期刊
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY
卷 142, 期 3-4, 页码 231-239出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cbpc.2005.10.007
关键词
thyroid hormone; calorigenesis; oxidative stress; liver; Kupffer cell; gene expression; nuclear factor-kappa B; cytokines
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 ail 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-kappa B 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 GdCl3, or an antisense oligonucleotide against TNF-alpha. In addition, T-3 treatment activates hepatic NF-kappa B, a response that is (i) inhibited by antioxidants and GdCl3 and (ii) accompanied by induced mRNA expression of the NF-kappa B-responsive genes for TNF-alpha and interleukin (IL)-10. T-3 also increases the hepatic levels of mRNA for IL-1 alpha and those of IL-1 alpha in serum. Up-regulation of liver iNOS expression is also achieved by T-3, through a cascade initiated by TNF-alpha and involving I kappa B-alpha phosphorylation and NF-kappa B activation. In conclusion, T-3-induced oxidative stress in the liver enhances the DNA-binding of NF-kappa B and the NF-kappa B-dependent expression of cytokines and iNOS by actions primarily exerted at the Kupffer cell level. (c) 2005 Elsevier Inc. All rights reserved.
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