyronine, T 3 ) 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 T 3 -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. T 3 -induced oxidative stress in the liver triggers the redox upregulation of the expression of cytokines (tumor necrosis factor-α [TNF-α], interleukin-10), enzymes (inducible nitric oxide synthase, manganese superoxide dismutase), and anti-apoptotic proteins (Bcl-2), via a cascade initiated by TNF-α produced by Kupffer cells, involving inhibitor of κB phosphorylation and nuclear factor-κB 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. Key terms: Thyroid hormone; Calorigenesis; Oxidative stress; Gene expression Corresponding author: Luis A. Videla, Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Casilla 70000, Santiago-7, Chile. Telephone: 56-2-9786256. Fax: 56-2-7372783. E-mail: lvidela@med.uchile.cl INTRODUCTION 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 O 2 consumption (QO 2 ) and metabolic rate (Videla, 2000). Current available data indicate that TH calorigenesis is achieved by both (i) a short-term nongenomic signaling mechanism mediated by 3,5- diiodothyronine and 3,3 , ,5-triiodothyronine (T 3 ) leading to the allosteric activation of cytochrome-c oxidase (Moreno et al., 2002), and (ii) a long-term pathway upregulating nuclear and mitochondrial gene transcription through T 3 signaling (Fig. 1) (Yen, 2001; Weitzel et al., 2001; Lanni et al., 2003). In several target organs such as liver, a higher pro-oxidant activity is developed as result of the functional interdependence established between TH calorigenesis, cellular QO 2 , and generation of reactive oxygen (ROS) (Fernández et al., 1985; 2003; Fernández & Videla, 1993a) and nitrogen (RNS) species (Fernández et al., 1997). This respiratory component accounts for 16-25% of the net increase in total QO 2 (Fernández & Videla, 1993b). T 3 - induced free radical activity decreases the cellular antioxidant defenses, leading to oxidative stress (Fernández & Videla, 1996) in liver and in extrahepatic tissues of experimental animals exhibiting a calorigenic response (Fig. 1), a phenomenon also observed in human hyperthyroidism (Videla, 2000). Recent