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.