Induction of type 1 iodothyronine deiodinase to prevent the nonthyroidal illness syndrome in mice.
Essentially all serious illness is associated with a decrease in circulating T(3), a condition known as the nonthyroidal illness syndrome. Substantial evidence suggests that a contributing factor to this syndrome is a cytokine-induced decrease in hepatic type 1 iodothyronine deiodinase (D1), an enzyme that converts T(4) to T(3). The type 1 deiodinase is induced at the transcriptional level by T(3), but illness-associated cytokines block this induction, resulting in decreased T(3) and hence a further decline in D1 expression. We demonstrated that IL-1 blocks the ability of T(3) to induce D1 in rat hepatocyte primary cultures and that forced expression of steroid receptor co- activator 1 (SRC-1) prevents this cytokine effect. This led us to test whether forced hepatic expression of SRC-1 can prevent the nonthyroidal illness syndrome in vivo. Pretreatment of endotoxin-treated mice with an adenovirus that expresses SRC-1, compared with a control adenovirus, prevented the endotoxin-induced decreases in hepatic D1 and plasma T(3). The data suggest that a cytokine-induced defect in T(3) receptor coactivators is an important component of this animal model of nonthyroidal illness and that the syndrome can be overcome by forced expression of the coactivator.
Yu
Jingcheng
J
Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical Center, Ann Arbor, 48109-0678, USA.
Koenig
Ronald J
RJ
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005067:Euthyroid Sick Syndromes / Q000235:genetics* / Q000517:prevention & control*; D022781:Hepatocytes / Q000378:metabolism; D007453:Iodide Peroxidase / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D013974:Thyroxine / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism
D016207:Cytokines; D008070:Lipopolysaccharides; D014284:Triiodothyronine; C109812:iodothyronine deiodinase type I; D007453:Iodide Peroxidase; D013974:Thyroxine