A potential role of activated NF-κB in the pathogenesis of euthyroid sick syndrome

Nagaya, Takashi; Fujieda, Miyuki; Otsuka, Goro; Yang, Jian-Ping; Okamoto, Takashi; Seo, Hisao

doi:10.1172/jci7771

Cited by 107 publications

(72 citation statements)

References 54 publications

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“…It was therefore hypothesized that cytokine-induced competition for limiting amounts of coactivators decreases hepatic D1 gene expression during illness. In addition, activation of NF-kB by TNFa interferes with thyroid hormone action, as demonstrated by impairment of T 3 -dependent induction of D1 gene expression in HepG2 cells (21). As mentioned before, the absence of IL-18 does not have significant effects on the LPS-induced decrease in liver D1 mRNA expression.…”

Section: Discussionmentioning

confidence: 76%

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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Section: Discussionmentioning

confidence: 76%

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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“…An important intracellular signalling pathway for cytokines is the nuclear factorkappa B (NF-kB) pathway. Nagaya et al (2000) show that TNFa impairs the T 3 dependent induction of Dio1 expression in HEPG2 cells via interference of NF-kB with TR function. There is, however, no evidence for a direct interaction between the TR and NF-kB which suggests a common cofactor by NF-kB and the TR to play a role (Nagaya et al 2000).…”

Section: Type 1 Deiodinasementioning

confidence: 78%

The molecular basis of the non-thyroidal illness syndrome

Vries¹,

Fliers²,

Boelen³

2015

Journal of Endocrinology

154

116

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The 'sick euthyroid syndrome' or 'non-thyroidal illness syndrome' (NTIS) occurs in a large proportion of hospitalized patients and comprises a variety of alterations in the hypothalamus-pituitary-thyroid (HPT) axis that are observed during illness. One of the hallmarks of NTIS is decreased thyroid hormone (TH) serum concentrations, often viewed as an adaptive mechanism to save energy. Downregulation of hypophysiotropic TRH neurons in the paraventricular nucleus of the hypothalamus and of TSH production in the pituitary gland points to disturbed negative feedback regulation during illness. In addition to these alterations in the central component of the HPT axis, changes in TH metabolism occur in a variety of TH target tissues during NTIS, dependent on the timing, nature and severity of the illness. Cytokines, released during illness, are known to affect a variety of genes involved in TH metabolism and are therefore considered a major determinant of NTIS. The availability of in vivo and in vitro models for NTIS has elucidated part of the mechanisms involved in the sometimes paradoxical changes in the HPT axis and TH responsive tissues. However, the pathogenesis of NTIS is still incompletely understood. This review focusses on the molecular mechanisms involved in the tissue changes in TH metabolism and discusses the gaps that still require further research.

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“…This response may have collaborated with prolonging the disease (9). It is known that necrosis tumoral factor inhibit the activity of hepatic D1 desiodase, which is the enzyme that catalyzed T3 and has been implicated in the pathogenesis of low T3 (21). Elevation of reverse T3 in the low T3 syndrome has been described in adults and children.…”

Section: Discussionmentioning

confidence: 99%

Nonthyroidal illnesses syndrome in full-term newborns with sepsis

Silva

Araújo

Diniz

et al. 2015

Arch. Endocrinol. Metab.

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Objective: To assess hormonal changes in nonthyroidal illness syndrome (NTIS) in full-term newborns (NT) with sepsis. Materials and methods: We included 28 NT with sepsis divided into 2 groups according to the time of normalization of serum and clinical indicators of infection: group A(A), 16 NT with improvement in up to 8 days; and group B(B), 12 NT improvement after 8 days. Among the 28 NT, 15 NT progressed to septic shock, with 5 NT group A and 10 NT in group B. NT were excluded when they showed severe sepsis and asphyxia, and congenital malformations, as well as those whose mothers had thyroid disease and IUGR. Results: 17 NT (60.7%) presented NTIS. Low T3 was observed in NTIS in 10 NT (58.8%), and low T4 and T3 in 5 NT (29.5%), all of them with septic shock. Two NT showed mixed changes (11.7%). After sepsis was cured, there was no hormonal change, except in 3 NT. Administration of dopamine, furosemide, and corticosteroids did not affect the results. Conclusions: This study indicates that nonthyroidal illness syndrome may be transiently present during sepsis in full-term newborns, especially in cases of prolonged sepsis. Low T3 can occur without changes in reverse T3 (different from adults), and low T4 and T3 occur mainly in patients with septic shock. Arch Endocrinol Metab. 2015;59(6):528-34

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A potential role of activated NF-κB in the pathogenesis of euthyroid sick syndrome

Cited by 107 publications

References 54 publications

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

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

The molecular basis of the non-thyroidal illness syndrome

Nonthyroidal illnesses syndrome in full-term newborns with sepsis

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