Redox regulation of thyroid hormone-induced Kupffer cell-dependent IkappaB-alpha phosphorylation in relation to...

Thyroid hormone-induced calorigenesis promotes oxidative stress in the liver with higher respiratory burst activity in Kupffer cells, which could increase the expression of redox-sensitive genes. Our aim was to test the hypothesis that L-3,3',5-triiodothyronine (T3) triggers inducible nitric oxide synthase (iNOS) expression in rat liver by upstream mechanisms involving the inhibitor of kappa (Ikappa) kinase activation. T3 administration (daily doses of 0.1 mg/kg for three consecutive days) induced a calorigenic response, with maximal increases in the content of hepatic thiobarbituric acid reactants or protein carbonyls and NOS activity at 48-72 h after treatment, compared to control values. In this time interval, the serum levels of tumor necrosis factor-alpha (TNF-alpha; ELISA) are enhanced, concomitantly with higher liver IkappaB-alpha phaphosphorylation (Western blot analysis), NF-kappaB DNA binding (electrophoretic mobility shift assay), and iNOS mRNA expression (reverse transcription-polymerase chain reaction). These changes and the increase in hepatic NOS activity are abolished by the administration of either alpha-tocopherol (100 mg/kg) or the Kupffer cell inactivator gadolinium chloride (10 mg/kg) prior to T3. It is concluded that T3-induced oxidative stress triggers the redox upregulation of liver iNOS expression through a cascade initiated by TNF-a produced by Kupffer cells and involving Ikappa-alpha phosphorylation and NF-kappaB activation, a response that may represent a defense mechanism by protecting the liver from cytokine-mediated lethality and ROS toxicity.