IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells

Wajner, Simone Magagnin; Goemann, Iuri Martin; Bueno, Ana Laura; Larsen, P. Reed; Maia, Ana Luiza

doi:10.1172/jci44678

Cited by 168Thyroid Disorders and TreatmentsGrowth Hormone and Insulin-like Growth FactorsAdrenal Hormones and Disorders

IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells

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Wajner, Simone Magagnin, Goemann, Iuri Martin, Bueno, Ana Laura, Larsen, P. Reed, Maia, Ana Luiza·2011·Journal of Clinical Investigation

DOI 10.1172/jci44678PMC PMC3083773

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Abstract

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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Decreased availability of glutathione (GSH) may also play a role in the downregulation of hepatic DIO1 during NTIS.
“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]
The Discussion (page unavailable) proposes that depletion of intracellular GSH impairs D1 function, and Figure 4 reports that an antioxidant prevented IL-6-induced suppression of D1 activity in HepG2 cells. This supports the hedged suggestion that reduced GSH may play a role. It does not establish GSH as a required D1 cofactor or show downregulation of hepatic DIO1 expression during NTIS; Figure 4 instead reports increased DIO1 mRNA in the treated cells. (LLM, conf=0.85)
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FOXO4 Induces Human Plasminogen Activator Inhibitor-1 Gene Expression via an Indirect Mechanism by Modulating HIF-1α and CREB Levels
Dimova, E. Y., Samoylenko, A., & Kietzmann, T. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2999 · Cited by 15 · see citing works

Flagged first, then by citations

1 of the 74 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

Adler SM, Wartofsky L. The nonthyroidal ill- ness syndrome. Endocrinol Metab Clin North Am. 2007;36(3):657-672.
Meister A, Anderson ME. Glutathione. Annu Rev Biochem. 1983;52:711-760.

Sorted by citations

Thyroid Hormones, Oxidative Stress, and Inflammation
Mancini, A., Segni, C. D., Raimondo, S., Olivieri, G., Silvestrini, A., Meucci, E., & Currò, D. (2016) · Mediators of Inflammation · doi:10.1155/2016/6757154 · Cited by 545 · see citing works
“This hypothesis is supported by the evidence that NAC, an antioxidant that restores intracellular GSH levels, prevents the IL-6-induced effects on the intracellular redox state [121, 122].”
Background
Non-Thyroidal Illness in the ICU: A Syndrome with Different Faces
Van den Berghe, G. (2014) · Thyroid® · doi:10.1089/thy.2014.0201 · Cited by 316 · see citing works
“Possible mediators of the acute fall in plasma T3 concentrations in critically ill patients include the release of cytokines, metabolites, and hypoxia-induced alterations (4,27,28).”
Background
Beyond Low Plasma T3: Local Thyroid Hormone Metabolism during Inflammation and Infection
Boelen, A., Kwakkel, J., & Fliers, E. (2011) · Endocrine Reviews · doi:10.1210/er.2011-0007 · Cited by 287 · see citing works
“First Published Online July 26, 2011 Abbreviations: AP-1, Activator protein-1; D1, deiodinase type 1; D2, deiodinase type 2; D3, deiodinase type 3; D3KO, D3 knockout; GHRP, GH-releasing peptide; GSH, glutathione; HIF, hypoxia inducible factor; HPT, hypothalamus pituitary thyroid; ICU, intensive care unit; IFN, infundi…”
BackgroundInfluential
Role of thyroid hormone in skeletal muscle physiology
Bloise, F. F., Cordeiro, A., & Ortiga-Carvalho, T. M. (2017) · Journal of Endocrinology · doi:10.1530/joe-16-0611 · Cited by 238 · see citing works
The teleost head kidney: Integrating thyroid and immune signalling
Geven, E. J. W., & Klaren, P. H. M. (2016) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2016.06.025 · Cited by 209 · see citing works
“In mammalian thyrocytes, IL-6 exerts roughly the same repertoire of inhibitory effects as TNFa and IL-1b: inhibition of TPO gene expression (Tominaga et al., 1991), and inhibition of basal and TSHinduced 50-deiodination (Hashimoto et al., 1995; Wajner et al., 2011).”
Background
An update on non-thyroidal illness syndrome
Fliers, E., & Boelen, A. (2021) · Journal of Endocrinological Investigation · doi:10.1007/s40618-020-01482-4 · Cited by 199 · see citing works
The molecular basis of the non-thyroidal illness syndrome
de Vries, E. M., Fliers, E., & Boelen, A. (2015) · Journal of Endocrinology · doi:10.1530/joe-15-0133 · Cited by 192 · see citing works
Thyroid Hormones Interaction With Immune Response, Inflammation and Non-thyroidal Illness Syndrome
Luca, R. D., Davis, P. J., Lin, H., Gionfra, F., Percario, Z. A., Affabris, E., Pedersen, J. Z., Marchese, C., Trivedi, P., Anastasiadou, E., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.614030 · Cited by 164 · see citing works
Thyroid Physiology and Diagnostic Evaluation of Patients with Thyroid Disorders
Salvatore, D., Davies, T. F., Schlumberger, M.-J., HAY, I. D., & Larsen, P. R. (2011) · Elsevier eBooks · doi:10.1016/b978-1-4377-0324-5.00011-0 · Cited by 155 · see citing works
Self-citation
Relationship between thyroid function and ICU mortality: a prospective observation study
Wang, F., Pan, W., Wang, H., Wang, S., Pan, S., & Ge, J. (2012) · Critical Care · doi:10.1186/cc11151 · Cited by 138 · see citing works
“Researchers in other studies have also found that inflammatory cytokines are associated with NTIS in vitro [34] and in clinical settings [35].”
Background
Role of the Iodothyronine Deiodinases in the Physiology and Pathophysiology of Thyroid Hormone Action
Larsen, P. R., & Zavacki, A. M. (2012) · European Thyroid Journal · doi:10.1159/000343922 · Cited by 114 · see citing works
Self-citation
Endocrine Responses to Critical Illness: Novel Insights and Therapeutic Implications
Boonen, E., & Van den Berghe, G. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-4115 · Cited by 105 · see citing works
New insights toward the acute non-thyroidal illness syndrome
Wajner, S. M., & Maia, A. L. (2012) · Frontiers in Endocrinology · doi:10.3389/fendo.2012.00008 · Cited by 105 · see citing works
“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).”
BackgroundSelf-citation
Abnormalities of thyroid hormone metabolism during systemic illness: the low T3 syndrome in different clinical settings
Moura Neto, A., & Zantut-Wittmann, D. E. (2016) · International Journal of Endocrinology · doi:10.1155/2016/2157583 · Cited by 91 · see citing works
The cytokine storm and thyroid hormone changes in COVID-19
Croce, L., Gangemi, D., Ancona, G., Liboà, F., Bendotti, G., Minelli, L., & Chiovato, L. (2021) · Journal of Endocrinological Investigation · doi:10.1007/s40618-021-01506-7 · Cited by 100 · see citing works
Thyroid hormone and the brain: Mechanisms of action in development and role in protection and promotion of recovery after brain injury
Liu, Y., & Brent, G. A. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.01.007 · Cited by 94 · see citing works
Mycobacterial HBHA induces endoplasmic reticulum stress-mediated apoptosis through the generation of reactive oxygen species and cytosolic Ca2+ in murine macrophage RAW 264.7 cells
Choi, J.-A., Lim, Y.-J., Cho, S.-N., Lee, J.-H., Jeong, J. A., Kim, E., Park, J. B., Kim, S., Park, H. S., Kim, H.-J., et al. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.489 · Cited by 81 · see citing works
Glutathione Supplementation as an Adjunctive Therapy in COVID-19
Guloyan, V., Oganesian, B., Baghdasaryan, N., Yeh, C., Singh, M., Guilford, F. T., Ting, Y.-S., & Venketaraman, V. (2020) · Antioxidants · doi:10.3390/antiox9100914 · Cited by 73 · see citing works
“A 2011 study showed that IL-6 induced a dose-dependent decrease in intracellular GSH levels in a number of human cell lines, including lung cells [57].”
Background
Low FT3: a possible marker of frailty in the elderly
Bertoli, A., Valentini, A., Cianfarani, M. A., Gasbarra, E., Tarantino, U., & Federici, M. (2017) · Clinical Interventions in Aging · doi:10.2147/cia.s125934 · Cited by 69 · see citing works
Role of thyroid hormones in the neoplastic process: an overview
Goemann, I. M., Romitti, M., Meyer, E. L. D. S., Wajner, S. M., & Maia, A. L. (2017) · Endocrine Related Cancer · doi:10.1530/erc-17-0192 · Cited by 66 · see citing works
Self-citation
Environmental heat stress modulates thyroid status and its response to repeated endotoxin challenge in steers
Kahl, S., Elsasser, T. H., Rhoads, R. P., Collier, R. J., & Baumgard, L. H. (2015) · Domestic Animal Endocrinology · doi:10.1016/j.domaniend.2015.02.001 · Cited by 63 · see citing works
A low fT3 level as a prognostic marker in patients with acute myocardial infarctions
Zhang, B., Peng, W., Wang, C., Li, W., & Xu, Y. (2012) · Internal Medicine · doi:10.2169/internalmedicine.51.7902 · Cited by 59 · see citing works
“All of these changes decrease the conversion of T4 to T3 and increase the degradation of T3 (15).”
Background
The Role of Thyroid Hormones in Hepatocyte Proliferation and Liver Cancer
Gionfra, F., Vito, P. D., Pallottini, V., Lin, H., Davis, P. J., Pedersen, J. Z., & Incerpi, S. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00532 · Cited by 60 · see citing works
“Oxidative stress alters the activity of deiodinases, as discussed in the paragraphs that follow, and thyroid hormones can modulate cell function through oxidative stress (30, 31).”
Background
N-Acetylcysteine Administration Prevents Nonthyroidal Illness Syndrome in Patients With Acute Myocardial Infarction: A Randomized Clinical Trial
Vidart, J., Wajner, S. M., Leite, R. S., Manica, A., Schaan, B. D., Larsen, P. R., & Maia, A. L. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-2192 · Cited by 54 · see citing works
“Notably, these results were paralleled, in a timely fashion, with serum thyroid hormone adjustment, suggesting that the T3 decrease is mainly due to oxidative stress-induced impairment of thyroid hormone activation (9).”
BackgroundResultInfluentialSelf-citation
Gene-specific regulation of hepatic selenoprotein expression by interleukin-6
Martitz, J., Becker, N., Renko, K., Stoedter, M., Hybsier, S., & Schomburg, L. (2015) · Metallomics · doi:10.1039/c5mt00211g · Cited by 51 · see citing works
Comparison and relationship of thyroid hormones, IL-6, IL-10 and albumin as mortality predictors in case-mix critically ill patients
Álvaro Quispe, E., Li, X., & Yi, H. L. (2016) · Cytokine · doi:10.1016/j.cyto.2016.03.004 · Cited by 50 · see citing works
Redox Signaling in Widespread Health Benefits of Exercise
Louzada, R. A. N., Bouvière, J., Matta, L., Werneck‐de‐Castro, J. P., Dupuy, C., de Carvalho, D. P., & Fortunato, R. S. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7949 · Cited by 47 · see citing works
“Further, IL-6 stimulates ROS production in plenty of different cell types (163), so it is possible that ROS can act as an intermediate in the effect of IL-6 in remote tissues during exercise.”
Association between ambient air pollution and thyroid hormones levels: A systematic review and meta-analysis
Liu, J., Zhao, K., Qian, T., Li, X., Yi, W., Pan, R., Huang, Y., Ji, Y., & Su, H. (2023) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2023.166780 · Cited by 46 · see citing works
Thyroid Physiology and Diagnostic Evaluation of Patients With Thyroid Disorders
Salvatore, D., Davies, T. F., Schlumberger, M.-J., HAY, I. D., & Larsen, P. R. (2016) · Elsevier eBooks · doi:10.1016/b978-0-323-29738-7.00011-3 · Cited by 44 · see citing works
Self-citation
INCREASED TYPE 3 DEIODINASE EXPRESSION IN PAPILLARY THYROID CARCINOMA
Maia, A. L., Romitti, M., Wajner, S. M., Zennig, N., Goemann, I. M., Bueno, A. L., & Meyer, E. L. D. S. (2012) · Thyroid · doi:10.1089/thy.2012.0031 · Cited by 42 · see citing works
“number of pathological states, unraveling an important role of D3 in both health and disease (16,21,25).”
MethodSelf-citation
Thyroid Hormone and Cardioprotection
Gerdes, A. M., & Ojamaa, K. (2016) · Comprehensive physiology · doi:10.1002/cphy.c150012 · Cited by 45 · see citing works
Thyroid hormones in extreme longevity
Garasto, S., Montesanto, A., Corsonello, A., Lattanzio, F., Fusco, S., Passarino, G., Giarritta, V. P., & Corica, F. (2017) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2017.03.002 · Cited by 41 · see citing works
Thyroid Hormone and Deiodination in Innate Immune Cells
van der Spek, A. H., Fliers, E., & Boelen, A. (2020) · Endocrinology · doi:10.1210/endocr/bqaa200 · Cited by 41 · see citing works
Response of Selenium and Selenogenome in Immune Tissues to LPS-Induced Inflammatory Reactions in Pigs
Sun, L., Pi, D., Zhao, L., Wang, X., Zhu, L.-Y., Qi, D., & Liu, Y. (2016) · Biological Trace Element Research · doi:10.1007/s12011-016-0863-4 · Cited by 38 · see citing works
“The results showed that the mRNA level of Dio3 (599”
Influential
MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma
Romitti, M., Wajner, S. M., Ceolin, L., Ferreira, C. V., Ribeiro, R. V. P., Rohenkohl, H. C., Weber, S. D. S., Lopez, P. L. D. C., Fuziwara, C. S., Kimura, E. T., et al. (2016) · Endocrine Related Cancer · doi:10.1530/erc-15-0162 · Cited by 38 · see citing works
“D3 activity was determined in PTC cells by ion-exchange column chromatography (Wajner et al. 2011).”
MethodSelf-citation
Relation of thyroid hormone abnormalities with subclinical inflammatory activity in patients with type 1 and type 2 diabetes mellitus
Neto, A. M., Parisi, M. C. R., Alegre, S. M., Pavin, E. J., Tambascia, M. A., & Zantut‐Wittmann, D. E. (2015) · Endocrine · doi:10.1007/s12020-015-0651-5 · Cited by 34 · see citing works
“Therefore, recognizing NTIS is important to avoid misdiagnosis with primary thyroid dysfunctions that would otherwise indicate treatments that have not been proven beneficial in patients with low T3 secondary to systemic illnesses [9] and also to be aware of the possibility that interplay between diabetes mellitus and…”
BackgroundInfluential
Thyroid Hormone Profile and Its Prognostic Impact on the Coronavirus Disease 2019 in Korean Patients
Ahn, J., Lee, M. K., Lee, J. H., & Sohn, S. Y. (2021) · Endocrinology and Metabolism · doi:10.3803/enm.2021.1109 · Cited by 33 · see citing works
“Circulating cytokines are known to decrease the D1 activity and increase the D3 activity, leading to acute fall in T3 levels in critically ill patients [27,28].”
Background
Prognostic significance of high free T4 and low free T3 levels in non-thyroidal illness syndrome
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 · see citing works
Sodium selenite supplementation does not fully restore oxidative stress-induced deiodinase dysfunction: Implications for the nonthyroidal illness syndrome
Wajner, S. M., Rohenkohl, H. C., Serrano, T., & Maia, A. L. (2015) · Redox Biology · doi:10.1016/j.redox.2015.09.002 · Cited by 33 · see citing works
“Cytokines are elevated as a generalized response to illness and available data suggest that interleukin (IL)-1β, tumor necrosis factor-α (TNFα) and, particularly IL6, play a central role in in NTIS [7].”
BackgroundMethodInfluentialSelf-citation
Differential Regulation of Thyroid Hormone Metabolism Target Genes during Non-thyroidal Illness Syndrome Triggered by Fasting or Sepsis in Adult Mice
Fontes, K. N., Cabanelas, A., Bloise, F. F., de Andrade, C. B. V., Souza, L. L., Wilieman, M., Trevenzoli, I. H., Agra, L. C., Silva, J. D., Bandeira‐Melo, C., et al. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00828 · Cited by 41 · see citing works
“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).”
Background
An update for the controversies and hypotheses of regulating nonthyroidal illness syndrome in chronic kidney diseases
Xu, G., Yan, W., & Li, J. (2014) · Clinical and Experimental Nephrology · doi:10.1007/s10157-014-0974-1 · Cited by 33 · see citing works
“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].”
Background
The Thyroid Hormone Inactivating Enzyme Type 3 Deiodinase is Present in Bactericidal Granules and the Cytoplasm of Human Neutrophils
van der Spek, A. H., Bloise, F. F., Tigchelaar, W., Dentice, M., Salvatore, D., van der Wel, N. N., Fliers, E., & Boelen, A. (2016) · Endocrinology · doi:10.1210/en.2016-1103 · Cited by 28 · see citing works
The Association of TSH and Thyroid Hormones With Lymphopenia in Bacterial Sepsis and COVID-19
Grondman, I., de Nooijer, A., Antonakos, N., Janssen, N. A. F., Mouktaroudi, M., Leventogiannis, K., Medici, M., Smit, J. W. A., van Herwaarden, A. E., Joosten, L. A. B., et al. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab148 · Cited by 25 · see citing works
“IL-6 (pg/mL) NA 110 (75-185) 22 (16-69) <0.”
Influential
Dissecting thyroid hormone transport and metabolism in dendritic cells
Gigena, N., Alamino, V. A., Montesinos, M. M., Nazar, M., Louzada, R. A. N., Wajner, S. M., Maia, A. L., Masini-Repiso, A. M., de Carvalho, D. P., Cremaschi, G., et al. (2017) · Journal of Endocrinology · doi:10.1530/joe-16-0423 · Cited by 27 · see citing works
Self-citation
Association between thyroid hormone levels and frailty in the community-dwelling oldest-old: a cross-sectional study
Guan, B., Luo, J., Huang, X., Fan, T., Sun, S., Ma, Y., Yu, Y., Liu, R., Cao, J., & Fan, L. H. (2022) · Chinese Medical Journal · doi:10.1097/cm9.0000000000002208 · Cited by 25 · see citing works
“[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.”
Background
Is there a link between autism and glyphosate-formulated herbicides?
Beecham, J. E., & Seneff, S. (2016) · Journal of Autism · doi:10.7243/2054-992x-3-1 · Cited by 24 · see citing works
Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Stanculescu, D., Larsson, L., & Bergquist, J. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.628029 · Cited by 25 · see citing works
N-Acetylcysteine Prevents Low T3 Syndrome and Attenuates Cardiac Dysfunction in a Male Rat Model of Myocardial Infarction
Lehnen, T. E., Santos, M. V., de Lima, A. G., Maia, A. L., & Wajner, S. M. (2017) · Endocrinology · doi:10.1210/en.2016-1586 · Cited by 23 · see citing works
“This indicates that thyroid hormone derangement occurs mainly as a result of changes in redox balance affecting peripheral thyroid hormone metabolism (3, 18).”
Self-citation
Low Tri-iodothyronine Syndrome Is Associated With Cognitive Impairment in Patients With Acute Ischemic Stroke: A Prospective Cohort Study
Chen, H., Wu, Y., Huang, G., He, W., Lin, S., Zhang, X., & He, J. (2018) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2018.07.007 · Cited by 24 · see citing works
The Role of Selenium in Oxidative Stress and in Nonthyroidal Illness Syndrome (NTIS): An Overview
Silvestrini, A., Mordente, A., Martino, G., Bruno, C., Vergani, E., Meucci, E., & Mancini, A. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867325666180201111159 · Cited by 24 · see citing works
Thyroid hormones and modulation of diastolic function: a promising target for heart failure with preserved ejection fraction
Neves, J. S., Vale, C., von Hafe, M., Borges‐Canha, M., Leite, A. R., Almeida‐Coelho, J., Lourenço, A. P., Falcão‐Pires, I., Carvalho, D. M., & Leite-Moreira, A. F. (2020) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/2042018820958331 · Cited by 24 · see citing works
Relationship between left ventricular mechanics and low free triiodothyronine levels after myocardial infarction: a prospective study
Jankauskienė, E., Orda, P., Barauskienė, G., Mickuvienė, N., Brožaitienė, J., Vaškelytė, J. J., & Bunevičius, R. (2015) · Internal and Emergency Medicine · doi:10.1007/s11739-015-1370-x · Cited by 23 · see citing works
“released during AMI may reduce fT3 levels by reducing the activity of type 1 and type 2 deiodinases, and thus inducing oxidative stress [2].”
Background
Relationship among Low T3 Levels, Type 3 Deiodinase, Oxidative Stress, and Mortality in Sepsis and Septic Shock: Defining Patient Outcomes
Vidart, J., Axelrud, L. K., Braun, A. C., Marschner, R. A., & Wajner, S. M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043935 · Cited by 20 · see citing works
“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].”
BackgroundSelf-citation
Regulation of Thyroid Function, Synthesis, and Function of Thyroid Hormones
Visser, T. J. (2018) · Endocrinology · doi:10.1007/978-3-319-45013-1_1 · Cited by 22 · see citing works
Persistent anemia and hypoalbuminemia in rheumatoid arthritis patients with low serum triiodothyronine level
Tsuji, H., Hashimoto, M., Harada, T., Tanaka, M., Ito, H., Murakami, K., Ohmura, K., Fujii, T., & Mimori, T. (2019) · Modern Rheumatology · doi:10.1080/14397595.2019.1649109 · Cited by 21 · see citing works
“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].”
Background
Downregulation of Caveolin-1 and Upregulation of Deiodinase 3, Associated with Hypoxia-Inducible Factor-1α Increase, Are Involved in the Oxidative Stress of Graves' Orbital Adipocytes
Regemorter, E. V., Joris, V., Regemorter, V. V., Marique, L., Behets, C., Lengelé, B., Boschi, A., Baldeschi, L., Daumerie, C., Many, M., et al. (2020) · Thyroid · doi:10.1089/thy.2020.0238 · Cited by 21 · see citing works
“IL-6 production has been shown to be increased in nonthyroidal illness syndrome (31).”
Effects of Perinatal Lipopolysaccharide (LPS) Exposure on the Developing Rat Brain; Modeling the Effect of Maternal Infection on the Developing Human CNS
Xu, M. Q., Sulkowski, Z. L., Parekh, P., Khan, A., Chen, T., Midha, S., Iwasaki, T., Shimokawa, N., Koibuchi, N., Zavacki, A. M., et al. (2013) · The Cerebellum · doi:10.1007/s12311-013-0465-z · Cited by 20 · see citing works
“and post-transcriptional mechanisms [23, 54].”
Current concepts and challenges to unravel the role of iodothyronine deiodinases in human neoplasias
Goemann, I. M., Marczyk, V. R., Romitti, M., Wajner, S. M., & Maia, A. L. (2018) · Endocrine Related Cancer · doi:10.1530/erc-18-0097 · Cited by 20 · see citing works
Self-citation
Free Thyroid Hormones and Mortality in Caucasians Undergoing Angiography: The Ludwigshafen Risk and Cardiovascular Health (Luric) Study
Merke, A., Merke, J., Silbernagel, G., & März, W. (2016) · Endocrine Practice · doi:10.4158/ep161217.or · Cited by 20 · see citing works
The Role of Glutathione in Prevention of COVID-19 Immunothrombosis: A Review
Glassman, I., Le, N., Mirhosseini, M., Alcantara, C. A., Asif, A., Goulding, A., Muneer, S., Singh, M., Robison, J., Guilford, F., et al. (2023) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2803059 · Cited by 18 · see citing works
“…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].”
Background
Cytokine Storm-Induced Thyroid Dysfunction in COVID-19: Insights into Pathogenesis and Therapeutic Approaches
Attiq, A., Afzal, S., Wahab, H. A., Ahmad, W., Kandeel, M. K., Almofti, Y. A., Alameen, A. O., & Wu, Y. S. (2024) · Drug Design Development and Therapy · doi:10.2147/dddt.s475005 · Cited by 18 · see citing works
“172 Total antioxidant capacity (TAC) is the ability to neutralise ROS, depending upon the extent of exogenous and endogenous antioxidants in the body fluids.”
Background
Treatment for non-thyroidal illness syndrome in advanced chronic kidney disease: a single-blind controlled study
Yan, W., Wang, L., Huang, T., & Xu, G. (2016) · Journal of Nephrology · doi:10.1007/s40620-016-0341-2 · Cited by 18 · see citing works
“glutathione (GSH) [18], and NAC may increase intracellular GSH concentrations by increasing intracellular GSH synthesis [25].”
Background
The influence of body mass index and low-grade systemic inflammation on thyroid hormone abnormalities in patients with type 2 diabetes
Neto, A. M., Parisi, M. C. R., Tambascia, M. A., Alegre, S. M., Pavin, E. J., & Zantut‐Wittmann, D. E. (2013) · Endocrine Journal · doi:10.1507/endocrj.ej13-0030 · Cited by 18 · see citing works
The role of thyroid hormone in the renal immune microenvironment
Han, Z., Chen, L., Zheng, H., Zheng, H., Lin, Y., Peng, F., Fan, Y., Xie, X., Wang, Z., Wang, Z., et al. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.110172 · Cited by 17 · see citing works
Low T3 syndrome in neuromyelitis optica spectrum disorder: Associations with disease activity and disability
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 · see citing works
Serum levels of thyroid hormones and thyroid stimulating hormone in patients with biliogenic and hyperlipidaemic acute pancreatitis: Difference and value in predicting disease severity
Yang, N., Zhang, D., Hao, J., & Wang, G. (2016) · Journal of International Medical Research · doi:10.1177/0300060515618052 · Cited by 16 · see citing works
Short-term exercise training improves cardiac function associated to a better antioxidant response and lower type 3 iodothyronine deiodinase activity after myocardial infarction
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 · see citing works
Self-citation
Free triiodothyronine and global registry of acute coronary events risk score on predicting long-term major adverse cardiac events in STEMI patients undergoing primary PCI
Chang, 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 · see citing works
Experimental evidence that maleic acid markedly compromises glutamate oxidation through inhibition of glutamate dehydrogenase and α-ketoglutarate dehydrogenase activities in kidney of developing rats
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 · see citing works
Self-citation
Recent 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 · see citing works
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BackgroundInfluential
Decreased expression of the thyroid hormone-inactivating enzyme type 3 deiodinase is associated with lower survival rates in breast cancer
Goemann, 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 · see citing works
Self-citation
Thyroid Function and Autoimmune Indications in Patients with Anti-N-Methyl-D-Aspartate Receptor Encephalitis
Ma, X., Yin, Q., Zeng, Z., Wang, C., Yang, Y., & Guo, S. (2018) · NeuroImmunoModulation · doi:10.1159/000492179 · Cited by 14 · see citing works
Uncovering Actions of Type 3 Deiodinase in the Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)
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 · see citing works
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Regulation of Thyroid Function, Synthesis and Function of Thyroid Hormones
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The relationship between deiodinase activity and inflammatory responses under the stimulation of uremic toxins
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“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].”
Chemokine (C–C motif) ligand 5 (RANTES) concentrations in the peripheral blood of patients with a depressive disorder
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Background
Osteoarthropathien und Myopathien bei Schilddrüsenerkrankungen
Nehls, V. (2018) · DMW - Deutsche Medizinische Wochenschrift · doi:10.1055/s-0043-121381 · Cited by 12 · see citing works
“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].”
Background
Reverse 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 · see citing works
Disruption of mitochondrial functions involving mitochondrial permeability transition pore opening caused by maleic acid in rat kidney
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 · see citing works
Self-citation
Relationship between thyroid function and dietary inflammatory index in Hashimoto thyroiditis patients
Chen, S., Peng, Y., Zhang, H., & Zou, Y. (2023) · Medicine · doi:10.1097/md.0000000000035951 · Cited by 11 · see citing works
“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.”
Background
Diabetes Modulates Iodothyronine Deiodinase 2 Expression in the Mouse Retina: A Role for Thyroid Hormone in the Pathogenesis of Diabetic Retinopathy
Bapputty, R., Sapa, H., Masaru, M., & Gubitosi‐Klug, R. (2023) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.64.15.3 · Cited by 11 · see citing works
“18–20 Low-grade inflammation causes coronary endothelial dysfunction in patients with hypothyroidism compared with euthyroid controls.”
Background
T3 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 · see citing works
Self-citation
Oxidative 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 · see citing works
Self-citation
Type 2 deiodinase Thr92Ala polymorphism is associated with disrupted placental activity but not with dysglycemia or adverse gestational outcomes: a genetic association study
Dora, 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 · see citing works
Self-citation
Evolution of non-thyroidal illness syndrome in acute decompensation of liver cirrhosis and acute-on-chronic liver failure
Langer, 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 · see citing works
“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).”
Background
Perspective: Drawing on Findings From Critical Illness to Explain Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Stanculescu, D., & Bergquist, J. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.818728 · Cited by 9 · see citing works
Decreased hepatic thyroid hormone signaling in systemic and liver-specific but not brain-specific accelerated aging due to DNA repair deficiency in mice
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 · see citing works
“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).”
Background
Low Triiodothyronine Syndrome in Patients With Radiation Enteritis: Risk Factors and Clinical Outcomes an Observational Study
Fan, 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 · see citing works
“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.”
Influential
High 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 · see citing works
Criminal of Adverse Pregnant Outcomes: A Perspective From Thyroid Hormone Disturbance Caused by SARS-CoV-2
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 · see citing works
Redefining the Role of Ornithine Aspartate and Vitamin E in Metabolic-Dysfunction-Associated Steatotic Liver Disease through Its Biochemical Properties
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 · see citing works
“This enzyme is known to be induced with inflammation and is a pro-oxidant in the illness [21–24].”
BackgroundSelf-citation
Thyroid Hormone and Cardioprotection
Gerdes, A. M., & Ojamaa, K. (2016) · Comprehensive physiology · doi:10.1002/j.2040-4603.2016.tb00704.x · Cited by 7 · see citing works
“…by which TH metabolism is altered in acute and chronic illnesses including heart disease are not entirely clear, although studies suggest that inflammatory mediators may play a role centrally on the HPT axis or possibly by peripherally inhibiting cellular D1 or inducing D3 (141, 255, 267).”
Association of thyroid hormones and thyroid-stimulating hormone with mortality in adults admitted to the intensive care unit: A systematic review and meta-analysis
Rao, 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 · see citing works
Involvement of toxic metals and PCBs mixture in the thyroid and male reproductive toxicity: In silico toxicogenomic data mining
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 · see citing works
Free Thyroxine Determination in the Emergency Department Is a Predictor of Acute Pancreatitis Evolution
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 · see citing works
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 · see citing works
“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].”
The Tri-iodothyronine (T3) Level Is a Prognostic Factor for Patients With Advanced NSCLC: Receiving Immune Checkpoint Inhibitors and Is Associated With Liver Metastasis
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Non-Thyroidal Illness: Physiopathology and Clinical Implications
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High vulnerability of the heart and liver to 3‐hydroxypalmitic acid–induced disruption of mitochondrial functions in intact cell systems
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 · see citing works
“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.”
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Evaluation of Thyroid Function in Patients Hospitalized for Acute Heart Failure
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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
ORCID: Wajner, Simone Magagnin
Goemann, Iuri Martin
Bueno, Ana Laura
Maia, Ana Luiza
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2011-05-02
Volume: 121
Issue: 5
Pages: 1834-1845
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci44678
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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IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells

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