Lipopolysaccharide Induces Type 2 Iodothyronine Deiodinase in the Mediobasal Hypothalamus: Implications for the Nonthyroidal Illness Syndrome

Fekete, Csaba; Gereben, Balázs; Doleschall, Márton; Harney, John W.; Dora, José Miguel; Bianco, Antonio C.; Sarkar, Sumit; Liposits, Zsolt; Rand, William; Emerson, Charles H.; Kacskovıcs, Imre; Larsen, P. Reed; Lechan, Ronald M.

doi:10.1210/en.2003-1439

Cited by 165 publications

(145 citation statements)

References 43 publications

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“…NF-κB, an important mediator of immune and inflammatory responses, has been strongly implicated in ALI (46)(47)(48)(49)(50)(51). Evidence supports the notion that NF-κB induces transcription of human and rat D2 gene expression, and, indeed, a potent NF-κB-binding site has been demonstrated in the human D2 gene (52,53). Interestingly in humans with sepsis and sepsis-associated ALI, D2 is associated with susceptibility to ALI (35).…”

Section: Discussionmentioning

confidence: 81%

Role of type 2 deiodinase in response to acute lung injury (ALI) in mice

Barca-Mayo

Liao

DiCosmo

et al. 2011

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

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Thyroid hormone (TH) metabolism, mediated by deiodinase types 1, 2, and 3 (D1, D2, and D3) is profoundly affected by acute illness. We examined the role of TH metabolism during ventilator-induced lung injury (VILI) in mice. Mice exposed to VILI recapitulated the serum TH findings of acute illness, namely a decrease in 3,5,3′-triiodothyronine (T 3 ) and thyroid-stimulating hormone and an increase in reverse T 3 . Both D2 immunoreactivity and D2 enzymatic activity were increased significantly. D1 and D3 activity did not change. Using D2 knockout (D2KO) mice, we determined whether the increase in D2 was an adaptive response. Although similar changes in serum TH levels were observed in D2KO and WT mice, D2KO mice exhibited greater susceptibility to VILI than WT mice, as evidenced by poorer alveoli integrity and quantified by lung chemokine and cytokine mRNA induction. These data suggest that an increase in lung D2 is protective against VILI. Similar findings of increased inflammatory markers were found in hypothyroid WT mice exposed to VILI compared with euthyroid mice, indicating that the lungs were functionally hypothyroid. Treatment of D2KO mice with T 3 reversed many of the lung chemokine and cytokine profiles seen in response to VILI, demonstrating a role for T 3 in the treatment of lung injury. We conclude that TH metabolism in the lung is linked to the response to inflammatory injury and speculate that D2 exerts its protective effect by making more TH available to the injured lung tissue.nonthyroidal illness | euthyroid sick | reverse triiodothyronine | bronchial alveolar lavage | sepsis T hyroid hormone [TH, here denoting the active hormone 3,5,3′-triiodothyronine (T 3 ) and its precursor thyroxine (T 4 )] is necessary for the normal development and function of virtually every vertebrate tissue. Although the thyroid gland is predominantly responsible for the production and release of T 4 , the cellular bioavailability of the active T 3 depends on TH-specific transporters and tissue TH metabolism. Metabolism of TH is regulated by three iodothyronine deiodinases. Both type 1 (D1) and type 2 (D2) deiodinases serve to generate bioactive T 3 by outer-ring deiodination of T 4 . D2 has a major role in the intracellular generation of the active TH in mouse; the role of the D1, with its broad substrate specificity and ability to carry out both outer-and inner-ring deiodination, is less well understood. In contrast, type 3 iodothyronine deiodinase (D3) inactivates TH by inner-ring deiodination of T 4 to reverse T 3 (3′,5,3-triiodothyronine; rT 3 ) and T 3 to 3,3′-diiodothyronine (T 2 ), both biologically inactive compounds (1).Studies have elucidated the dynamic effects of TH action on brain, bone, liver (2-5), and maturation of the fetal lung (6, 7), but little is known regarding the role of TH in adult lung physiology. Until now, evidence suggesting that TH influences adult lung physiology has been indirect and based on the presence of TH receptors (8), deiodinases (9-12), and measured TH concentrations (10,13,14) i...

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Section: Discussionmentioning

confidence: 81%

Role of type 2 deiodinase in response to acute lung injury (ALI) in mice

Barca-Mayo

Liao

DiCosmo

et al. 2011

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

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“…FLAG epitope-tagged human D1 and D2 encoding plasmids have been described (8) as well as the von Hippel-Lindau protein-interacting deubiquitinating enzyme-1 (VDU-1)/ubiquitin-specific peptidase (USP)-33 and VDU-2/USP-20 encoding plasmids (9). Firefly luciferase reporter hdio2 promoter has been described (10). The cyclic AMP responsive element-luciferase plasmid was from BD Biosciences Clontech (Palo Alto, CA).…”

Section: Methodsmentioning

confidence: 99%

The Small Polyphenolic Molecule Kaempferol Increases Cellular Energy Expenditure and Thyroid Hormone Activation

et al. 2007

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Disturbances in energy homeostasis can result in obesity and other metabolic diseases. Here we report a metabolic pathway present in normal human skeletal muscle myoblasts that is activated by the small polyphenolic molecule kaempferol (KPF). Treatment with KPF leads to an ϳ30% increase in skeletal myocyte oxygen consumption. The mechanism involves a several-fold increase in cyclic AMP (cAMP) generation and protein kinase A activation, and the effect of KPF can be mimicked via treatment with dibutyryl cAMP. Microarray and real-time PCR studies identified a set of metabolically relevant genes influenced by KPF including peroxisome proliferator-activated receptor ␥ coactivator-1␣, carnitine palmitoyl transferase-1, mitochondrial transcription factor 1, citrate synthase, and uncoupling protein-3, although KPF itself is not a direct mitochondrial uncoupler. The cAMP-responsive gene for type 2 iodothyronine deiodinase (D2), an intracellular enzyme that activates thyroid hormone (T3) for the nucleus, is approximately threefold upregulated by KPF; furthermore, the activity half-life for D2 is dramatically and selectively increased as well. The net effect is an ϳ10-fold stimulation of D2 activity as measured in cell sonicates, with a concurrent increase of ϳ2.6-fold in the rate of T3 production, which persists even 24 h after KPF has been removed from the system. The effects of KPF on D2 are independent of sirtuin activation and only weakly reproduced by other small polyphenolic molecules such as quercetin and fisetin. These data document a novel mechanism by which a xenobiotic-activated pathway can regulate metabolically important genes as well as thyroid hormone activation and thus may influence metabolic control in humans. Diabetes 56:767-776, 2007

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“…A paracrine paradigm for T3 supply is thought to occur in the central nervous system: D2 is highly expressed in glial cells providing T3 for neurons, which have higher D3 than D2 activity (34). This paracrine response is present in vivo as well, since the systemic administration of LPS, which induces a rapid increase of D2 in the tanycytes of the mediobasal hypothalamus and a consequent suppression of TRH expression (38), is absent in D2KO mice (39).…”

Section: Deiodinases and Developmentmentioning

confidence: 99%

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

Marsili

Zavacki

Harney

et al. 2011

J Endocrinol Invest

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Thyroxine (T4) is a prohormone secreted by the thyroid. T4 has a long half life in circulation and it is tightly regulated to remain constant in a variety of circumstances. However, the availability of iodothyronine selenodeiodinases allow both the initiation or the cessation of thyroid hormone action and can result in surprisingly acute changes in the intracellular concentration of the active hormone T3, in a tissue-specific and chronologically-determined fashion, in spite of the constant circulating levels of the prohormone. This fine-tuning of thyroid hormone signaling is becoming widely appreciated in the context of situations where the rapid modifications in intracellular T3 concentrations are necessary for developmental changes or tissue repair. Given the increasing availability of genetic models of deiodinase deficiency, new insights into the role of these important enzymes are being recognized. In this review, we have incorporated new information regarding the special role played by these enzymes into our current knowledge of thyroid physiology, emphasizing the clinical significance of these new insights.

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Lipopolysaccharide Induces Type 2 Iodothyronine Deiodinase in the Mediobasal Hypothalamus: Implications for the Nonthyroidal Illness Syndrome

Cited by 165 publications

References 43 publications

Role of type 2 deiodinase in response to acute lung injury (ALI) in mice

Role of type 2 deiodinase in response to acute lung injury (ALI) in mice

The Small Polyphenolic Molecule Kaempferol Increases Cellular Energy Expenditure and Thyroid Hormone Activation

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

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