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DOI: 10.1055/s-2004-814219
Contribution of Interleukin-12 to the Pathogenesis of Non-thyroidal Illness
Publikationsverlauf
Received 25 March 2003
Accepted after revision 19 August 2003
Publikationsdatum:
05. März 2004 (online)

Abstract
Changes in both central and peripheral thyroid hormone (TH) metabolism occur during illness. These changes, known collectively as non-thyroidal illness, are apparently mediated by the proinflammatory cytokines IL-6, TNFα and IFNγ. IL-12 is involved in regulation of IFNγ and TNFα. The aim of this study was to evaluate the role of IL-12 in TH metabolism during illness. We studied TH metabolism both centrally (in the pituitary) and peripherally (in the liver) in IL-12 knock-out (IL-12-/-) and wild type (WT) mice during illness induced by administration of bacterial endotoxin (LPS). LPS induced a similar decrease in serum T3, T4 and liver 5′-DI mRNA expression in IL-12-/- and WT mice with the exception of a smaller reduction of serum T4 in IL-12-/- mice. In the pituitary, the LPS-induced decline in 5′-DI activity in WT mice was not observed in IL-12-/- mice (p < 0.001), whereas the decrease in DII activity tended to be smaller in IL-12-/- mice (p = 0.066). The lower decrease in pituitary activity of both DI and DII in IL-12-/- mice is possibly related to the lower LPS-induced T4 decrease. In conclusion, IL-12 is involved in the central regulation of the HPT axis during illness but not in the peripheral regulation.
Key words
5′-deiodinase - Pituitary - Liver - Cytokines - IL-12-/- mice
References
-
1 Wiersinga W M.
Nonthyroidal illness. In: Braverman LE, Utiger RD (eds) The Thyroid. Philadelphia; Lippincott 2000: 281-295 - 2 Docter R, Krenning E P, de Jong M, Hennemann G. The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol (Oxf). 1993; 39 499-518
- 3 Fliers E, Guldenaar S E, Wiersinga W M, Swaab D F. Decreased hypothalamic thyrotropin-releasing hormone gene expression in patients with nonthyroidal illness. J Clin Endocrinol Metab. 1997; 82 4032-4036
- 4 van der Poll T, Romijn J A, Wiersinga W M, Sauerwein H P. Tumor necrosis factor: a putative mediator of the sick euthyroid syndrome in man. J Clin Endocrinol Metab. 1990; 71 1567-1572
- 5 Stouthard J M, van der Poll T, Endert E, Bakker P J, Veenhof C H, Sauerwein H P, Romijn J A. Effects of acute and chronic interleukin-6 administration on thyroid hormone metabolism in humans. J Clin Endocrinol Metab. 1994; 79 1342-1346
- 6 Boelen A, Platvoet-ter Schiphorst M C, Wiersinga W M. Association between serum interleukin-6 and serum 3,5,3′-triiodothyronine in nonthyroidal illness. J Clin Endocrinol Metab. 1993; 77 1695-1699
- 7 Boelen A, Maas M A, Lowik C W, Platvoet M C, Wiersinga W M. Induced illness in interleukin-6 (IL-6) knock-out mice: a causal role of IL-6 in the development of the low 3,5,3′-triiodothyronine syndrome. Endocrinology. 1996; 137 5250-5254
- 8 Tang K T, Braverman L E, DeVito W J. 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; 136 881-888
- 9 Hashimoto H, Igarashi N, Miyawaki T, Sato T. Effects of tumor necrosis factor-α, interleukin-1β, and interleukin-6 on type I iodothyronine 5′-deiodination in rat thyroid cell line, FRTL-5. J Interferon Cytokine Res. 1995; 15 367-375
- 10 Ongphiphadhanakul B, Fang S L, Tang K T, Patwardhan N A, Braverman L E. Tumor necrosis factor-α decreases thyrotropin-induced 5′-deiodinase activity in FRTL-5 thyroid cells. Eur J Endocrinol. 1994; 130 502-507
- 11 Jakobs T C, 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; 146 559-566
- 12 Nagaya T, Fujieda M, Otsuka G, Yang J P, Okamoto T, Seo H. A potential role of activated NF-kappa B in the pathogenesis of euthyroid sick syndrome. J Clin Invest. 2000; 106 393-402
- 13 Na S Y, Lee S K, Han S J, Choi H S, Im S Y, Lee J W. Steroid receptor coactivator-1 interacts with the p50 subunit and coactivates nuclear factor kappaB-mediated transactivations. J Biol Chem. 1998; 273 10 831-10 834
- 14 Yu J, Koenig R J. 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 38 296-38 301
- 15 Ramadori G, Christ B. Cytokines and the hepatic acute-phase response. Semin Liver Dis. 1999; 19 141-155
- 16 Fasshauer M, Klein J, Lossner U, Paschke R. Interleukin (IL)-6 mRNA expression is stimulated by insulin, isoprotererenol, tumour necrosis factor alpha, growth hormone, and IL-6 in 3T3-L1 adipocytes. Horm Metab Res. 2003; 35 147-152
- 17 Trinchieri G. Interleukin-12: a cytokine at the interface of inflammation and immunity. Adv Immunol. 1998; 70 83-243
- 18 Wiersinga W M, Chopra I J. Radioimmunoassay of thyroxine (T4), 3,5,3′-triiodothyronine (T3), 3,3′,5′-triiodothyronine (reverse T3, rT3), and 3,3′-diiodothyronine (T2). Methods Enzymol. 1982; 84 272-303
- 19 Sweet M J, Leung B P, Kang D, Sogaard M, Schulz K, Trajkovic V, Campbell C C, Xu D, Liew F Y. A novel pathway regulating lipopolysaccharide-induced shock by ST2/T1 via inhibition of Toll-like receptor 4 expression. J Immunol. 2001; 166 6633-6639
- 20 Bouaboula M, Legoux P, Pessegue B, Delpech B, Dumont X, Piechaczyk M, Casellas P, Shire D. Standardization of mRNA titration using a polymerase chain reaction method involving co-amplification with a multispecific internal control. J Biol Chem. 1992; 267 21 830-21 838
- 21 Köhrle J, Rasmussen U B, Rokos H, Leonard J L, Hesch R D. Selective affinity labeling of a 27-kDa integral membrane protein in rat liver and kidney with N-bromoacetyl derivatives of L-thyroxine and 3,5,3′-triiodo-L-thyronine. J Biol Chem. 1990; 265 6146-6154
- 22 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; 167 505-515
- 23 O’Mara B A, Dittrich W, Lauterio T J, St Germain D L. Pretranslational regulation of type I 5′-deiodinase by thyroid hormones and in fasted and diabetic rats. Endocrinology. 1993; 133 1715-1723
- 24 Boelen A, Platvoet-ter Schiphorst M C, Bakker O, Wiersinga W M. The role of cytokines in the lipopolysaccharide-induced sick euthyroid syndrome in mice. J Endocrinol. 1995; 146 475-483
- 25 Davies P H, Sheppard M C, Franklyn J A. Inflammatory cytokines and type I 5′-deiodinase expression in phi1 rat liver cells. Mol Cell Endocrinol. 1997; 129 191-198
- 26 Köhrle J. Local activation and inactivation of thyroid hormones: the deiodinase family. Mol Cell Endocrinol. 1999; 151 103-119
- 27 Köhrle J. The selenoenzyme family of deiodinase isozymes controls local thyroid hormone availability. Rev Endocr Metab Disord. 2000; 1 49-58
- 28 Baur A, Buchfelder M, Köhrle J. Expression of 5′-deiodinase enzymes in normal pituitaries and in various human pituitary adenomas. Eur J Endocrinol. 2002; 147 263-268
- 29 Nakahira M, Ahn H J, Park W R, Gao P, Tomura M, Park C S, Hamaoka T, Ohta T, Kurimoto M, Fujiwara H. Synergy of IL-12 and IL-18 for IFN-gamma gene expression: IL-12-induced STAT4 contributes to IFN-gamma promoter activation by up-regulating the binding activity of IL-18-induced activator protein 1. J Immunol. 2002; 168 1146-1153
- 30 Zhou Y C, Waxman D J. STAT5b down-regulates peroxisome proliferator-activated receptorα transcription by inhibition of ligand-independent activation function region-1 trans-activation domain. J Biol Chem. 1999; 274 29 874-29 882
- 31 Forrest D, Reh T A, Rusch A. Neurodevelopmental control by thyroid hormone receptors. Curr Opin Neurobiol. 2002; 12 49-56
Dr. A. Boelen
Department of Endocrinology & Metabolism · F5-171, Academic Medical Center ·
Meibergdreef 9 · 1105 AZ Amsterdam · The Netherlands
Telefon: + 31 (20) 566 57 49 ·
eMail: a.boelen@amc.uva.nl