Regulation of Hepatocyte Thyroxine 5′-Deiodinase by T3 and Nuclear Receptor Coactivators as a Model of the Sick Euthyroid Syndrome

Abstract

The syndrome of nonthyroidal illness, also known as the sick euthyroid syndrome, is characterized by a low plasma T3 and an "inappropriately normal" plasma thyrotropin in the absence of intrinsic disease of the hypothalamic-pituitary-thyroid axis. The syndrome is due in part to decreased activity of type I iodothyronine 5-deiodinase (5 D-I), the hepatic enzyme that converts thyroxine to T3 and that is induced at the transcriptional level by T3. The hypothesis tested is that cytokines decrease T3 induction of 5 D-I, resulting in decreased T3 production and hence a further decrease in 5 D-I. The proposed mechanism is competition for limiting amounts of nuclear receptor coactivators between the 5 D-I promoter and the promoters of cytokine-induced genes. Using primary cultures of rat hepatocytes, we demonstrate that interleukins 1 and 6 inhibit the Under ordinary circumstances, plasma levels of thyroid hormone are tightly regulated by a homeostatic feedback loop in which hypothalamic thyrotropin-releasing hormone stimulates secretion of TSH 1 by the anterior pituitary, which in turn stimulates secretion of thyroid hormones by the thyroid gland. 3,5,3Ј-triiodothyronine represses the synthesis and secretion of thyrotropin-releasing hormone and TSH to complete the negative feedback loop. However, this regulatory system is perturbed by virtually any medical illness or surgical stress, resulting in what is known as the syndrome of nonthyroidal illness or the sick euthyroid syndrome (for reviews, see Refs. 1 and 2). The characteristic features of this syndrome are a low plasma T3 concentration with an "inappropriately normal" TSH. The syndrome is seen with both acute and chronic illnesses such as trauma, myocardial infarction, infection, malignancy, and renal failure. The more severe the nonthyroidal illness, the more depressed is the T3 level. Hospitalized patients will often have a frankly low TSH, and occasionally the T4 level also is low in very sick individuals. In fact, a correlation exists between the magnitude of the thyroid function test abnormalities and the mortality rate. The thyroid function test abnormalities resolve if the patient recovers from the nonthyroidal illness.The mechanism that underlies the sick euthyroid syndrome is poorly understood but is clearly multifactorial. Both central (pituitary or hypothalamic) and peripheral defects are apparent. The central defect is manifest by abnormally low secretion of TSH in response to low circulating thyroid hormone levels. Multiple peripheral defects in the distribution and metabolism of thyroid hormone have been observed, but perhaps the most important is a decrease in the conversion of T4 to T3 (3, 4). It is estimated that direct thyroidal secretion accounts for only approximately 20% of plasma T3. The majority of plasma T3 derives from thyroxine deiodination, primarily by the hepatocyte enzyme type I iodothyronine 5Ј-deiodinase. The activity of this enzyme is diminished in the sick euthyroid syndrome, thus accounting for the low plasma T3 despite a normal ...

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Interleukin-18, a proinflammatory cytokine, contributes to the pathogenesis of non-thyroidal illness mainly via the central part of the hypothalamus-pituitary-thyroid axis

“…It is known that both AP-1 and NF-kB interact with SRC-1 and CREB-binding protein (CBP), which are needed for transcription activation by NF-kB and AP-1 (19,20). Yu and Koenig (13) recently showed that inhibition of T 3 -dependent induction of D1 mRNA and activity by IL-1 and IL-6 (in vitro) can be partially overcome by exogenous SRC-1. It was therefore hypothesized that cytokine-induced competition for limiting amounts of coactivators decreases hepatic D1 gene expression during illness.…”

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

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