Abstract
Background
Thyroid hormones (TH) are involved in modulation of the immune system and inflammation. TH dysregulation is associated with depressive disorders. The iodothyronine deiodinases (DIOs), the key enzymes for TH synthesis, can be affected and induced by pro-inflammatory cytokines. We aimed to investigate the levels of and correlation between type 2 DIO (DIO2) and interferon-gamma (IFN-γ) in patients with recurrent depressive disorders (rDD).
Methods
Data from 91 rDD patients and 105 healthy controls were analyzed. The diagnoses are based on the ICD-10 criteria (F33.0-F33.8). Expression levels of DIO2 and IFN-γ were estimated using the method based on the polymerase chain reaction and the enzyme-linked immunosorbent assay (ELISA).
Results
The DIO2 expression on mRNA/protein levels in rDD patients (both female and males) was reduced as compared with the control subjects. No correlation between DIO2 and IFN-γ expression was observed.
Conclusion
This is the first study to reveal that one may cautiously suggest that DIO2 may be involved in the development and/or progression of rDD. The mechanisms of TH regulation on depression, however, need further investigation.
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References
Yen PM, Ando S, Feng X, Liu Y, Maruvada P, Xia X. Thyroid hormone action at the cellular, genomic and target gene levels. Mol Cell Endocrinol 2006;246(1–2):121–7.
Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev 2010;31(2):139–70.
Bianco AC, Kim BW. Deiodinases: implications of the local control of thyroid hormone action. J Clin Invest 2006;116(10):2571–9.
Bernal J, Guadaño-Ferraz A, Morte B. Thyroid hormone transporters-functions and clinical implications. Nat Rev Endocrinol 2015;11(12):690.
Köhrle J. Local activation and inactivation of thyroid hormones: the deiodinase family. Mol Cell Endocrinol 1999;151(1–2):103–19.
de Vries EM, Fliers E, Boelen A. The molecular basis of the non-thyroidal illness syndrome. J Endocrinol 2015;225(3):R67–81.
Davies PH, Black EG, Sheppard MC, Franklyn JA, Davies PH, Black EG, et al. Relation between serum interleukin-6 and thyroid hormone concentrations in 270 hospital in-patients with non-thyroidal illness. Clin Endocrinol (Oxf) 1996;44(2):199–205.
Sato K, Satoh T, Shizume K, Ozawa M, Han DC, Imamura H, et al. Inhibition of 125I organification and thyroid hormone release by interleukin-1, tumor necrosis factor-alpha, and interferon-gamma in human thyrocytes in suspension culture. J Clin Endocrinol Metab 1990;70(6):1735–43.
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):38296–383301.
Baur A, Bauer K, Jarry H, Köhrle J. Effects of proinflammatory cytokines on anterior pituitary 5′-deiodinase type I and type II. J Endocrinol 2000;167(3):505–15.
Wittmann G, Harney JW, Singru PS, Nouriel SS, Reed Larsen P, Lechan RM. Inflammation-inducible type 2 deiodinase expression in the leptomeninges, choroid plexus, and at brain blood vessels in male rodents. Endocrinology 2014;155(5):2009–19.
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):3293–300.
De Vito P, Balducci V, Leone S, Percario Z, Mangino G, Davis PJ, et al. Nongenomic effects of thyroid hormones on the immune system cells: new targets, old players. Steroids 2012;77(10):988–95.
Bauer M, Heinz A, Whybrow PC. Thyroid hormones, serotonin and mood: of synergy and significance in the adult brain. Mol Psychiatry 2002;7(2):140–56.
Bauer M, Goetz T, Glenn T, Whybrow PC. The thyroid-brain interaction in thyroid disorders and mood disorders. J Neuroendocrinol 2008;10:1011–4.
Maes M. Depression is an inflammatory disease: but cell-mediated immune activation is the key component of depression. Prog Neuropsychopharmacol Biol Psychiatry 2011;35(3):664–75.
Baumgartner A, Gräf KJ, Kürten I, Meinhold H. The hypothalamic-pituitary-thyroid axis in psychiatric patients and healthy subjects: parts 1-4. Psychiatry Res 1988;24(3):271–332.
Eker SS, Akkaya C, Sarandol A, Cangur S, Sarandol E, Kirli S. Effects of various antidepressants on serum thyroid hormone levels in patients with major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2008;32(4):955–61.
Linnoila M, Lamberg BA, Potter WZ, Gold PW, Goodwin FK. High reverse T3 levels in manic and unipolar depressed women. Psychiatry Res 1982;3(3):271–6.
Maes M, Meltzer HY, Cosyns P, Suy E, Schotte C. An evaluation of basalhypothalamic-pituitary-thyroid axis function in depression: results of a large-scaled and controlled study. Psychoneuroendocrinology 1993;18(8):607–20.
Tichomirowa MA, Keck ME, Schneider HJ, Paez-Pereda M, Renner U, Holsboer F, Stalla GK, et al. Endocrine disturbances in depression. J Endocrinol Invest 2005;28(1):89–99.
Fountoulakis KN, Kantartzis S, Siamouli M, Panagiotidis P, Kaprinis S, Iacovides A, et al. Peripheral thyroid dysfunction in depression. World J Biol Psychiatry 2006;7(3):131–7.
Bocco BM, Werneck-de-Castro JP, Oliveira KC, Fernandes GW, Fonseca TL, Nascimento BP, McAninch EA, Ricci E, Kvárta-Papp Z, Fekete C, Bernardi MM, Gereben B, Bianco AC, Ribeiro MO, et al. Type 2 deiodinase disruption in astrocytes results in anxiety-Depressive-Like behavior in male mice. Endocrinology 2016;157(9):3682–95.
Malmgaard L. Induction and regulation of IFNs during viral infections. J Interferon Cytokine Res 2004;2:439–54.
Chung F. Anti-inflammatory cytokines in asthma and allergy: interleukin-10, interleukin-12, interferon-gamma. Mediators Inflamm 2001;109(2):51–9.
Maes M, Scharpé S, Cosyns P, Meltzer H. Relationships between basal hypothalamic-pituitary-thyroid-axis activity and plasma haptoglobin levels in depression. J Psychiatr Res 1994;28(2):123–34.
Patten S. Performance of the composite international diagnostic interview short form for major depression in community and clinical samples. Chronic Dis Can 1997;18(3):109–12.
Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate- phenol — chloroform extraction. Anal Biochem 1987;162(1):156–9.
Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative CT method. Nat Protoc 2008;3(6):1101–8.
Schmidt FM, Lichtblau N, Minkwitz J, Chittka T, Thormann J, Kirkby KC, et al. Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity. J Psychiatr Res 2014;55:29–34.
Xiong GL, Prybol K, Boyle SH, Hall R, Streilein RD, Steffens DC, et al. Inflammation markers and major depressive disorder in patients with chronic heart failure: results from the sertraline against depression and heart disease in chronic heart failure study. Psychosom Med 2015;77(7):808–15.
Hocaoglu C, Kural B, Aliyazıcıoglu R, Deger O, Cengiz S. IL-1b, IL-6, IL-8, IL-10, IFN-γ, TNF-α and its relationship with lipid parameters in patients with major depression. Metab Brain Dis 2012;27(4):425–30.
Dahl J, Ormstad H, Aass HC, Malt UF, Bendz LT, Sandvik L, et al. The plasma levels of various cytokines are increased during ongoing depression and are reduced to normal levels after recovery. Psychoneuroendocrinology 2014;45:77–86.
Pollard KM, Cauvi DM, Toomey CB, Morris KV, Kono DH. Interferon-(and systemic autoimmunity. Discov Med 2013;16(87):123–31.
Aune TM, Collins PL, Collier SP, Henderson MA, Chang S. Epigenetic activation and silencing of the gene that encodes IFN-g. Front Immunol 2013;16(4):112.
Boelen A, Schiphorst MC, Wiersinga WM. Relationship between serum 3,5,3′-triiodothyronine and serum interleukin-8, interleukin-10 or interferon gamma in patients with nonthyroidal illness. J Endocrinol Invest 1996;19(7):480–3.
Boelen A, Platvoet-ter Schiphorst MC, Bakker O, Wiersinga WM. The role of cytokines in the lipopolysaccharide-induced sick euthyroid syndrome in mice. J Endocrinol 1995;146(3):475–83.
Wajner SM, Maia AL. New insights toward the acute non-Thyroidal illness syndrome. Front Endocrinol (Lausanne) 2012;26(3):8.
Kwakkel J, Fliers E, Boelen A. Illness-induced changes in thyroid hormone metabolism: focus on the tissue level. Neth J Med 2011;69(5):224–8.
Forner MA, Barriga C, Ortega E. Exercise-induced stimulation of murine macrophage phagocytosis may be mediated by thyroxine. J Appl Physiol 1996;80(3):899–903.
Han J, Wang W, Qu C, Liu R, Li W, Gao Z, et al. Role of inflammation in the process of clinical Kashin-Beck disease: latest findings and interpretations. Inflamm Res 2015;64(11):853–60.
Wen Y, Zhang F, Li C, He S, Tan W, Lei Y, et al. Gene expression analysis suggests bone development-related genes GDF5 and DIO2 are involved in the development of Kashin-Beck disease in children rather than adults. PLoS One 2014;9:e103618.
Cheng AW, Bolognesi M, Kraus VB. DIO2 modifies inflammatory responses in chondrocytes. Osteoarthr Cartil 2012;20(5):440–5.
Gałecka E, Talarowska M, Orzechowska A, Górski P, Bienkiewicz M, Szemraj J. Association of the DIO2 gene single nucleotide polymorphisms with recurrent depressive disorder. Acta Biochim 2015;62(2):297–302.
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):559–66.
Tang KT, Braverman LE, DeVito WJ. Tumor necrosis factor-alpha and interferon-gamma modulate gene expression of type I 5′-deiodinase: thyroid peroxidase, and thyroglobulin in FRTL-5 rat thyroid cells. Endocrinology 1995;136(3):881–8.
Rodriguez-Perez A, Palos-Paz F, Kaptein E, Visser TJ, Dominguez-Gerpe L, Alvarez-Escudero J, 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;689(5):821–7.
Kwakkel J, van Beeren HC, Ackermans MT, Platvoet-Ter Schiphorst M, Fliers E, et al. Skeletal muscle deiodinase type 2 regulation during illness in mice. J. Endocrinol 2009;203(2):263–70.
Zeöld A, Doleschall M, Haffner MC, Capelo LP, Menyhért J, Liposits Z, et al. Characterization of the nuclear factor-kappa B responsiveness of the human dio2 gene. Endocrinology 2006;147(9):4419–29.
de Vries EM, Kwakkel J, Eggels L, Kalsbeek A, Barrett P, Fliers E, et al. NFκB signaling is essential for the lipopolysaccharide-induced increase of type 2 deiodinase in tanycytes. Endocrinology 2014;155(5):2000–8.
Kwakkel J, Surovtseva OV, de Vries EM, Stap J, Fliers E, Boelen A. A novel role for the thyroid hormone-activating enzyme type 2 deiodinase in the inflammatory response of macrophages. Endocrinology 2014;155(7):2725–34.
Barca-Mayo O, Liao XH, DiCosmo C, Dumitrescu A, Moreno-Vinasco L, Wade MS, et al. Role of type 2 deiodinase in response to acute lung injury (ALI) in mice. Proc Natl Acad Sci U S A 2011;108(49):E1321–9.
Stipcević T, Pivac N, Kozarić-Kovacić D, Mück-Seler D. Thyroid activity in patients with major depression. Coll Antropol 2008;32(3):973–6.
Chueire VB, Romaldini JH, Ward LS. Subclinical hypothyroidism increases the risk for depression in the elderly. Arch Gerontol Geriatr 2007;44(1):21–8.
Samuels MH. Cognitive function in untreated hypothyroidism and hyperthyroidism. Curr Opin Endocrinol Diabetes Obes 2008;15(5):429–33.
Bonnin CM, Martinez-Aran A, Sanchez-Moreno J, Torrent C, Franco C, Pacchiarotti I, et al. Bipolar disorder: cognitive functioning and hypothalamic-pituitary-thyroid axis. Actas Esp Psiquiatr 2010;38(4):223–8.
Almandoz JP, Gharib H. Hypothyroidism: etiology, diagnosis, and management. Med Clin North Am 2012;96(2):203–21.
Cooper-Kazaz R, Lerer B. Efficacy and safety of triiodothyronine supplementation in patients with major depressive disorder treated with specific serotonin reuptake inhibitors. Int J Neuropsychopharmacol 2008;11(5):685–99.
Mehta D, Menke A, Binder E. Gene expression studies in major depression. Curr Psychiatry Rep 2010;12(2):135–44.
Castagna MG, Dentice M, Cantara S, Ambrosio R, Maino F, Porcelli T, Marzocchi C, Garbi C, Pacini F, Salvatore D, et al. DIO2 Thr92Ala reduces deiodinase-2 activity and serum-T3 levels in thyroid-Deficient patients. J Clin Endocrinol Metab 2017;102(5):1623–30.
Peeters RP, van den Beld AW, Attalki H, Toor Hv de Rijke YB, Kuiper GG, Lamberts SW, Janssen JA, Uitterlinden AG, Visser TJ, et al. A new polymorphism in the type II deiodinase gene is associated with circulating thyroid hormone parameters. Am J Physiol Endocrinol Metab 2005;289(1):E75–81.
Campbell S, Macqueen G. The role of the hippocampus in the pathophysiology of major depression. J Psychiatry Neurosci 2004;29(6):417–26.
Takano K, Yamasaki H, Kawabe K, Moriyama M, Nakamura Imipramine Y. induces brain-derived neurotrophic factor mRNA expression in cultured astrocytes. J Pharmacol Sci 2012;120(3):176–86.
Tordera RM, Pei Q, Sharp T. Evidence for increased expression of the vesicular glutamate transporter, VGLUT1, by a course of antidepressant treatment. J Neurochem 2005;94(4):875–83.
Arjona A, Sarkar DK. Circadian oscillations of clock genes, cytolytic factors, and cytokines in rat NK cells. J Immunol 2005;174(12):7618–24.
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Gałecka, E., Talarowska, M., Maes, M. et al. Expression levels of interferon-γ and type 2 deiodinase in patients diagnosed with recurrent depressive disorders. Pharmacol. Rep 70, 133–138 (2018). https://doi.org/10.1016/j.pharep.2017.08.009
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DOI: https://doi.org/10.1016/j.pharep.2017.08.009