Interleukin-1β modulates endogenous thyroid hormone receptor α gene transcription in liver cells
Abstract
One of the main characteristics of nonthyroidal illness (NTI) is a decrease in serum triiodothyronine, partly caused by a decrease in liver deiodinase type 1 (D1) mRNA and activity. Proinflammatory cytokines have been associated with NTI in view of their capability to decrease D1 and thyroid hormone receptor (TR)β1 mRNA expression in hepatoma cells. Proinflammatory cytokine induction leads to activation of the inflammatory pathways nuclear factor (NF)κB and activator protein (AP)-1. The proinflammatory cytokine interleukin (IL)-1β decreases thyroid hormone receptor (TR)β1 mRNA in an NFκB-dependent way. The aim of this study was to unravel the effects of IL-1β on endogenous TR α gene expression in an animal model and in a liver cell line. The TR α gene product is alternatively spliced in TRα1 and TRα2, TRα2 is capable of inhibiting TR α 1 -induced gene transcription. We showed that both TRα1 and TRα2 mRNA decreased not only after lipopolysaccharide administration in liver of mice, but also after IL-1β stimulation of hepatoma cells (HepG2). Using the NFκB inhibitor sulfasalazine and the AP-1 inhibitor SP600125, it became clear that the IL-1β-induced decrease in TRα mRNA expression in HepG2 cells can only be abolished by simultaneous inhibition of NFκB and AP-1. The IL-1β-induced TRα1 and TRα2 mRNA decrease in HepG2 cells is the result of decreased TR α gene promoter activity, as evident from actinomycin D experiments. Cycloheximide experiments showed that the decreased promoter activity is independent of de novo protein synthesis and therefore most likely due to posttranslational modifications such as phosphorylation or subcellular relocalization.
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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 [60]
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 [60]
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Self-citation
- 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
- 2007-08
- Volume
- 194
- Issue
- 2
- Pages
- 257-265
- ISSN
- 0022-0795 (ISSN-L)
- 1479-6805
- OpenAlex
- W2133040712
- Cited by
- 34
- References
- 41
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 2 · 2016: 1 · 2015: 1 · 2013: 1 · 2012: 3
- FWCI
- 3.17
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- IL-1β, thyroid hormone receptor alpha, thyroid hormone receptor alpha 1, TRα2, low T3 syndrome, NF-κB, AP-1, inflammatory cytokines, liver, hepatoma cells, gene transcription, promoter activity, lipopolysaccharide, sulfasalazine, SP600125, post-translational modification
- MeSH terms
- Animals, Anthracenes, Female, Lipopolysaccharides, Mice, Inbred BALB C, Promoter Regions, Genetic, RNA, Messenger, Sulfasalazine, Transcription, Genetic, Gene Expression, NF-kappa B, Transcription Factor AP-1, Reverse Transcriptase Polymerase Chain Reaction, Hepatocytes, Models, Animal, Thyroid Hormone Receptors alpha, Cell Line, Tumor, Mice, Interleukin-1beta
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