The role of cytokines in the lipopolysaccharide-induced sick euthyroid syndrome in mice
Abstract
To evaluate the role of cytokines in the sick euthyroid syndrome, we tried to establish an animal model of non-thyroidal illness in mice by the administration of a sub-lethal dose of bacterial endotoxin (lipopolysaccharide; LPS) which induces a variety of cytokines, including tumour necrosis factor (TNFα), interleukin-1 (IL-1α), interleukin-6 (IL-6) and interferon-γ (IFNγ). When compared with pair-fed controls, a single dose of LPS resulted in (a) systemic illness, (b) induction of TNFα and IL-6 and (c) a decrease of liver 5′-deiodinase mRNA from 4 h onwards followed by a decrease of serum tri-iodothyronine (T3) and thyroxine (T4) at 8 h and of serum free T3 (fT3) and free T4 (fT4) at 24 h; serum TSH remained unchanged. We then studied whether a single dose or a combination of IL-1α, TNFα, IL-6 or IFNγ could induce the sick euthyroid syndrome in mice, again using pair-fed controls. None of the cytokines except IL-1α caused systemic illness, and IL-1α was the only cytokine that decreased liver 5′-deiodinase mRNA transiently. IL-1α, TNFα or IL-6 did not decrease serum T3, T4 and TSH, but administration of IFNγ decreased serum T4, T3 and fT3 in a dose-dependent manner without changes in serum TSH. Administration of all four cytokines together had no synergistic effects; observed changes were of a smaller magnitude than after LPS. The following conclusions were reached. (1) Administration of LPS in mice is a suitable experimental model for the acute induction of the sick euthyroid syndrome. (2) Acute administration of IL-1α, TNFα or IL-6 in mice does not induce changes in thyroid hormones but IFNγ results in a dose-dependent decrease of serum T4, T3 and fT3 and IL-1α decreases liver 5′-deiodinase mRNA transiently. (3) Combined administration of IL-1α, TNFα, IL-6 and IFNγ had no synergistic effects; observed changes were of a smaller magnitude than after LPS. (4) The LPS-induced sick euthyroid syndrome is currently best explained by a direct thyroidal inhibition due to IFNγ and an extrathyroidal inhibition of liver 5′-deiodinase due to IL-1α, but other still unidentified factors seem to be involved as well. Journal of Endocrinology (1995) 146, 475–483
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In an acute NTIS mouse model, an increase in serum IL-6 and TNFα concentrations precedes the decrease in serum T3 and T4.
“In an acute NTIS mouse model, an increase in serum IL-6 and TNFα concentrations precedes the decrease in serum T3 and T4 [51].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [51]
A causal role for IL-6 is likely since IL-6 knockout mice show a smaller decrease in serum T3 during acute illness, although acute injection of IL-6 failed to induce NTIS in mice.
“A causal role for IL-6 is likely since IL-6 knockout mice show a smaller decrease in serum T3 during acute illness [52], although acute injection of IL-6 failed to induce NTIS in mice [51].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [51]
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Dominguez, L. J., Belvedere, M., & Barbagallo, M. (2012) · Pathy's Principles and Practice of Geriatric Medicine · doi:10.1002/9781119952930.ch98
Multisystem Inflammatory Syndrome in Children
(2024) · Frontiers research topics · doi:10.3389/978-2-8325-4694-9
Dominguez, L. J., & Barbagallo, M. (2022) · Wiley eBooks · doi:10.1002/9781119484288.ch83
Bakker, O. (1998) · Springer eBooks · doi:10.1007/978-3-662-08431-1_4
Self-citationIjaz, A., Anjum, M. U., Ahmed, F., Paracha, S. N., Habib, F., Shaukat, M. B., Najeeb, S., & Hafeez, N. (2026) · Pakistan Journal of Pathology · doi:10.55629/pakjpathol.v37i2.991
Fourie-Viljoen, N., Goddard, A., Thompson, P. N., Daminet, S., & Schoeman, J. P. (2026) · Journal of Veterinary Internal Medicine · doi:10.1093/jvimsj/aalag005
Hypothyroidism Improves Survival in Experimental Peritonitis
Guerrero-Espinosa, E., Navarro-Ramirez, E., Martín-Barrasa, J. L., Castrillo, A., Laparra, J. M., Garrido, A., Balsinde, J., Aranda, A., & Alemany, S. (2026) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.6c00077
Gereben, B., Zeöld, A., Dentice, M., Salvatore, D., & Bianco, A. C. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-007-7396-0 · Cited by 207 · see citing works
- Authors
- Boelen, A., Platvoet-ter Schiphorst, M. C., Bakker, O., & Wiersinga, W. M.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- ORCID
- Boelen, A
- Venue
- Journal of Endocrinology
- Publisher
- Bioscientifica
- Published
- 1995-09-01
- Volume
- 146
- Issue
- 3
- Pages
- 475-483
- ISSN
- 0022-0795 (ISSN-L)
- 1479-6805
- OpenAlex
- W2076225876
- Cited by
- 93
- References
- 0
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2020: 2 · 2018: 1 · 2017: 3 · 2016: 2 · 2015: 6 · 2014: 3 · 2013: 3 · 2012: 1
- FWCI
- 3.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- low T3 syndrome, lipopolysaccharide, cytokines, interferon-gamma, interleukin-1 alpha, TNF-α, interleukin-6, thyroid hormones, 5'-deiodinase, animal models, serum triiodothyronine, thyroxine, thyroid-stimulating hormone, mice, endotoxin
- MeSH terms
- Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Euthyroid Sick Syndromes, Female, Interferon-gamma, Interleukin-1, Iodide Peroxidase, Lipopolysaccharides, Liver, Mice, Inbred Strains, Thyrotropin, Thyroxine, Triiodothyronine, Tumor Necrosis Factor-alpha, Interleukin-6, Cytokines, Mice
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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