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, T(3)) exerts significant actions on energy metabolism, with mitochondria being the major target for its calorigenic effects. Acceleration of O(2) consumption by T(3) 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-kappaB thus up-regulating gene expression. T(3) elicits an 80-fold increase in the serum levels of tumor necrosis factor-alpha (TNF-alpha), which is abolished by pretreatment with the antioxidants alpha-tocopherol and N-acetylcysteine, the Kupffer-cell inactivator GdCl(3), or an antisense oligonucleotide against TNF-alpha. In addition, T(3) treatment activates hepatic NF-kappaB, a response that is (i) inhibited by antioxidants and GdCl(3) and (ii) accompanied by induced mRNA expression of the NF-kappaB-responsive genes for TNF-alpha and interleukin (IL)-10. T(3) also increases the hepatic levels of mRNA for IL-1alpha and those of IL-1alpha in serum. Up-regulation of liver iNOS expression is also achieved by T(3), through a cascade initiated by TNF-alpha and involving IkappaB-alpha phosphorylation and NF-kappaB activation. In conclusion, T(3)-induced oxidative stress in the liver enhances the DNA-binding of NF-kappaB and the NF-kappaB-dependent expression of cytokines and iNOS by actions primarily exerted at the Kupffer cell level.
Fernández
Virginia
V
Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Casilla 70000, Santiago-7, Chile.
Tapia
Gladys
G
Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Casilla 70000, Santiago-7, Chile.
Varela
Patricia
P
Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Casilla 70000, Santiago-7, Chile.
Romanque
Pamela
P
Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Casilla 70000, Santiago-7, Chile.
Cartier-Ugarte
Denise
D
Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Casilla 70000, Santiago-7, Chile.
Videla
Luis A
LA
Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Casilla 70000, Santiago-7, Chile. Electronic address: lvidela@med.uchile.cl.
D000818:Animals; D019069:Cell Respiration; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D012377:Rodentia; D014284:Triiodothyronine / Q000494:pharmacology*
D016207:Cytokines; D014284:Triiodothyronine