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IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells
Open accessAbstract
Nonthyroidal illness syndrome (NTIS) is a state of low serum 3,5,3' triiodothyronine (T₃) that occurs in chronically ill patients; the degree of reduction in T₃ is associated with overall prognosis and survival. Iodthyronine deiodinases are enzymes that catalyze iodine removal from thyroid hormones; type I and II deiodinase (D1 and D2, respectively) convert the prohormone thyroxine T₄ to active T₃, whereas the type III enzyme (D3) inactivates T₄ and T₃. Increased production of cytokines, including IL-6, is a hallmark of the acute phase of NTIS, but the role of cytokines in altered thyroid hormone metabolism is poorly understood. Here, we measured the effect of IL-6 on both endogenous cofactor-mediated and dithiothreitol-stimulated (DTT-stimulated) cell sonicate deiodinase activities in human cell lines. Active T₃ generation by D1 and D2 in intact cells was suppressed by IL-6, despite an increase in sonicate deiodinases (and mRNAs). N-acetyl-cysteine (NAC), an antioxidant that restores intracellular glutathione (GSH) concentrations, prevented the IL-6-induced inhibitory effect on D1- and D2-mediated T₃ production, which suggests that IL-6 might function by depleting an intracellular thiol cofactor, perhaps GSH. In contrast, IL-6 stimulated endogenous D3-mediated inactivation of T₃. Taken together, these results identify a single pathway by which IL-6-induced oxidative stress can reduce D1- and D2-mediated T₄-to-T₃ conversion as well as increasing D3-mediated T₃ (and T₄) inactivation, thus mimicking events during illness.
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“In addition, decreased availability of glutathione (GSH), a co-factor required for DIO1 catalytic activity, may also play a role [80].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [80]
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“Recently, the effects of cytokines, at pathophysiological concentrations as observed in NTIS, were investigated in a human cell culture system that mimics the physiological actions of the endogenous deiodinase cofactor(s) and FT4 levels (Wajner et al., 2011).”
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Self-citationINCREASED TYPE 3 DEIODINASE EXPRESSION IN PAPILLARY THYROID CARCINOMA
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InfluentialMAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma
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Ataoğlu, H. E., Ahbab, S., Serez, K., Yamak, M., Kayaş, D., Canbaz, E. T., Çetin, F., Seçmeler, Ş., Şar, F., & Yenigün, M. (2018) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2018.07.018 · Cited by 32
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“This finding is related to the influence of inflammatory cytokines on THRβ and THRα expression (Boelen et al., 2004a; Kwakkel et al., 2010) and the redox state of the hepatocytes (Wajner et al., 2011).”
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“Consistent with clinical findings that serum T3 levels are the first parameter to alter and the last to recover in patients with critical illness, the effect of IL-6 was obvious within a 2-h exposure of the HEK-293 cell, was prevented by the antioxidant NAC, which increases intracellular GSH synthesis [54].”
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“[35] Because no patients with acute illness were included in our study, the NTIS may be triggered by chronic comorbidities that activate the inflammatory process causing bunted conversion from T4 to T3.”
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“This indicates that IL-6 inhibits the function of deiodinases by increasing cellular ROS, which subsequently reduces the levels of GSH or GSH-like endogenous cofactors [21].”
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“TNF or IL-6 are responsible for decreasing T3 via the reduction of D1-and D2-mediated conversion from T4 to T3 as well as increasing D3-mediated T3 inactivation [6,7].”
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“…that IL-6 has an ability to suppress the enzymes iodothyronine deiodinases type I (D1) and II (D2), reducing the conversion of prohormone thyroxine T4 to its active form T3, which ensures the deregulation of glutamate cysteine ligase (GCL) and the successive reduction of GSH synthesis [72,73].”
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“172 Total antioxidant capacity (TAC) is the ability to neutralise ROS, depending upon the extent of exogenous and endogenous antioxidants in the body fluids.”
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“glutathione (GSH) [18], and NAC may increase intracellular GSH concentrations by increasing intracellular GSH synthesis [25].”
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The role of thyroid hormone in the renal immune microenvironment
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Cho, E. B., Min, J., Cho, H., Seok, J. M., Lee, H. L., Shin, H. Y., Lee, K. H., & Kim, B. J. (2016) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2016.09.039 · Cited by 17
Yang, N., Zhang, D., Hao, J., & Wang, G. (2016) · Journal of International Medical Research · doi:10.1177/0300060515618052 · Cited by 16
Marschner, R. A., Banda, P., Wajner, S. M., Markoski, M. M., Schaun, M. I., & Lehnen, A. M. (2019) · PLoS ONE · doi:10.1371/journal.pone.0222334 · Cited by 15
Self-citationChang, X., Zhang, S., Zhang, M., Wang, H., Fan, C., Gu, Y., Wei, J., & Qiu, C. (2018) · Lipids in Health and Disease · doi:10.1186/s12944-018-0881-7 · Cited by 15
Roginski, A. C., Cecatto, C., Wajner, S. M., Camera, F. D., Castilho, R. F., Wajner, M., & Amaral, A. U. (2019) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-019-03534-7 · Cited by 15
Self-citationRecent Developments in the Understanding of Immunity, Pathogenesis and Management of COVID-19
Yegiazaryan, A., Abnousian, A., Alexander, L. J., Badaoui, A., Flaig, B., Sheren, N., Aghazarian, A., Alsaigh, D., Amin, A., Mundra, A., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169297 · Cited by 14
“Additionally, it was shown that IL-6 induced a dose-dependent decrease in intracellular GSH levels in a number of human cell lines, including lung cells [21].”
BackgroundInfluentialGoemann, I. M., Marczyk, V. R., Recamonde‐Mendoza, M., Wajner, S. M., Graudenz, M. S., & Maia, A. L. (2020) · Scientific Reports · doi:10.1038/s41598-020-70892-4 · Cited by 14
Self-citationMa, X., Yin, Q., Zeng, Z., Wang, C., Yang, Y., & Guo, S. (2018) · NeuroImmunoModulation · doi:10.1159/000492179 · Cited by 14
Marschner, R. A., Roginski, A. C., Ribeiro, R. T., Longo, L., Álvares‐da‐Silva, M. R., & Wajner, S. M. (2023) · Cells · doi:10.3390/cells12071022 · Cited by 13
Self-citationRegulation of Thyroid Function, Synthesis and Function of Thyroid Hormones
Visser, T. J. (2018) · Endocrinology · doi:10.1007/978-3-319-29195-6_1-1 · Cited by 18
Xu, G., Tu, W., & Qin, S.-L. (2014) · Journal of Translational Medicine · doi:10.1186/s12967-014-0239-5 · Cited by 13
“The addition of the antioxidant N-acetyl-cysteine (NAC), which restores intracellular GSH levels, prevented the IL-6-induced inhibitory effects on T3-mediated production, suggesting that the effect of IL-6 on DIO1 is mediated by oxidative stress [11].”
Małujło-Balcerska, E., Kumor‐Kisielewska, A., Szemraj, J., & Pietras, T. (2022) · Pharmacological Reports · doi:10.1007/s43440-022-00360-5 · Cited by 12
“1 3 iodothyronine types 1 and 3 (DIO1, DIO3) [4].”
BackgroundOsteoarthropathien und Myopathien bei Schilddrüsenerkrankungen
Nehls, V. (2018) · DMW - Deutsche Medizinische Wochenschrift · doi:10.1055/s-0043-121381 · Cited by 12
“Merke Für Interleukin-6 wurde gezeigt, dass dieses entzündungsfördernde Schlüsselmolekül die DIO2 hemmt und die DIO3 stimuliert und so zu einer Abnahme des T3 beiträgt [9].”
BackgroundReverse T3 or perverse T3? Still puzzling after 40 years
Gomes-Lima, C., & Burman, K. D. (2018) · Cleveland Clinic Journal of Medicine · doi:10.3949/ccjm.85a.17079 · Cited by 11
Roginski, A. C., Zemniaçak, Â. B., Marschner, R. A., Wajner, S. M., Ribeiro, R. T., Wajner, M., & Amaral, A. U. (2022) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-022-09945-4 · Cited by 11
Self-citationChen, S., Peng, Y., Zhang, H., & Zou, Y. (2023) · Medicine · doi:10.1097/md.0000000000035951 · Cited by 14
“Studies had shown that IL-6 can inhibit the transformation of T4 to T3 mediated by deiodinase, [46] resulting in higher levels of TT4 in peripheral blood.”
BackgroundBapputty, R., Sapa, H., Masaru, M., & Gubitosi‐Klug, R. (2023) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.64.15.3 · Cited by 11
“18–20 Low-grade inflammation causes coronary endothelial dysfunction in patients with hypothyroidism compared with euthyroid controls.”
BackgroundT3 as predictor of mortality in any cause non-critically ill patients
Biegelmeyer, E., Scanagata, I., Alves, L. D. S., Reveilleau, M., Schwengber, F. P., & Wajner, S. M. (2021) · Endocrine Connections · doi:10.1530/ec-21-0080 · Cited by 11
Self-citationOxidative remote induction of type 3 deiodinase impacts nonthyroidal illness syndrome
Lehnen, T. E., Marschner, R. A., Dias, F. R., Maia, A. L., & Wajner, S. M. (2020) · Journal of Endocrinology · doi:10.1530/joe-19-0574 · Cited by 10
Self-citationDora, J. M., Wajner, S. M., Costa, J. D., Ribeiro, R. V. P., Leiria, L. B., Lopes, M. G. D. S. M., da Silva, A. V., Crispim, D., & Maia, A. L. (2013) · Fertility and Sterility · doi:10.1016/j.fertnstert.2013.11.018 · Cited by 11
Self-citationLanger, M., Bauschen, A., Guckenbiehl, S., Klauss, S., Lutz, T., Denk, G., Zwanziger, D., Moeller, L. C., & Lange, C. M. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1104388 · Cited by 9
“a study has shown that generation of the active T3 by DIO1 and DIO2 is inhibited by IL-6, which – interestingly – could be prevented by Nacetyl-cysteine-induced glutathione restoration (17).”
BackgroundStanculescu, D., & Bergquist, J. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.818728 · Cited by 10
Barnhoorn, S., Meima, M. E., Peeters, R. P., Darras, V., Leeuwenburgh, S., Hoeijmakers, J. H. J., Vermeij, W. P., & Visser, W. E. (2023) · European Thyroid Journal · doi:10.1530/etj-22-0231 · Cited by 8
“Should this be a causal link between aging, senescence and thyroid hormonal state, it can be speculated that activity of deiodinases may be downstream of inflammation pathways that are changed upon aging (2, 40).”
BackgroundFan, S., Ni, X., Wang, J., Zhang, Y., Tao, S., Chen, M., Li, Y., & Li, J. (2016) · Medicine · doi:10.1097/md.0000000000002640 · Cited by 7
“Of note, we did not evaluate the efficacy of ALB supplementation for improving clinical variables and prognosis, and the effect of ALB supplementation on thyroid hormone metabolism in RE patients with LT3S.”
InfluentialHigh prevalence of non-thyroidal illness syndrome in patients at long-term care facilities
Lado‐Abeal, J., Diaz, C., Berdine, G. G., IWUJI, K. C., Araújo‐Vilar, D., Lampon-Fernandez, N., Wang, M., Lojo, S., Rodriguez‐Perez, A., & Rivas, A. M. (2020) · Endocrine · doi:10.1007/s12020-020-02321-5 · Cited by 7
Shi, Q., Wu, M., Chen, P., Wei, B., Tan, H., Huang, P., & Chang, S. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.791654 · Cited by 7
Longo, L., Marschner, R. A., de Freitas, L. B. R., de Bona, L. R., Behrens, L. M. P., Pereira, M. H. M., de Souza, V. E. G., Leonhard, L. C., Zanettini, G., Pinzon, C. E., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25136839 · Cited by 7
“This enzyme is known to be induced with inflammation and is a pro-oxidant in the illness [21–24].”
BackgroundSelf-citationRao, M.-J., Zhang, Y., Peng, W.-Z., & Pan, P.-H. (2022) · Journal of the Chinese Medical Association · doi:10.1097/jcma.0000000000000697 · Cited by 6
Stojilković, N., Radović, B., Vukelić, D., Ćurčić, M., Miljaković, E. A., Djordjević, A. B., Baralić, K., Marić, Đ., Bulat, Z., Đukić-Ćosić, D., et al. (2023) · Environmental Research · doi:10.1016/j.envres.2023.117274 · Cited by 6
Callejón, G., Redondo, E., García‐Aranda, M., Castilla, J. A., Prados‐Torres, A., & Redondo, M. (2018) · Pancreas · doi:10.1097/mpa.0000000000001156 · Cited by 6
ICU ‘Magic Numbers’: The Role of Biomarkers in Supporting Clinical Decision-Making
Cipulli, F., Balzani, E., Marini, G., Lassola, S., Rosa, S. D., & Bellani, G. (2025) · Diagnostics · doi:10.3390/diagnostics15080975 · Cited by 5
“This hormonal surge acts as an acute metabolic booster, amplifying the primary cytokine wave and supporting energy demands by promoting lipid oxidation and glycolysis in tissues [68].”
Kim, Y., Koh, J. S., Woo, S., Lee, S., Kang, D. H., Park, D., Chung, C., Kwon, I., & Lee, J. E. (2022) · Clinical Medicine Insights Oncology · doi:10.1177/11795549221139522 · Cited by 5
Non-Thyroidal Illness: Physiopathology and Clinical Implications
Mancini, A., Raimondo, S., Di, C., Persano, M., & Pontecorvi, A. (2013) · InTech eBooks · doi:10.5772/55644 · Cited by 6
Cecatto, C., Wajner, A., Vargas, C. R., Wajner, S. M., Amaral, A. U., & Wajner, M. (2018) · Journal of Cellular Biochemistry · doi:10.1002/jcb.27115 · Cited by 5
“Experiments were performed using cells between passages 10 and 14 at the time of the experiments that were performed in cell cultures with 50% to 60% confluence.(23,24) Usually, new cultures were re‐established from frozen stocks every 3 months.”
MethodSelf-citationEvaluation of Thyroid Function in Patients Hospitalized for Acute Heart Failure
Leite, A. R., Neves, J. S., Borges‐Canha, M., Vale, C., von Hafe, M., Carvalho, D. M., & Leite-Moreira, A. F. (2021) · International Journal of Endocrinology · doi:10.1155/2021/6616681 · Cited by 5
Παππά, Θ., & Alevizaki, M. K. (2018) · Endocrinology · doi:10.1007/978-3-319-45013-1_26 · Cited by 5
Metadata
- Authors
- Wajner, S. M., Goemann, I. M., Bueno, A. L., Larsen, P. R., & Maia, A. L.
- Affiliations
- Universidade Federal do Rio Grande do Sul (BR)
- Brigham and Women's Hospital (US)
- Corresponding author
- Maia, Ana Luiza
- Venue
- Journal of Clinical Investigation
- Published
- 2011-05-02
- Volume
- 121
- Issue
- 5
- Pages
- 1834-1845
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3083773
- OpenAlex
- W2114397821
- Cited by
- 168
- References
- 74
- Citations by year
- 2026: 14 · 2025: 11 · 2024: 13 · 2023: 13 · 2022: 13 · 2021: 10 · 2020: 11 · 2019: 6 · 2018: 15 · 2017: 13 · 2016: 18 · 2015: 9 · 2014: 6 · 2013: 6 · 2012: 8
- FWCI
- 5.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Dartmouth College
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul
- Universidade Federal do Rio Grande do Sul
- Fundação Instituto de Pesquisas Econômicas
- National Institutes of Health
- Fogarty International Center (R03TW007559, TW007559)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK36256, R01DK036256)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- low T3 syndrome, interleukin-6, thyroid hormone metabolism, deiodinases, type I deiodinase, type 2 deiodinase, type III deiodinase, triiodothyronine, thyroxine, oxidative stress, glutathione, N-acetylcysteine, cytokines, thyroid hormone inactivation
- MeSH terms
- Acetylcysteine, Cell Line, Dithiothreitol, Glutathione, Humans, RNA, Messenger, Thyroid Diseases, Thyroid Hormones, Thyroxine, Interleukin-6, Cytokines, Reactive Oxygen Species, Oxidative Stress, Cell Line, Tumor
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