Lipopolysaccharide Induces Type 2 Iodothyronine Deiodinase in the Mediobasal Hypothalamus: Implications for the Nonthyroidal Illness Syndrome
Abstract
To determine whether the type 2 iodothyronine deiodinase (D2), the principal central nervous system enzyme converting T(4) to biologically active T(3), is regulated in tanycytes by immune activation, D2 activity was measured in the mediobasal hypothalamus (MBH) 4, 12, and 24 h after administration of bacterial lipopolysaccharide (LPS) and compared with D2 levels in the cortex and anterior pituitary of rats. In contrast to D2 activity in the cortex and anterior pituitary that showed a steady linear increase over 24 h, which was coincident with a decline in thyroid hormone and TSH levels, D2 activity peaked in the MBH 12 h after LPS administration. By in situ hybridization, the increased D2 mRNA synthesis induced by LPS was specifically localized to tanycytes lining the third ventricle. In vitro assays in HC11 and HEK-293 cells demonstrated that the p65 subunit of nuclear factor-kappaB markedly increased both rat and human D2 genes (dio2) as analyzed by promoter assays. No activation of human dio2 was observed when an 83-bp minimal promoter was used. We propose that LPS or LPS-induced cytokines directly induce D2 mRNA in tanycytes. The ensuing MBH-specific D2-mediated local thyrotoxicosis may suppress the hypothalamus-pituitary-thyroid axis by local feedback inhibition of hypophysiotropic TRH and/or TSH and contribute to the mechanism of central hypothyroidism associated with infection.
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Illness results in increased hypothalamic DIO2 mRNA expression and activity while hypothalamic DIO3 decreases.
“Illness results in increased DIO2 mRNA expression and activity [12, 15–17] while hypothalamic DIO3 decreases [18, 19].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [16]
The 65kD subunit of NF-κB (RelA) activates the Dio2 promoter.
“The NF-κB protein family consists of several subunits of which the 65kD subunit of NF-κB (RelA) activates the Dio2 promoter [16, 62].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [16]
LPS administration increases TSHβ mRNA expression in the pars tuberalis.
“Note increased expression of TSH mRNA in the PT after LPS administration.”
From Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions (2014) · cites this paper as [99]
Twelve hours after LPS, I-Bα mRNA is detected in only a subset of α tanycytes.
“I-B␣ mRNA is only seen in a subset of ␣ tanycytes 12 hours after LPS administration (arrows in panel E).”
From Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions (2014) · cites this paper as [99]
Nine hours after LPS administration, phospho-CREB is found in the nucleus of tanycytes.
“Double-labeled fluorescent image illustrates the presence of phospho-CREB (green and yellow, arrows) in the nucleus of tanycytes (red) 9 hours after administration of LPS.”
From Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions (2014) · cites this paper as [99]
LPS administration increases D2 expression in tanycytes, particularly in the external zone of the median eminence.
“Note marked increase in the density of silver grains, particularly in the external zone of the median eminence.”
From Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions (2014) · cites this paper as [99]
LPS administration increases I-Bα mRNA in the pars tuberalis 3 hours later.
“Note the marked accumulation of silver grains over the pars tuberalis in panel D 3 hours after the administration of LPS.”
From Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions (2014) · cites this paper as [99]
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- Authors
- Fekete, C., Gereben, B., Doleschall, M., Harney, J. W., Dora, J. M., Bianco, A. C., Sarkar, S., Liposits, Z., Rand, W., Emerson, C., Kacskovics, I., Larsen, P. R., & Lechan, R. M.
- Affiliations
- HUN-REN Institute of Experimental Medicine (HU)
- Hungarian Academy of Sciences (HU)
- Magyar Agrár- és Élettudományi Egyetem (HU)
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Tufts University (US)
- University of Massachusetts Chan Medical School (US)
- ORCID
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2004-04
- Volume
- 145
- Issue
- 4
- Pages
- 1649-1655
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2005744729
- Cited by
- 179
- References
- 36
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 2 · 2023: 6 · 2022: 9 · 2021: 4 · 2020: 5 · 2019: 7 · 2018: 5 · 2017: 5 · 2016: 11 · 2015: 7 · 2014: 9 · 2013: 8 · 2012: 7
- FWCI
- 5.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Pennsylvania
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 37021, DK36256, R01DK036256)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- type 2 deiodinase, lipopolysaccharide, mediobasal hypothalamus, tanycytes, low T3 syndrome, NF-κB p65, hypothalamic-pituitary-thyroid axis, central hypothyroidism, infection, thyroid hormone metabolism, thyroid-stimulating hormone, thyrotropin-releasing hormone
- MeSH terms
- Iodothyronine Deiodinase Type II, Animals, Body Temperature, Cerebral Cortex, Enzyme Induction, Hormones, Humans, Hypothalamus, Middle, Iodide Peroxidase, Lipopolysaccharides, Male, Pituitary Gland, Anterior, Promoter Regions, Genetic, RNA, Messenger, Time Factors, NF-kappa B, Rats, Sprague-Dawley, Rats, Transcription Factor RelA
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