Thyroid hormone-induced oxidative stress in rodents and humans: A comparative view and relation to redox regulation of gene expression

Thyroid hormone (3,3′,5-triiodothyronine, T3) exerts significant actions on energy metabolism, with mitochondria being the major target for its calorigenic effects. Acceleration of O2 consumption by T3 leads to an enhanced generation of reactive oxygen and nitrogen species in target tissues, with a higher consumption of cellular antioxidants and inactivation of antioxidant enzymes, thus inducing oxidative stress. This redox imbalance occurring in rodent liver and extrahepatic tissues with a calorigenic response, as well as in hyperthyroid patients, is further enhanced by an increased respiratory burst activity in Kupffer cells, which may activate redox-sensitive transcription factors such as NF-κB thus up-regulating gene expression. T3 elicits an 80-fold increase in the serum levels of tumor necrosis factor-α (TNF-α), which is abolished by pretreatment with the antioxidants α-tocopherol and N-acetylcysteine, the Kupffer-cell inactivator GdCl3, or an antisense oligonucleotide against TNF-α. In addition, T3 treatment activates hepatic NF-κB, a response that is (i) inhibited by antioxidants and GdCl3 and (ii) accompanied by induced mRNA expression of the NF-κB-responsive genes for TNF-α and interleukin (IL)-10. T3 also increases the hepatic levels of mRNA for IL-1α and those of IL-1α in serum. Up-regulation of liver iNOS expression is also achieved by T3, through a cascade initiated by TNF-α and involving IκB-α phosphorylation and NF-κB activation. In conclusion, T3-induced oxidative stress in the liver enhances the DNA-binding of NF-κB and the NF-κB-dependent expression of cytokines and iNOS by actions primarily exerted at the Kupffer cell level.