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Cited by 56Thyroid Disorders and TreatmentsNF-κB Signaling PathwaysNeuropeptides and Animal Physiology

Differential involvement of nuclear factor-κB and activator protein-1 pathways in the interleukin-1β-mediated decrease of deiodinase type 1 and thyroid hormone receptor β1 mRNA

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Kwakkel, J, Wiersinga, W M, Boelen, A·2006·Journal of Endocrinology
DOI 10.1677/joe.1.06354
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Abstract

One of the hallmarks of the sick euthyroid syndrome or non-thyroidal illness is a decrease of serum triiodothyronine, caused mainly by a decrease in liver deiodinase type 1 (D1) mRNA and activity. Proinflammatory cytokines like interleukin (IL)-1β are likely involved in this disease, but are also known to inhibit thyroid hormone receptor (TR)-β1 gene expression, which is of interest as the D1 promoter contains TREs. The aim of the present study was to evaluate whether the IL-1β-induced decrease of D1 and TRβ1 mRNA is mediated by the same cytokine signalling pathways in a human hepatoma cell line (HepG2). We observed a downregulation of both D1 and TRβ1 mRNA after 4 h of incubating the cells with IL-1β. Sulfasalazine was used to inhibit the nuclear factor-κB (NFκB) pathway and SP600125, a chemical inhibitor of the c-Jun N-terminal kinase, was used as an inhibitor of the activator protein-1 (AP-1) pathway. AP-1 inhibition did not affect the decrease of D1 and TRβ1 mRNA, but the TRβ1 mRNA decrease was completely abolished after inhibiting NFκB, while D1 mRNA was unaffected. Only simultaneous inhibition of both the NFκB and AP-1 pathways abolished the D1 mRNA decrease. We concluded that IL-1β stimulation of HepG2 cells results in a marked decrease of D1 and TRβ1 mRNA. The decrease of TRβ1 mRNA is exclusively mediated by the NFκB pathway, while the decrease of D1 mRNA requires inhibition of both the AP-1 and the NFκB pathways.

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  • NTIS affects D1 via NF-κB, as the IL-1-β induced decrease in DIO1 and TRβ mRNA expression in HepG2 cells depends on NF-kB signaling.

    “In addition to DIO2, NTIS affects D1 via NF-κB. This is clear, e.g., from the observation that the IL-1-β induced decrease in DIO1 and TRβ mRNA expression in HepG2 cells, which is a hepatocyte derived cell line, depends on NF-kB signaling [59, 60].”

    From An update on non-thyroidal illness syndrome (2021) · cites this paper as [59]

    The Discussion (journal pp. 37–44) says NF-κB inhibition prevented the IL-1β-induced decrease in TRβ1 mRNA in HepG2 cells. It also says NF-κB inhibition alone did not prevent the D1/DIO1 mRNA decrease; only simultaneous inhibition of NF-κB and AP-1 did. Thus the claim overstates NF-κB dependence for DIO1. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Proinflammatory cytokines can downregulate various components of TH synthesis and metabolism in thyrocytes and hepatocytes.

    “Cellular studies clearly showed that proinflammatory cytokines can downregulate various components of TH synthesis and metabolism in thyrocytes [58] and hepatocytes [59–61].”

    From An update on non-thyroidal illness syndrome (2021) · cites this paper as [59]

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Research works printed but not linked: 1

  1. Eds LE Braverman & Utiger RD. Philadelphia, PA, USA: Lippincott.

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Authors
Kwakkel, J., Wiersinga, W. M., & Boelen, A.
Affiliations
Amsterdam UMC Location University of Amsterdam (NL)
ORCID
Boelen, A
Venue
Journal of Endocrinology
Publisher
Bioscientifica
Published
2006-04
Volume
189
Issue
1
Pages
37-44
ISSN
  • 0022-0795 (ISSN-L)
  • 1479-6805
DOI
10.1677/joe.1.06354
OpenAlex
W2127134544
Cited by
56
References
20
Citations by year
2026: 2 · 2025: 1 · 2024: 4 · 2023: 4 · 2022: 1 · 2021: 4 · 2020: 3 · 2019: 5 · 2018: 1 · 2017: 3 · 2016: 2 · 2015: 2 · 2014: 1 · 2013: 2 · 2012: 1
FWCI
2.50
Type
journal article
Language
en
Open access
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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
IL-1β, thyroid hormone receptor beta 1, NF-κB signaling, AP-1 signaling, c-Jun N-terminal kinase, low T3 syndrome, triiodothyronine, hepatic gene expression, HepG2 cells, sulfasalazine, SP600125, thyroid hormone response element
MeSH terms
Anthracenes, Enzyme Inhibitors, Humans, Interleukin-1, Iodide Peroxidase, Liver, Neoplasm Proteins, RNA, Messenger, Sulfasalazine, Signal Transduction, Down-Regulation, NF-kappa B, Transcription Factor AP-1, Thyroid Hormone Receptors beta, Cell Line, Tumor

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