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

Journal of Clinical Investigation

Volumn 121, Issue 5, 2011, Pages 1834-1845

  Wajner, Simone Magagnin ^a   Goemann, Iuri Martin ^a   Bueno, Ana Laura ^a   Larsen, P Reed ^b   Maia, Ana Luiza ^a  

^a HOSPITAL DE CLÍNICAS DE PORTO ALEGRE   (Brazil)

^b BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLCYSTEINE; GLUTATHIONE; INTERLEUKIN 6; LIOTHYRONINE; MESSENGER RNA; THYROID HORMONE; THYROXINE; THYROXINE DEIODINASE;

ARTICLE; CHRONIC DISEASE; CYTOKINE PRODUCTION; ENZYME ANALYSIS; HUMAN; HUMAN CELL; HYPOTHYROIDISM; NONTHYROIDAL ILLNESS SYNDROME; OXIDATIVE STRESS; PRIORITY JOURNAL; RNA ANALYSIS; SYNDROME;

ACETYLCYSTEINE; CELL LINE; CELL LINE, TUMOR; CYTOKINES; DITHIOTHREITOL; GLUTATHIONE; HUMANS; INTERLEUKIN-6; OXIDATIVE STRESS; REACTIVE OXYGEN SPECIES; RNA, MESSENGER; THYROID DISEASES; THYROID HORMONES; THYROXINE;

EID: 79955499181     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI44678     Document Type: Article

References (70)

1. Larsen PR, Davies TF, Schlumberger MJ, Hay IA. Thyroid physiology and diagnostic evaluation of patients with thyroid disorders. In: Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, eds. Williams Textbook of Endocrinology. Philadelphia, Pennsylvania, USA: Saunders Elsevier; 2008:439-442.
2. Adler SM, Wartofsky L. The nonthyroidal illness syndrome. Endocrinol Metab Clin North Am. 2007;36(3):657-672. (Pubitemid 47135590)
3. Peeters RP, Wouters PJ, van Toor H, Kaptein E, Visser TJ, Van den Berghe G. Serum 3,3′,5′-triiodothyronine (rT3) and 3,5,3′- triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities. J Clin Endocrinol Metab. 2005;90(8):4559-4565. (Pubitemid 41159343)
4. Iervasi G, et al. Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation. 2003;107(5):708-713. (Pubitemid 36222598)
5. Maia AL, Kim BW, Huang SA, Harney JW, Larsen PR. Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans. J Clin Invest. 2005;115(9):2524-2533. (Pubitemid 41266215)
6. Kaptein EM, Robinson WJ, Grieb DA, Nicoloff JT. Peripheral serum thyroxine, triiodothyronine and reverse triiodothyronine kinetics in the low thyroxine state of acute nonthyroidal illnesses. A noncompartmental analysis. J Clin Invest. 1982;69(3):526-535. (Pubitemid 12184948)
7. Chopra IJ. Clinical review 86: Euthyroid sick syndrome: is it a misnomer? J Clin Endocrinol Metab. 1997;82(2):329-334.
8. Peeters RP, Wouters PJ, Kaptein E, van Toor H, Visser TJ, Van den Berghe G. Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. J Clin Endocrinol Metab. 2003;88(7):3202-3211. (Pubitemid 36877495)
9. St Germain DL, Galton VA, Hernandez A. Minireview: Defining the roles of the iodothyronine deiodinases: current concepts and challenges. Endocrinology. 2009;150(3):1097-1107.
10. Rodriguez-Perez A, et al. Identification of molecular mechanisms related to nonthyroidal illness syndrome in skeletal muscle and adipose tissue from patients with septic shock. Clin Endocrinol (Oxf). 2008;68(5):821-827. (Pubitemid 351533438)
11. Mebis L, Langouche L, Visser TJ, Van den Berghe G. The type II iodothyronine deiodinase is up-regulated in skeletal muscle during prolonged critical illness. J Clin Endocrinol Metab. 2007;92(8):3330-3333. (Pubitemid 47236410)
12. Larsen PR. Type 2 iodothyronine deiodinase in human skeletal muscle: new insights into its physiological role and regulation. J Clin Endocrinol Metab. 2009;94(6):1893-1895.
13. Goswami A, Rosenberg IN. Thioredoxin stimulates enzymatic outer ring monodeiodination of reverse triiodothronine. Endocrinology. 1987;121(6):1937- 1945. (Pubitemid 18016962)
14. Sharifi J, St Germain DL. The cDNA for the type I iodothyronine 5′-deiodinase encodes an enzyme manifesting both high Km and low Km activity. Evidence that rat liver and kidney contain a single enzyme which converts thyroxine to 3,5,3′-triiodothyronine. J Biol Chem. 1992;267(18):12539-12544.
15. St Germain DL. The effects and interactions of substrates, inhibitors, and the cellular thiol-disulfide balance on the regulation of type II iodothyronine 5′- deiodinase. Endocrinology. 1988;122(5):1860-1868.
16. Goemann IM, Gereben B, Harney JW, Zhu B, Maia AL, Larsen PR. Substitution of serine for proline in the active center of type 2 iodothyronine deiodinase substantially alters its in vitro biochemical properties with dithiothreitol but not its function in intact cells. Endocrinology. 2010;151(2):821-829.
17. Bartalena L, Brogioni S, Grasso L, Velluzzi F, Martino E. Relationship of the increased serum interleukin-6 concentration to changes of thyroid function in nonthyroidal illness. J Endocrinol Invest. 1994;17(4):269-274.
18. Torpy DJ, Tsigos C, Lotsikas AJ, Defensor R, Chrousos GP, Papanicolaou DA. Acute and delayed effects of a single-dose injection of interleukin-6 on thyroid function in healthy humans. Metabolism. 1998;47(10):1289-1293. (Pubitemid 28469259)
19. Boelen A, Platvoet-Ter Schiphorst MC, Wiersinga WM. Association between serum interleukin-6 and serum 3,5,3′-triiodothyronine in nonthyroidal illness. J Clin Endocrinol Metab. 1993;77(6):1695-1699. (Pubitemid 24000937)
20. Boelen A, Platvoet-Ter Schiphorst MC, Wiersinga WM. Soluble cytokine receptors and the low 3,5,3′-triiodothyronine syndrome in patients with nonthyroidal disease. J Clin Endocrinol Metab. 1995;80(3):971-976.
21. Davies PH, Black EG, Sheppard MC, Franklyn JA. Relation between serum interleukin-6 and thyroid hormone concentrations in 270 hospital inpatients with non-thyroidal illness. Clin Endocrinol (Oxf). 1996;44(2):199-205. (Pubitemid 26042974)
22. Friberg L, Werner S, Eggertsen G, Ahnve S. Rapid down-regulation of thyroid hormones in acute myocardial infarction: is it cardioprotective in patients with angina? Arch Intern Med. 2002; 162(12):1388-1394. (Pubitemid 34655199)
23. Yu J, Koenig RJ. Regulation of hepatocyte thyroxine 5′-deiodinase by T3 and nuclear receptor coactivators as a model of the sick euthyroid syndrome. J Biol Chem. 2000;275(49):38296-38301. (Pubitemid 32009151)
24. Jakobs TC, Mentrup B, Schmutzler C, Dreher I, Köhrle J. Proinflammatory cytokines inhibit the expression and function of human type I 5′-deiodinase in HepG2 hepatocarcinoma cells. Eur J Endocrinol. 2002;146(4):559-566. (Pubitemid 34436470)
25. Inada M, et al. Estimation of thyroxine and triiodothyronine distribution and of the conversion rate of thyroxine to triiodothyronine in man. J Clin Invest. 1975;55(6):1337-1348. (Pubitemid 8036496)
26. Hosoi Y, Murakami M, Mizuma H, Ogiwara T, Imamura M, Mori M. Expression and regulation of type II iodothyronine deiodinase in cultured human skeletal muscle cells. J Clin Endocrinol Metab. 1999;84(9):3293-3300. (Pubitemid 30646958)
27. Mönig H, Arendt T, Meyer M, Kloehn S, Bewig B. Activation of the hypothalamo-pituitary-adrenal axis in response to septic or non-septic diseasesimplications for the euthyroid sick syndrome. Intensive Care Med. 1999;25(12):1402-1406. (Pubitemid 30021167)
28. Meyer EL, Goemann IM, Dora JM, Wagner MS, Maia AL. Type 2 iodothyronine deiodinase is highly expressed in medullary thyroid carcinoma. Mol Cell Endocrinol. 2008;289(1-2):16-22.
29. Curcio C, et al. The human type 2 iodothyronine deiodinase is a selenoprotein highly expressed in a mesothelioma cell line. J Biol Chem. 2001; 276(32):30183-30187.
30. Lamirand A, Pallud-Mothré S, Ramaugé M, Pierre M, Courtin F. Oxidative stress regulates type 3 deiodinase and type 2 deiodinase in cultured rat astrocytes. Endocrinology. 2008;149(7):3713-3721. (Pubitemid 351919624)
31. Meier B, et al. Human fibroblasts release reactive oxygen species in response to interleukin-1 or tumour necrosis factor-alpha. Biochem J. 1989; 263(2):539-545. (Pubitemid 19254159)
32. Haddad JJ, Land SC. Redox/ROS regulation of lipopolysaccharide-induced mitogen-activated protein kinase (MAPK) activation and MAPK-mediated TNF-alpha biosynthesis. Br J Pharmacol. 2002;135(2):520-536. (Pubitemid 34151185)
33. Rutgers M, Bonthuis F, de Herder WW, Visser TJ. Accumulation of plasma triiodothyronine sulfate in rats treated with propylthiouracil. J Clin Invest. 1987;80(3):758-762. (Pubitemid 18003947)
34. Peeters R, et al. Regional physiological adaptation of the central nervous system deiodinases to iodine deficiency. Am J Physiol Endocrinol Metab. 2001;281(1):E54-E61.
35. Baigi MG, et al. Apoptosis/necrosis switch in two different cancer cell lines: influence of benzoquinone- and hydrogen peroxide-induced oxidative stress intensity, and glutathione. Toxicol In Vitro. 2008;22(6):1547-1554.
36. Toyoda N, Harney JW, Berry MJ, Larsen PR. Identification of critical amino acids for 3,5,3′-triiodothyronine deiodination by human type 1 deiodinase based on comparative functional-structural analyses of the human, dog, and rat enzymes. J Biol Chem. 1994;269(32):20329-20334.
37. Baqui MM, Gereben B, Harney JW, Larsen PR, Bianco AC. Distinct subcellular localization of transiently expressed types 1 and 2 iodothyronine deiodinases as determined by immunofluorescence confocal microscopy. Endocrinology. 2000;141(11):4309-4312.
38. Baqui M, et al. Human type 3 iodothyronine selenodeiodinase is located in the plasma membrane and undergoes rapid internalization to endosomes. J Biol Chem. 2003;278(2):1206-1211. (Pubitemid 36790803)
39. Haddad JJ, Harb HL. L-gamma-Glutamyl-L-cysteinyl- glycine (glutathione; GSH) and GSH-related enzymes in the regulation of pro- and anti-inflammatory cytokines: a signaling transcriptional scenario for redox(y) immunologic sensor(s)? Mol Immunol. 2005;42(9):987-1014.
40. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39(1):44-84. (Pubitemid 44566469)
41. Schafer FQ, Buettner GR. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med. 2001;30(11):1191-1212. (Pubitemid 32463931)
42. Abilés J, et al. Oxidative stress is increased in critically ill patients according to antioxidant vitamins intake, independent of severity: a cohort study. Crit Care. 2006;10(5):R146.
43. Hammarqvist F, Luo JL, Cotgreave IA, Andersson K, Wernerman J. Skeletal muscle glutathione is depleted in critically ill patients. Crit Care Med. 1997;25(1):78-84.
44. Haddad JJ. Redox regulation of pro-inflammatory cytokines and IkappaB-alpha/NF-kappaB nuclear translocation and activation. Biochem Biophys Res Commun. 2002;296(4):847-856.
45. Papp LV, Lu J, Striebel F, Kennedy D, Holmgren A, Khanna KK. The redox state of SECIS binding protein 2 controls its localization and selenocysteine incorporation function. Mol Cell Biol. 2006;26(13):4895-4910. (Pubitemid 43955807)
46. Linke K, Jakob U. Not every disulfide lasts forever: disulfide bond formation as a redox switch. Antioxid Redox Signal. 2003;5(4):425-434. (Pubitemid 37087402)
47. Lu J, Holmgren A. Selenoproteins. J Biol Chem. 2009;284(2):723-727.
48. Kuiper GG, Klootwijk W, Visser TJ. Substitution of cysteine for a conserved alanine residue in the catalytic center of type II iodothyronine deiodinase alters interaction with reducing cofactor. Endocrinology. 2002;143(4):1190-1198. (Pubitemid 34274346)
49. Steinsapir J, Bianco AC, Buettner C, Harney J, Larsen PR. Substrate-induced down-regulation of human type 2 deiodinase (hD2) is mediated through proteasomal degradation and requires interaction with the enzyme's active center. Endocrinology. 2000;141(3):1127-1135. (Pubitemid 32260455)
50. Takahashi-Tezuka M, et al. Gab1 acts as an adapter molecule linking the cytokine receptor gp130 to ERK mitogen-activated protein kinase. Mol Cell Biol. 1998;18(7):4109-4117. (Pubitemid 28287934)
51. Sano M, et al. ERK and p38 MAPK, but not NFkappaB, are critically involved in reactive oxygen species-mediated induction of IL-6 by angiotensin II in cardiac fibroblasts. Circ Res. 2001; 89(8):661-669. (Pubitemid 34627065)
52. Zauberman A, Zipori D, Krupsky M, Ben-Levy R. Stress activated protein kinase p38 is involved in IL-6 induced transcriptional activation of STAT3. Oncogene. 1999;18(26):3886-3893. (Pubitemid 29358567)
53. Dimova EY, Samoylenko A, Kietzmann T. FOXO4 induces human plasminogen activator inhibitor-1 gene expression via an indirect mechanism by modulating HIF-1alpha and CREB levels. Antioxid Redox Signal. 2010;13(4):413-424.
54. Martinez-deMena R, Obregón MJ. Insulin increases the adrenergic stimulation of 5′ deiodinase activity and mRNA expression in rat brown adipocytes; role of MAPK and PI3K. J Mol Endocrinol. 2005;34(1):139-151. (Pubitemid 40305556)
55. Pekary AE, Berg L, Santini F, Chopra I, Hershman JM. Cytokines modulate type I iodothyronine deiodinase mRNA levels and enzyme activity in FRTL-5 rat thyroid cells. Mol Cell Endocrinol. 1994; 101(1-2):R31-R35. (Pubitemid 24132772)
56. Gereben B, Goncalves C, Harney JW, Larsen PR, Bianco AC. Selective proteolysis of human type 2 deiodinase: a novel ubiquitin-proteasomal mediated mechanism for regulation of hormone activation. Mol Endocrinol. 2000;14(11):1697-1708.
57. O'Mara BA, Dittrich W, Lauterio TJ, St Germain DL. Pretranslational regulation of type I 5′deiodinase by thyroid hormones and in fasted and diabetic rats. Endocrinology. 1993;133(4):1715-1723. (Pubitemid 23295200)
58. Olivares EL, et al. Thyroid function disturbance and type 3 iodothyronine deiodinase induction after myocardial infarction in rats a time course study. Endocrinology. 2007;148(10):4786-4792. (Pubitemid 47481559)
59. Kwakkel J, et al. Skeletal muscle deiodinase type 2 regulation during illness in mice. J Endocrinol. 2009;203(2):263-270.
60. Redout EM, et al. Antioxidant treatment attenuates pulmonary arterial hypertension-induced heart failure. Am J Physiol Heart Circ Physiol. 2010; 298(3):H1038-H1047.
61. Meister A, Anderson ME. Glutathione. Annu Rev Biochem. 1983;52:711-760. (Pubitemid 13030692)
62. Everts ME, et al. Uptake of thyroxine in cultured anterior pituitary cells of euthyroid rats. Endocrinology. 1994;134(6):2490-2497. (Pubitemid 24170862)
63. Brent GA, Larsen PR, Harney JW, Koenig RJ, Moore DD. Functional characterization of the rat growth hormone promoter elements required for induction by thyroid hormone with and without a cotransfected beta type thyroid hormone receptor. J Biol Chem. 1989;264(1):178-182. (Pubitemid 19027589)
64. Verhoeven FA, Van der Putten HH, Hennemann G, Lamers JM, Visser TJ, Everts ME. Uptake of triiodothyronine and triiodothyroacetic acid in neonatal rat cardiomyocytes: effects of metabolites and analogs. J Endocrinol. 2002;173(2):247-255. (Pubitemid 34552453)
65. Dentice M, et al. The FoxO3/type 2 deiodinase pathway is required for normal mouse myogenesis and muscle regeneration. J Clin Invest. 2010; 120(11):4021-4030.
66. Marsili A, et al. Type 2 iodothyronine deiodinase levels are higher in slow-twitch than fast-twitch mouse skeletal muscle and are increased in hypothyroidism. Endocrinology. 2010;151(12):5952-5960.
67. Hernandez A, Martinez ME, Fiering S, Galton VA, St Germain D. Type 3 deiodinase is critical for the maturation and function of the thyroid axis. J Clin Invest. 2006;116(2):476-484. (Pubitemid 43228365)
68. Galton VA, Schneider MJ, Clark AS, St Germain DL. Life without thyroxine to 3,5,3′-triiodothyronine conversion: studies in mice devoid of the 5′-deiodinases. Endocrinology. 2009;150(6):2957-2963.
69. Mol JA, Visser TJ. Rapid and selective inner ring deiodination of thyroxine sulfate by rat liver deiodinase. Endocrinology. 1985;117(1):8-12. (Pubitemid 15019840)
70. Tonin AM, et al. Long-chain 3-hydroxy fatty acids accumulating in LCHAD and MTP deficiencies induce oxidative stress in rat brain. Neurochem Int. 2010;56(8):930-936.