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Submitted on November 14, 2005
Accepted on March 27, 2006
Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0678
* To whom correspondence should be addressed. 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 interleukin-1 blocks the ability of T3 to induce D1 in rat hepatocyte primary cultures, and that forced expression of Steroid receptor coactivator 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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