Increases in tumor necrosis factor-alpha in response to thyroid hormone-induced liver oxidative stress in the rat.
Thyroid hormone-induced calorigenesis contributes to liver oxidative stress and promotes an increased respiratory burst activity in Kupffer cells, which could conceivably increase the expression of redox-sensitive genes, including those coding for cytokines. Our aim was to test the hypothesis that L-3,3',5-triiodothyronine (T3)-induced liver oxidative stress would markedly increase the production of TNF-alpha by Kupffer cells and its release into the circulation. Sprague-Dawley rats receive a single dose of 0.1 mg T3/kg or vehicle (controls) and determinations of liver O2 consumption, serum TNF-alpha, rectal temperature, and serum T3 levels, were carried out at different times after treatment. Hepatic content of total reduced glutathione (GSH) and biliary glutathione disulfide (GSSG) efflux were measured as indices of oxidative stress. In some studies, prior to T3 injection animals were administered either (i) the Kupffer cell inactivator gadolinium chloride (GdCl3), (ii) the antioxidants alpha-tocopherol and N-acetyl-L-cysteine (NAC), or (iii) an antisense oligonucleotide against TNF-alpha (ASO TJU-2755). T3 elicited an 80-fold increase in the serum levels of TNF-alpha at 22h after treatment, which coincided with the onset of thyroid calorigenesis. Pretreatment with GdCl3, alpha-tocopherol, NAC, and ASO TJU-2755 virtually abolished this effect and markedly reduced T3-induced liver GSH depletion and the increases in biliary GSSG efflux. It is concluded that the hyperthyroid state in the rat increases the circulating levels of TNF-alpha by actions exerted at the Kupffer cell level and these are related to the oxidative stress status established in the liver by thyroid calorigenesis.
Molecular and Clinical Pharmacology Program, Faculty of Medicine, Institute of Biomedical Sciences, University of Chile, Casilla 70000, Santiago 7, Chile. vfernand@machi.med.uchile.cl
Virginia
V
Fernandez
Luis A
LA
Videla
Gladys
G
Tapia
Yedy
Y
Israel
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D005682:Gadolinium / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D009946:Organothiophosphorus Compounds / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D010101:Oxygen Consumption; D054735:Phosphorothioate Oligonucleotides; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D024505:Tocopherols / Q000494:pharmacology; D014284:Triiodothyronine / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016166:Free Radical Scavengers; D016376:Oligonucleotides, Antisense; D009946:Organothiophosphorus Compounds; D054735:Phosphorothioate Oligonucleotides; C428116:TJU 2755; D014409:Tumor Necrosis Factor-alpha; D014284:Triiodothyronine; D005682:Gadolinium; D005978:Glutathione; C038958:gadolinium chloride; D024505:Tocopherols; D019803:Glutathione Disulfide; D000111:Acetylcysteine