A Novel Role for the Thyroid Hormone-Activating Enzyme Type 2 Deiodinase in the Inflammatory Response of Macrophages
Abstract
Deiodinase type 2 (D2) is a thyroid hormone-activating enzyme converting the prohormone T4 into the active hormone T3. In the present study, we show for the first time that D2 is up-regulated in the mouse liver during acute and chronic inflammation, in close correlation with the proinflammatory cytokine IL-1β and independently of serum T3. Inflammation-induced D2 expression was confirmed in macrophages, in conjunction with selective thyroid hormone transporter (monocarboxylate transporter 10) and thyroid hormone receptor (TR)α1 stimulation, and was absent in hepatocytes. Moreover, D2 knockdown in macrophages resulted in a clear attenuation of the lipopolysaccharide (LPS)-induced IL-1β and GM-CSF expression, in addition to aberrant phagocytosis. Locally produced T3, acting via the TRα, may be instrumental in this novel inflammatory response, because LPS-treated TRα0/0 mice showed a markedly decreased LPS-induced GM-CSF mRNA expression. We now propose that hepatic D2 favors the innate immune response by specifically regulating cellular thyroid hormone levels in macrophages.
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DIO2 is the main deiodinase present in macrophages and TRα1 is their dominant TR.
“DIO2 is the main deiodinase present in macrophages and TRα1 is their dominant TR [36].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [36]
In the section on D2 expression in macrophages (page unavailable), D2 mRNA was detected in the RAW264.7 macrophage cell line, while D1 and D3 mRNA were near the detection limit. The same section reports TRα1 and TRα2 expression, no detectable TRβ, and an increase in TRα1—but not TRα2—after LPS stimulation. It does not establish that TRα1 is the dominant receptor isoform. (LLM, conf=0.84)
Experimental — accuracy not yet measuredActivation of macrophages results in increased DIO2 expression together with increased TRα1 and MCT10, pointing to increased TH action in these cells during inflammation.
“Activation of macrophages results in increased DIO2 expression together with increased TRα1 and MCT10, together pointing to increased TH action in these cells during inflammation [36].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [36]
DIO2 knockdown impairs macrophage phagocytosis while blunting the cytokine response upon stimulation with bacterial endotoxin.
“In addition, DIO2 knockdown impairs macrophage phagocytosis while blunting the cytokine response upon stimulation with bacterial endotoxin [36, 37].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [36]
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Self-citation
- Authors
- Kwakkel, J., Surovtseva, O. V., de Vries, E. M., Stap, J., Fliers, E., & Boelen, A.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Departments of Endocrinology and Metabolism (J.K., O.V.S., E.M.d.V., A.B., E.F.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Corresponding author
- Kwakkel, J.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2014-07-01
- Volume
- 155
- Issue
- 7
- Pages
- 2725-2734
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W1990877858
- Cited by
- 88
- References
- 44
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 7 · 2023: 10 · 2022: 9 · 2021: 7 · 2020: 8 · 2019: 8 · 2018: 4 · 2017: 9 · 2016: 7 · 2015: 7 · 2014: 1
- FWCI
- 6.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Universiteit van Amsterdam
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- type 2 deiodinase, thyroid hormone activation, macrophages, inflammation, IL-1β, GM-CSF, thyroid hormone receptor alpha, lipopolysaccharide, innate immunity, liver, phagocytosis, T3
- MeSH terms
- Iodothyronine Deiodinase Type II, Animals, Cell Line, Female, Humans, Inflammation, Iodide Peroxidase, Lipopolysaccharides, Liver, Macrophages, Male, Mice, Inbred C57BL, Thyroid Hormones, Triiodothyronine, Gene Expression, Granulocyte-Macrophage Colony-Stimulating Factor, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Thyroid Hormone Receptors alpha, Cell Line, Tumor, Mice, Interleukin-1beta, Hep G2 Cells, Mice, 129 Strain
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