Induced illness in interleukin-6 (IL-6) knock-out mice: a causal role of IL-6 in the development of the low 3,5,3'-triiodothyronine syndrome.

Boelen, Anita; Maas, Marjolein; Löwik, C.W.G.M.; Platvoet, M. C.; Wiersinga, Wilmar M.

doi:10.1210/endo.137.12.8940342

Cited by 77 publications

(41 citation statements)

References 17 publications

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“…An analysis of 100 consecutive hospitalized patients revealed a weak inverse correlation between the serum levels of IL-6 and T3 (30). These data are consistent with studies in wild-type versus IL-6 null mice (31). For example, following injection of lipopolysaccharide, serum T3 fell in both wild-type and null mice, but the drop was smaller in the IL-6 null animals.…”

Section: Discussionsupporting

confidence: 80%

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

Koenig

2000

Journal of Biological Chemistry

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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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Section: Discussionsupporting

confidence: 80%

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

Koenig

2000

Journal of Biological Chemistry

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“…Third, the model shows that reverse T3 decreases during bacterial NTI, in contrast to the typical increase observed in patients. Previous murine studies reported that liver type I deiodinase decreases significantly between 4 and 8 h and normalizes at 24 h after LPS injection (18,19,28,29). Our reverse T3 findings suggest that type I deiodinase activity is not significantly impaired, allowing the degradation of reverse T3 to di-iodo-thyronine.…”

Section: Discussionsupporting

confidence: 50%

Toll-like receptor-MyD88 and Fc receptor pathways of mast cells mediate the thyroid dysfunctions observed during nonthyroidal illness

Rocchi¹,

Kimura²,

Tzou³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Bacterial infections and other pathologic conditions induce complex dysfunctions of the hypothalamic-pituitary-thyroid axis, collectively known as nonthyroidal illness (NTI).innate immunity ͉ euthyroid sick syndrome ͉ mastocyte ͉ hypothyroidism N onthyroidal illness (NTI) is a common clinical condition defined as the biochemical changes of the hypothalamicpituitary-thyroid axis that occur in patients suffering from illnesses not primarily originating in the thyroid (1, 2). These illnesses include bacterial infections, burns, myocardial infarction, respiratory distress syndrome, cirrhosis, end-stage renal disease, psychosis, and starvation. The key serum biochemical changes in NTI, although varying with the type and severity of the initiating illness, consist of: (i) increased reverse tri-iodothyronine (T3), principally due to decreased activity of type I deiodinase (3), an enzyme in peripheral tissues (mainly liver) that converts reverse T3 to di-iodo-thyronine and, in decreasing order of affinity, thyroxine (T4) to T3 and T3 to di-iodothyronine; (ii) decreased T3, also secondary to decreased type I deiodinase activity (4); (iii) decreased T4 more likely due to a reduced binding capacity and/or affinity of serum carrier proteins for T4, given that the T4 production rate appears similar to that of healthy euthyroid individuals with low or absent T4-binding globulin (5, 6); and (iv) inappropriately normal or low levels of thyroid stimulating hormone (TSH) with respect to the decreased thyroid hormone levels. This defective TSH production is likely of hypothalamic origin in light of demonstrated reduction in TSH-releasing hormone (TRH) secretion from paraventricular nucleus neurons (7-9) and blunting of the physiological nocturnal TSH surge (10). It is unclear whether the thyroid gland is directly affected during NTI. An autopsy study showed that thyroids from deceased patients with chronic illness had lower weight, smaller follicles, and less colloid than thyroids from suddenly deceased, previously healthy controls (11).NTI has an incompletely understood pathogenesis (9). Some scholars consider it a salutary, physiologic adaptation to illness (to conserve energy by suppressing the catabolic effects of thyroid hormones), whereas others consider it a true pathologic state. Consequently, a frequent clinical debate is whether to administer synthetic T4 (12) or not (13) to patients with NTI, although the majority opinion opposes T4 administration. To gain mechanistic insights into the pathogenesis of bacterial NTI, numerous experiments have been performed in humans, mice, and rats by using injections of LPS. In humans, LPS induces flu-like symptoms (fever, chills, general malaise, muscle ache, headache, exacerbated sensitivity to light, and nausea), monocytopenia (14), and release of proinflammatory cytokines, including IL-1, IL-6, and TNF-␣ (15). Serum T4, T3, and TSH decrease, reaching a nadir after 6 h, and then return to baseline by 15 h (16). In mice and rats, LPS induces similar systemic illness (decreased food i...

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“…Previously, we have shown that IL-6, an important proinflammatory cytokine, is involved in alterations of the peripheral part of the HPT axis (12 mice. These differences might be due to unknown genetic differences induced by genetic manipulation or to unknown inflammation-independent effects of IL-18 on basal IFNg expression (IFNg could interfere with several mechanisms in thyrocytes (3)), because the observed differences were present in both IL-18…”

Section: Discussionmentioning

confidence: 96%

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

Boelen

Kwakkel

Schiphorst

et al. 2004

European Journal of Endocrinology

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Objective: Proinflammatory cytokines are involved in the pathogenesis of non-thyroidal illness (NTI), as shown by studies with IL-6 2/2 and IL-12 2/2 mice. Interleukin (IL)-6 changes peripheral thyroid hormone metabolism, and IL-12 seems to be involved in the regulation of the central part of the hypothalamic-pituitary-thyroid (HPT) axis during illness. IL-18 is a proinflammatory cytokine which shares important biological properties with IL-12, such as interferon (IFN)-g-inducing activity. Design: By studying the changes in the HPT-axis during bacterial lipopolysaccharide (LPS)-induced illness in IL-18 2/2 , IFNgR 2/2 and wild-type (WT) mice, we wanted to unravel the putative role of IL-18 and IFNg in the pathogenesis of NTI. Results: LPS induced a decrease in pituitary type 1 deiodinase (D1) activity (P , 0.05, ANOVA) in WT mice, but not in IL-18 2/2 mice, while the decrease in D2 activity was similar in both strains. LPS decreased serum thyroid hormone levels and liver D1 mRNA within 24 h similarly in IL-18 2/2 , and WT mice. The expression of IL-1, IL-6 and IFNg mRNA expression was significantly lower in IL-18 2/2 mice than in WT, while IL-12 mRNA expression was similar. IFNgR 2/2 mice had higher basal D1 activity in the pituitary than WT mice (P , 0.05); LPS induced a decrease of D2, but not of D1, activity in the pituitary which was similar in both strains. In the liver, the LPS-induced increase in cytokine expression was not different between IFNgR 2/2 mice and WT mice, and the decrease in serum T 3 and T 4 levels and hepatic D1 mRNA was also similar. Conclusions: The relative decrease in serum T 3 and T 4 and liver D1 mRNA in response to LPS is similar in IL-18 2/2 , IFNgR 2/2 and WT mice despite significant changes in hepatic cytokine induction. However, the LPS-induced decrease in D1 activity in the pituitary of WT mice is absent in IL-18 2/2 mice; in contrast, LPS did not decrease pituitary D1 activity in the IFNgR 2/2 mice or their WT, which might be due to the genetic background of the mice. Our results suggest that IL-18 is also involved in the regulation of the central part of the HPT axis during illness.

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Induced illness in interleukin-6 (IL-6) knock-out mice: a causal role of IL-6 in the development of the low 3,5,3'-triiodothyronine syndrome.

Cited by 77 publications

References 17 publications

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

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

Toll-like receptor-MyD88 and Fc receptor pathways of mast cells mediate the thyroid dysfunctions observed during nonthyroidal illness

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

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