title: Proinflammatory cytokines inhibit the expression and function of human type I 5'-deiodinase in HepG2 hepatocarcinoma cells.
abstract: OBJECTIVE
  The sick euthyroid syndrome in critically ill patients without primary disease of the thyroid gland is characterised by low serum total triiodothyronine (T3), normal to elevated thyroxine (T4), elevated reverse T3 (rT3) and normal TSH levels. The aim of this work was to clarify if impaired T4 and rT3 5'-deiodination is an underlying mechanism.
  
  
  METHODS
  We analysed the effect of the human recombinant proinflammatory cytokines interleukin (IL)-6 and IL-1beta, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on human type I 5'-iodothyronine deiodinase (5'DI) enzyme activity in the human hepatocarcinoma cell line HepG2, i.e. in a homologous human system. Furthermore, we analysed transcriptional effects of the cytokines by transient transfection assays using the luciferase or chloramphenicol acetyltransferase (CAT) reporter genes under the control of 1480 nucleotides of the human 5'DI promoter.
  
  
  RESULTS
  IL-6 at 500 pg/ml and TNF-alpha at 25 ng/ml had no significant effect, whereas 100 ng/ml IFN-gamma or 10 ng/ml IL-1beta reduced 5'DI enzyme activity to 77.9 and 59.5% of control values. IFN-gamma did not alter, IL-6 and TNF-alpha moderately decreased (in the case of IL-6 only in the CAT system), and IL-1beta (0.01-10 ng/ml) dose-dependently inhibited 5'DI promoter activity to a minimum of 38.1%.
  
  
  CONCLUSIONS
  IL-1beta inhibited both 5'DI enzyme and promoter activity and, thus, may exert its effect on thyroid hormone metabolism at least partially through direct inhibition of hepatic 5'DI gene transcription.
authors.affiliation: Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 021114, USA.
authors.forename: Tatjana C
authors.initials: TC
authors.lastname: Jakobs
authors.forename: Birgit
authors.initials: B
authors.lastname: Mentrup
authors.forename: Cornelia
authors.initials: C
authors.lastname: Schmutzler
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Dreher
authors.forename: Josef
authors.initials: J
authors.lastname: Köhrle
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000473:pathology; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D007453:Iodide Peroxidase / Q000037:antagonists & inhibitors* / Q000235:genetics; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics; D008113:Liver Neoplasms / Q000201:enzymology* / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D007527:Isoenzymes; D007453:Iodide Peroxidase; D008156:Luciferases; D015500:Chloramphenicol O-Acetyltransferase