Redox up-regulated expression of rat liver manganese superoxide dismutase and Bcl-2 by thyroid hormone is associated with inhibitor of κB-α phosphorylation and nuclear factor-κB activation

Abstract

Recently, we demonstrated that 3,3, ,5-triiodothyronine (T3) induces oxidative stress in rat liver, with enhancement in the DNA binding of nuclear factor-B (NF-B) and the NF-B-dependent expression of tumor necrosis factor-(TNF-). In this study, we show that T3 administration (daily doses of 0·1 mg/kg i.p. for three consecutive days) elicited a calorigenic response and higher liver O 2 consumption rates, with increased serum levels of TNF-(ELISA), liver inhibitor of B (I B-) phosphorylation (Western blot analysis), and hepatic NF-B DNA binding (EMSA) at 56-72 h after treatment. Within this time interval, liver manganese superoxide dismutase (MnSOD) activity and the protein expression of MnSOD and Bcl-2 are enhanced. These changes are abrogated by the administration of -tocopherol (100 mg/kg i.p.) prior to T3. It is concluded that T3 treatment leads to the redox upregulation of MnSOD and Bcl-2 in rat liver, in association with TNF-release and activation of the I Bkinase/NF-B cascade, which may constitute a protective mechanism against free radical toxicity involving cell death signaling.

Hyperthyroidism induces apoptosis in rat liver through activation of death receptor-mediated pathways

“…Bcl-2, SOD and JNK-phosphatases and thereby inhibiting sustained JNK activation [32,36]. NF-jB activation in rat liver, exposed to T 3 for 1, 3 and 5 days is in agreement with previous studies [30,37], on the contrary further exposure of rats to T 3 leads to the deactivation of NF-jB that may lead to sustained JNK activation and apoptosis [32].…”

The role of thyroid hormone calorigenesis in the redox regulation of gene expression

“…1), a phenomenon also observed in human hyperthyroidism (Videla, 2000). Recent 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).…”

“…Of particular importance is the role that T 3 administration may have in liver preconditioning, based on the redox upregulation of hepatic proteins involved in cell survival achieved ( Fig. 1) (Fernández et al, 2005a;2005b) and the actions of T 3 as a primary hepatic mitogen (Malik et al, 2003), mechanisms that may increase the tolerance of the liver to a subsequent injury (Romanque et al, 2005). This novel hepatic preconditioning strategy is currently under study in our laboratory using the ischemiareperfusion liver injury, a model that is relevant to temporary clamping of the hepatoduodenal ligament during liver surgery and graft failure after liver transplantation in man (Romanque et al, 2005).…”

“…Daily T 3 administration for three consecutive days resulted in a progressive increase in the oxidative stress status of the liver, with maximal increases in lipid peroxidation and protein carbonylation at 72 h after hormone treatment (Fernández et al, 2005a). Under these conditions, the serum levels of TNF-α are also enhanced, concomitantly with higher liver inhibitor of κB-α (IκB-α ) serine 32 phosphorylation, NF-κB DNA binding, and the mRNA expression of the NF-κB-responsive genes encoding inducible NOS (iNOS) (Fernández et al, 2005a), manganese superoxide dismutase (MnSOD), and Bcl-2 (Fernández et al, 2005b). The latter changes and the increase in the hepatic activity of NOS and MnSOD induced by T 3 are abrogated by the administration of α-tocopherol prior to T 3 (Fernández et al, 2005a;2005b).…”

“…Under these conditions, the serum levels of TNF-α are also enhanced, concomitantly with higher liver inhibitor of κB-α (IκB-α ) serine 32 phosphorylation, NF-κB DNA binding, and the mRNA expression of the NF-κB-responsive genes encoding inducible NOS (iNOS) (Fernández et al, 2005a), manganese superoxide dismutase (MnSOD), and Bcl-2 (Fernández et al, 2005b). The latter changes and the increase in the hepatic activity of NOS and MnSOD induced by T 3 are abrogated by the administration of α-tocopherol prior to T 3 (Fernández et al, 2005a;2005b). This is in agreement with the normalization or diminution of oxidative stress-related parameters induced by hyperthyroid state in response to α-tocopherol (Asayama et al, 1989;Fernández et al, 2002), NAC (Fernández et al, 2002), or ascorbic acid (Seven et al, 1998), as well as antithyroid therapy alone (Videla et al, 1988;Adali et al, 1999) or combined with α-tocopherol (Adali et al, 1999).…”