Induction of Type 1 Iodothyronine Deiodinase to Prevent the Nonthyroidal Illness Syndrome in Mice
Abstract
Essentially all serious illness is associated with a decrease in circulating T(3), a condition known as the nonthyroidal illness syndrome. Substantial evidence suggests that a contributing factor to this syndrome is a cytokine-induced decrease in hepatic type 1 iodothyronine deiodinase (D1), an enzyme that converts T(4) to T(3). The type 1 deiodinase is induced at the transcriptional level by T(3), but illness-associated cytokines block this induction, resulting in decreased T(3) and hence a further decline in D1 expression. We demonstrated that IL-1 blocks the ability of T(3) to induce D1 in rat hepatocyte primary cultures and that forced expression of steroid receptor co- activator 1 (SRC-1) prevents this cytokine effect. This led us to test whether forced hepatic expression of SRC-1 can prevent the nonthyroidal illness syndrome in vivo. Pretreatment of endotoxin-treated mice with an adenovirus that expresses SRC-1, compared with a control adenovirus, prevented the endotoxin-induced decreases in hepatic D1 and plasma T(3). The data suggest that a cytokine-induced defect in T(3) receptor coactivators is an important component of this animal model of nonthyroidal illness and that the syndrome can be overcome by forced expression of the coactivator.
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Liver TRβ1 expression decreases during acute inflammation in mice and limited availability of SRC-1 might be partly responsible for the illness induced decrease of liver DIO1.
“Indeed, liver TRβ1 expression decreases during acute inflammation in mice [15, 39, 77] and limited availability of SRC-1, a shared coactivator for TR and inflammatory signaling pathways, might be partly responsible for the illness induced decrease of liver DIO1 [78, 79].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [79]
Cites
Sequence and Characterization of a Coactivator for the Steroid Hormone Receptor Superfamily
Oñate, S., Tsai, S., Tsai, M.-J., & O'Malley, B. (1995) · Science · doi:10.1126/science.270.5240.1354 · Cited by 2,507 · see citing works
Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease
Iervasi, G., Pingitore, A., Landi, P., Raciti, M., Ripoli, A., Scarlattini, M., L’Abbate, A., & Donato, L. (2003) · Circulation · doi:10.1161/01.cir.0000048124.64204.3f · Cited by 472 · see citing works
Peeters, R. P., Wouters, P. J., Kaptein, E., van Toor, H., Visser, T. J., & Van den Berghe, G. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-022013 · Cited by 452 · see citing works
Euthyroid Sick Syndrome: Is It a Misnomer?
Chopra, I. J. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.2.3745 · Cited by 374 · see citing works
Brent, G. A., & Hershman, J. M. (1986) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-63-1-1 · Cited by 366 · see citing works
Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans
Luiza Maia, A. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25083 · Cited by 360 · see citing works
The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism
Docter, R., Krenning, E. P., de Jong, M., & Hennemann, G. (1993) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1993.tb02401.x · Cited by 345 · see citing works
Adenovirus mediated expression of therapeutic plasma levels of human factor IX in mice
Smith, T. A., Mehaffey, M. G., Kayda, D. B., Saunders, J. M., Yei, S., Trapnell, B. C., McClelland, A., & Kaleko, M. (1993) · Nature Genetics · doi:10.1038/ng1293-397 · Cited by 336 · see citing works
Euthyroid Sick Syndrome: An Overview
McIver, B., & Gorman, C. A. (1997) · Thyroid · doi:10.1089/thy.1997.7.125 · Cited by 258 · see citing works
Na, S.-Y., Lee, S., Han, S., Choi, H., Im, S., & Lee, J. W. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.18.10831 · Cited by 235 · see citing works
Lee, S., Kim, H.-J., Na, S., Kim, T. S., Choi, H., Im, S., & Lee, J. W. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.27.16651 · Cited by 207 · see citing works
Fliers, E., Guldenaar, S. E. F., Wiersinga, W. M., & Swaab, D. F. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.12.4404 · Cited by 206 · see citing works
Hypermetabolic low triiodothyronine syndrome of burn injury
BECKER, R. A., Vaughan, G. M., Ziegler, M. G., Seraile, L. G., Goldfarb, I. W., MANSOUR, E. H., McManus, W. F., Pruitt, B. A., & Mason, A. D. (1982) · Critical Care Medicine · doi:10.1097/00003246-198212000-00014 · Cited by 204 · see citing works
The Relationship between Serum Triiodothyronine and Thyrotropin during Systemic Illness*
Bacci, V., Schussler, G. C., & KAPLAN, T. B. (1982) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-54-6-1229 · Cited by 200 · see citing works
Association between serum interleukin-6 and serum 3,5,3'-triiodothyronine in nonthyroidal illness.
Boelen, A., Platvoet-Ter Schiphorst, M. C., & Wiersinga, W. M. (1993) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.77.6.8263160 · Cited by 196 · see citing works
Triiodothyronine levels for risk stratification of patients with chronic heart failure
Pingitore, A., Landi, P., Taddei, M. C., Ripoli, A., L’Abbate, A., & Iervasi, G. (2005) · The American Journal of Medicine · doi:10.1016/j.amjmed.2004.07.052 · Cited by 192 · see citing works
Kaptein, E. M., Robinson, W. J., Grieb, D. A., & Nicoloff, J. T. (1982) · Journal of Clinical Investigation · doi:10.1172/jci110478 · Cited by 183 · see citing works
Fekete, C., Gereben, B., Doleschall, M., Harney, J. W., Dora, J. M., Bianco, A. C., Sarkar, S., Liposits, Z., Rand, W., Emerson, C., et al. (2004) · Endocrinology · doi:10.1210/en.2003-1439 · Cited by 179 · see citing works
Tissue Thyroid Hormone Levels in Critical Illness
Peeters, R. P., van der Geyten, S., Wouters, P. J., Darras, V. M., van Toor, H., Kaptein, E., Visser, T. J., & Van den Berghe, G. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-1013 · Cited by 145 · see citing works
Toyoda, N., Zavacki, A. M., Maia, A. L., Harney, J. W., & Larsen, P. R. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.9.5100 · Cited by 142 · see citing works
Ghose, R., Zimmerman, T. L., Thevananther, S., & Karpen, S. J. (2004) · Nuclear Receptor · doi:10.1186/1478-1336-2-4 · Cited by 134 · see citing works
Boelen, A., Kwakkel, J., Alkemade, A., Renckens, R., Kaptein, E., Kuiper, G., Wiersinga, W. M., & Visser, T. J. (2005) · Endocrinology · doi:10.1210/en.2005-0608 · Cited by 117 · see citing works
Boelen, A., Maas, M. A., Lowik, C. W., Platvoet, M. C., & Wiersinga, W. M. (1996) · Endocrinology · doi:10.1210/endo.137.12.8940342 · Cited by 108 · see citing works
A potential role of activated NF-κB in the pathogenesis of euthyroid sick syndrome
Nagaya, T., Fujieda, M., Otsuka, G., Yang, J.-P., Okamoto, T., & Seo, H. (2000) · Journal of Clinical Investigation · doi:10.1172/jci7771 · Cited by 107 · see citing works
Role of cytokines in the pathogenesis of the euthyroid sick syndrome
Bartalena, L., Bogazzi, F., Brogioni, S., Grasso, L., & Martino, E. (1998) · European Journal of Endocrinology · doi:10.1530/eje.0.1380603 · Cited by 100 · see citing works
Scoscia, E., Baglioni, S., Eslami, A., Iervasi, G., Monti, S., & Todisco, T. (2004) · European Journal of Endocrinology · doi:10.1530/eje.0.1510557 · Cited by 96 · see citing works
Torpy, D. J., Tsigos, C., Lotsikas, A. J., Defensor, R., Chrousos, G. P., & Papanicolaou, D. A. (1998) · Metabolism · doi:10.1016/s0026-0495(98)90338-9 · Cited by 95 · see citing works
Yu, J., & Koenig, R. J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m004866200 · Cited by 94 · see citing works
Self-citationThe role of cytokines in the lipopolysaccharide-induced sick euthyroid syndrome in mice
Boelen, A., Platvoet-ter Schiphorst, M. C., Bakker, O., & Wiersinga, W. M. (1995) · Journal of Endocrinology · doi:10.1677/joe.0.1460475 · Cited by 93 · cited 1× · see citing works
“IL-1 administration results in a decline in hepatic D1 in mice (18).”
BackgroundEuthyroid Sick Syndrome and the Role of Cytokines
Papanicolaou, D. A. (2000) · Reviews in Endocrine and Metabolic Disorders · doi:10.1023/a:1010060303031 · Cited by 72 · see citing works
Jakobs, T., Mentrup, B., Schmutzler, C., Dreher, I., & Köhrle, J. (2002) · European Journal of Endocrinology · doi:10.1530/eje.0.1460559 · Cited by 72 · see citing works
Chinga-Alayo, E., Villena, J., Evans, A. T., & Zimic, M. (2005) · Intensive Care Medicine · doi:10.1007/s00134-005-2719-9 · Cited by 71 · see citing works
Kim, H.-J., Kim, J., & Lee, J. W. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.44.28564 · Cited by 70 · see citing works
Sick euthyroid syndrome is associated with decreased TR expression and DNA binding in mouse liver
Beigneux, A. P., Moser, A. H., Shigenaga, J. K., Grunfeld, C., & Feingold, K. R. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00155.2002 · Cited by 64 · see citing works
Toyoda, N., Harney, J. W., Berry, M. J., & Larsen, P. R. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)31995-6 · Cited by 59 · see citing works
Effect of endotoxin challenge on hepatic 5′-deiodinase activity in cattle
Kahl, S., Elsasser, T. H., & Blum, J. W. (2000) · Domestic Animal Endocrinology · doi:10.1016/s0739-7240(99)00069-7 · Cited by 31 · see citing works
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Mechanisms behind the non-thyroidal illness syndrome: an update
Warner, M., & Beckett, G. J. (2009) · Journal of Endocrinology · doi:10.1677/joe-09-0412 · Cited by 433 · see citing works
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
Type 1 iodothyronine deiodinase in human physiology and disease
Maia, A. L., Goemann, I. M., Meyer, E. L. D. S., & Wajner, S. M. (2011) · Journal of Endocrinology · doi:10.1530/joe-10-0481 · Cited by 220 · see citing works
Gereben, B., Zeöld, A., Dentice, M., Salvatore, D., & Bianco, A. C. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-007-7396-0 · Cited by 207 · see citing works
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 Disease and the Cardiovascular System
Danzi, S. E., & Klein, I. L. (2014) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2014.02.005 · Cited by 160 · see citing works
Olivares, E. L., Marassi, M. P., Fortunato, R. S., da Silva, A. C. M., Costa-e-Sousa, R. H., Araújo, I. G., Mattos, E. C., Masuda, M. O., Mulcahey, M. A., Huang, S. A., et al. (2007) · Endocrinology · doi:10.1210/en.2007-0043 · Cited by 145 · see citing works
Rodriguez‐Perez, A., Palos‐Paz, F., Kaptein, E., Visser, T. J., Dominguez‐Gerpe, L., Alvarez‐Escudero, J., & Lado‐Abeal, J. (2008) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2007.03102.x · Cited by 110 · see citing works
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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
Reawakened interest in type III iodothyronine deiodinase in critical illness and injury
Huang, S. A., & Bianco, A. C. (2008) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0727 · Cited by 95 · see citing works
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Fisher, D. A. (2008) · Seminars in Perinatology · doi:10.1053/j.semperi.2008.09.003 · Cited by 95 · see citing works
Flowers, M. T., Keller, M. P., Choi, Y., Hong, L., Kendziorski, C. M., Ntambi, J. M., & Attie, A. (2008) · Physiological Genomics · doi:10.1152/physiolgenomics.00139.2007 · Cited by 92 · see citing works
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Laghi, F. A., Adıgüzel, N., & Tobin, M. J. (2009) · European Respiratory Journal · doi:10.1183/09031936.00103708 · Cited by 90 · see citing works
Thyroid hormone transporters in health and disease: advances in thyroid hormone deiodination
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Xu, G., Yan, W., & Li, J. (2014) · Clinical and Experimental Nephrology · doi:10.1007/s10157-014-0974-1 · Cited by 33 · see citing works
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Kwakkel, J., Chassande, O., van Beeren, H. C., Wiersinga, W. M., & Boelen, A. (2008) · Journal of Endocrinology · doi:10.1677/joe-07-0601 · Cited by 26 · see citing works
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Boelen, A., Wiersinga, W. M., & Köhrle, J. (2006) · Current Opinion in Endocrinology & Diabetes · doi:10.1097/01.med.0000244227.21776.70 · Cited by 9 · see citing works
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
Yaglova, N. V. (2011) · Bulletin of Experimental Biology and Medicine · doi:10.1007/s10517-011-1501-y · Cited by 6 · see citing works
Huang, S. A., & Castroneves, L. A. (2010) · Endocrine updates · doi:10.1007/978-1-4419-1485-9_1 · Cited by 5 · see citing works
Παππά, Θ., & Alevizaki, M. K. (2018) · Endocrinology · doi:10.1007/978-3-319-45013-1_26 · Cited by 5 · see citing works
Thyroid Abnormalities in Heart Failure
Danzi, S. E., & Klein, I. L. (2022) · Cardiology Clinics · doi:10.1016/j.ccl.2021.12.002 · Cited by 4 · see citing works
Danzi, S. E., & Klein, I. L. (2009) · Springer eBooks · doi:10.1007/978-88-470-1143-4_10 · Cited by 4 · see citing works
Martocchia, A., Cola, S., Frugoni, P., Indiano, I., D’URSO, R., & Falaschi, P. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.05291.x · Cited by 2 · see citing works
Changes Within the Thyroid Axis During the Course of Critical Illness
Mebis, L., Langouche, L., & den Berghe, G. V. (2008) · Humana Press eBooks · doi:10.1007/978-1-60327-177-6_10 · Cited by 2 · see citing works
NON-THYROIDAL ILLNESS SYNDROME IN PATIENTS WITH CHRONIC HEPATITIS OF NON-VIRAL ETHIOLOGY
Chympoi, K., Olinik, O. Y., Teleki, Y., Palibroda, N. M., & Patratiy, M. V. (2018) · CBU International Conference Proceedings · doi:10.12955/cbup.v6.1266 · Cited by 1 · see citing works
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Abramova, N., & Pashkovska, N. V. (2017) · Likarska sprava · doi:10.31640/ls-2017(1-2)04 · Cited by 1 · see citing works
Παππά, Θ., & Alevizaki, M. K. (2017) · Endocrinology · doi:10.1007/978-3-319-29195-6_26-1 · Cited by 1 · see citing works
Koenig, R. J. (2009) · Elsevier eBooks · doi:10.1016/b978-1-4160-4745-2.00020-1
Self-citation(2006) · Current Opinion in Endocrinology & Diabetes · doi:10.1097/01.med.0000244230.06529.0f
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- Authors
- Yu, J., & Koenig, R. J.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Koenig, Ronald J.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2006-07
- Volume
- 147
- Issue
- 7
- Pages
- 3580-3585
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2054637593
- Cited by
- 46
- References
- 36
- Citations by year
- 2025: 2 · 2022: 2 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 4 · 2015: 1 · 2014: 2 · 2012: 2
- FWCI
- 4.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (P60DK020572, R01DK044155, P60 DK 20572, R01 DK44155)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- low T3 syndrome, type 1 iodothyronine deiodinase, triiodothyronine, interleukin-1, SRC-1, cytokines, hepatic gene expression, endotoxin, adenoviral gene transfer, hepatocytes
- MeSH terms
- Animals, Cells, Cultured, Euthyroid Sick Syndromes, Iodide Peroxidase, Lipopolysaccharides, Liver, Male, Mice, Inbred C57BL, Thyroxine, Triiodothyronine, Cytokines, Hepatocytes, Mice, Rats
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