Regulation of hepatocyte thyroxine 5'-deiodinase by T3 and nuclear receptor coactivators as a model of the sick euthyroid syndrome.
The syndrome of nonthyroidal illness, also known as the sick euthyroid syndrome, is characterized by a low plasma T3 and an "inappropriately normal" plasma thyrotropin in the absence of intrinsic disease of the hypothalamic-pituitary-thyroid axis. The syndrome is due in part to decreased activity of type I iodothyronine 5'-deiodinase (5' D-I), the hepatic enzyme that converts thyroxine to T3 and that is induced at the transcriptional level by T3. The hypothesis tested is that cytokines decrease T3 induction of 5' D-I, resulting in decreased T3 production and hence a further decrease in 5' D-I. The proposed mechanism is competition for limiting amounts of nuclear receptor coactivators between the 5' D-I promoter and the promoters of cytokine-induced genes. Using primary cultures of rat hepatocytes, we demonstrate that interleukins 1 and 6 inhibit the T3 induction of 5' D-I RNA and enzyme activity. This effect is at the level of transcription and can be partially overcome by exogenous steroid receptor coactivator-1 (SRC-1). The physical mass of endogenous SRC-1 is not affected by cytokine exposure, and exogenous SRC-1 does not affect 5' D-I in the absence of cytokines. The data support the hypothesis that cytokine-induced competition for limiting amounts of coactivators decreases hepatic 5' D-I expression, contributing to the etiology of the sick euthyroid syndrome.
Yu
J
J
Endocrinology Division, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0678, USA.
Koenig
R J
RJ
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004790:Enzyme Induction; D005067:Euthyroid Sick Syndromes / Q000201:enzymology* / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D022781:Hepatocytes / Q000201:enzymology*; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D007453:Iodide Peroxidase / Q000096:biosynthesis / Q000235:genetics*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D014284:Triiodothyronine / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D014284:Triiodothyronine; D007453:Iodide Peroxidase