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.