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Induction of Type 1 Iodothyronine Deiodinase to Prevent the Nonthyroidal Illness Syndrome in Mice

Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Dr. Ronald J. Koenig, University of Michigan, 5560 MSRB-2, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109-0678. E-mail: rkoenig{at}umich.edu.

Essentially all serious illness is associated with a decrease in circulating T₃, 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 T₄ to T₃. The type 1 deiodinase is induced at the transcriptional level by T₃, but illness-associated cytokines block this induction, resulting in decreased T₃ and hence a further decline in D1 expression. We demonstrated that IL-1 blocks the ability of T₃ 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 T₃. The data suggest that a cytokine-induced defect in T₃ 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.

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