Download PDF
Horm Metab Res 2011; 43(3): 194-199
DOI: 10.1055/s-0031-1271620
Humans, Clinical

© Georg Thieme Verlag KG Stuttgart · New York

Influence of Methimazole and Radioactive Iodine Treatment in the Serum Levels of the Chemokine CXCL10 in Hyperthyroid Patients with Graves’ Disease

A. C. Leite1 , A. B. P. Pedro1 , J. H. Romaldini1
  • 1Endocrinology Division, Hospital do Servidor Publico Estadual de São Paulo-IAMSPE, São Paulo, SP, Brazil
Further Information

Publication History

received 03.08.2010

accepted 14.12.2010

Publication Date:
31 January 2011 (online)

Also available at
    Permissions and Reprints

Abstract

The chemokine CXCL10 plays an important role in Graves’ disease (GD); however, data regarding the effectiveness of therapy are contradictory. Serum CXCL10 levels in 31 hyperthyroid patients were measured before and after establishing euthyroidism: 16 newly diagnosed GD patients received methimazole (MMI), 15 relapsed GD patients were treated with radioactive iodine (RAI), and 18 healthy subjects served as a control group. Baseline serum CXCL10 levels were higher than in controls (MMI group 144.0±48.24, RAI group 156.3±71.81 and control 71.32±26.03 pg/ml;p<0.01). In the MMI group, serum CXCL10 levels decreased following euthyroidism at 6 months (76.51±22.06 pg/ml; p<0.01) and 12 (76.42±34.07 pg/ml; p<0.01). In the RAI group, serum CXCL10 levels decreased after 3, 6, 9, and 12 months of RAI administration (82.37±55.01, 66.35±48.62, 68.76±28.87, and 74.94±49.74 pg/ml, respectively; p<0.05). Elevated serum TRAb levels in the MMI group (33.15±30.84) decreased at 6 months (14.64±16.57 IU/l; p=0.0070), whereas in the RAI group (44.61±60.66 IU/l) they increased to a peak level at 6 months (66.40±104.2 IU/l; p=0.003), which was significantly higher than those of the MMI group, but were decreased at 12 months (28.91±35.13 IU/l). Serum CXCL10 levels correlated with FT3 (r=0.48, p<0.0001), FT4 (r=0.47, p<0.0001) and TRAb (r=0.37, p=0.0014). In conclusion, these data show a relationship between serum CXCL10 and GD activity and suggest that a more complex mechanism is involved in the generation of the thyroid auto-antibodies TPOAb and TRAb.

Key words

hyperthyroidism - autoimmunity - CXC chemokines - CXL10 - autoantibodies - TSH-receptor antibodies - antibodies to thyroperoxidase

References

  • 1 Weetman AP. Graves’ disease.  N Engl J Med. 2000;  343 1236-1248
    Google Scholar
  • 2 Davies TF, Greenberg D, Tomer Y. The genetics of the autoimmune thyroid diseases.  Ann Endocrinol (Paris). 2003;  64 28-30
    Google Scholar
  • 3 Liu C, Papewalis C, Domberg J, Scherbaum WA, Schott M. Chemokines and autoimmune thyroid diseases.  Horm Metab Res. 2008;  40 361-368
    Google Scholar
  • 4 Weetman AP, McGregor AM. Autoimmune thyroid disease: further developments in our understanding.  Endocr Rev. 1994;  15 788-830
    Google Scholar
  • 5 Aniszewski JP, Valyasevi RW, Bahn RS. Relationship between disease duration and predominant orbital T cell subset in Graves’ ophthalmopathy.  J Clin Endocrinol Metab. 2000;  85 776-780
    Google Scholar
  • 6 Romagnani P, Rotondi M, Lazzeri E, Lasagni L, Francalanci M, Buonamano A, Milani S, Vitti P, Chiovato L, Tonacchera M, Bellastella A, Serio M. Expression of IP-10/CXCL10 and MIG/CXCL9 in the thyroid and increased levels of IP-10/CXCL10 in the serum of patients with recent-onset Graves’ disease.  Am J Pathol. 2002;  161 195-206
    Google Scholar
  • 7 Antonelli A, Rotondi M, Fallahi P, Romagnani P, Ferrari SM, Buonamano A, Ferrannini E, Serio M. High levels of circulating CXC chemokine ligand 10 are associated with chronic autoimmune thyroiditis and hypothyroidism.  J Clin Endocrinol Metab. 2004;  89 5496-5499
    Google Scholar
  • 8 Antonelli A, Rotondi M, Fallahi P, Romagnani P, Ferrari SM, Paolicchi A, Ferrannini E, Serio M. Increase of interferon-gamma inducible alpha chemokine CXCL10 but not beta chemokine CCL2 serum levels in chronic autoimmune thyroiditis.  Eur J Endocrinol. 2005;  152 171-177
    Google Scholar
  • 9 Garcia-Lopez MA, Sancho D, Sanchez-Madrid F, Marazuela M. Thyrocytes from autoimmune thyroid disorders produce the chemokines IP-10 and Mig and attract CXCR3+ lymphocytes.  J Clin Endocrinol Metab. 2001;  86 5008-5016
    Google Scholar
  • 10 Kemp EH, Metcalfe RA, Smith KA, Woodroofe MN, Watson PF, Weetman AP. Detection and localization of chemokine gene expression in autoimmune thyroid disease.  Clin Endocrinol (Oxf). 2003;  59 207-213
    Google Scholar
  • 11 Rossi D, Zlotnik A. The biology of chemokines and their receptors.  Annu Rev Immunol. 2000;  18 217-242
    Google Scholar
  • 12 Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity.  Immunity. 2000;  12 121-127
    Google Scholar
  • 13 Adams DH, Shaw S. Leucocyte-endothelial interactions and regulation of leucocyte migration.  Lancet. 1994;  343 831-836
    Google Scholar
  • 14 Baggiolini M. Chemokines and leukocyte traffic.  Nature. 1998;  392 565-568
    Google Scholar
  • 15 Luster AD. Chemokines – chemotactic cytokines that mediate inflammation.  N Engl J Med. 1998;  338 436-445
    Google Scholar
  • 16 Adams DH, Lloyd AR. Chemokines: leucocyte recruitment and activation cytokines.  Lancet. 1997;  349 490-495
    Google Scholar
  • 17 Rotondi M, Minelli R, Magri F, Leporati P, Romagnani P, Baroni MC, Delsignore R, Serio M, Chiovato L. Serum CXCL10 levels and occurrence of thyroid dysfunction in patients treated with interferon-alpha therapy for hepatitis C virus-related hepatitis.  Eur J Endocrinol. 2007;  156 409-414
    Google Scholar
  • 18 Braunersreuther V, Mach F, Steffens S. The specific role of chemokines in atherosclerosis.  Thromb Haemost. 2007;  97 714-721
    Google Scholar
  • 19 Romagnani P, Annunziato F, Lasagni L, Lazzeri E, Beltrame C, Francalanci M, Uguccioni M, Galli G, Cosmi L, Maurenzig L, Baggiolini M, Maggi E, Romagnani S. Cell cycle-dependent expression of CXC chemokine receptor 3 by endothelial cells mediates angiostatic activity.  J Clin Invest. 2001;  107 53-63
    Google Scholar
  • 20 Romagnani P, Lasagni L, Annunziato F, Serio M, Romagnani S. CXC chemokines: the regulatory link between inflammation and angiogenesis.  Trends Immunol. 2004;  25 201-209
    Google Scholar
  • 21 Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E, Zlotnik A. Involvement of chemokine receptors in breast cancer metastasis.  Nature. 2001;  410 50-56
    Google Scholar
  • 22 Corona G, Biagini C, Rotondi M, Bonamano A, Cremonini N, Petrone L, Conforti B, Forti G, Serio M. Correlation between, clinical, biochemical, color Doppler ultrasound thyroid parameters, and CXCL-10 in autoimmune thyroid diseases.  Endocr J. 2008;  55 345-350
    Google Scholar
  • 23 Kimura H, Caturegli P. Chemokine orchestration of autoimmune thyroiditis.  Thyroid. 2007;  17 1005-1011
    Google Scholar
  • 24 Rotondi M, Chiovato L, Romagnani S, Serio M, Romagnani P. Role of chemokines in endocrine autoimmune diseases.  Endocr Rev. 2007;  28 492-520
    Google Scholar
  • 25 Rotondi M, Lazzeri E, Romagnani P, Serio M. Role for interferon-gamma inducible chemokines in endocrine autoimmunity: an expanding field.  J Endocrinol Invest. 2003;  26 177-180
    Google Scholar
  • 26 Shigihara T, Oikawa Y, Kanazawa Y, Okubo Y, Narumi S, Saruta T, Shimada A. Significance of serum CXCL10/IP-10 level in type 1 diabetes.  J Autoimmun. 2006;  26 66-71
    Google Scholar
  • 27 Rotondi M, Falorni A, de Bellis A, Laureti S, Ferruzzi P, Romagnani P, Buonamano A, Lazzeri E, Crescioli C, Mannelli M, Santeusanio F, Bellastella A, Serio M. Elevated serum interferon-gamma-inducible chemokine-10/CXC chemokine ligand-10 in autoimmune primary adrenal insufficiency and in vitro expression in human adrenal cells primary cultures after stimulation with proinflammatory cytokines.  J Clin Endocrinol Metab. 2005;  90 2357-2363
    Google Scholar
  • 28 Weetman AP, Bennett GL, Wong WL. Thyroid follicular cells produce interleukin-8.  J Clin Endocrinol Metab. 1992;  75 328-330
    Google Scholar
  • 29 Antonelli A, Fallahi P, Rotondi M, Ferrari SM, Romagnani P, Grosso M, Ferrannini E, Serio M. Increased serum CXCL10 in Graves’ disease or autoimmune thyroiditis is not associated with hyper- or hypothyroidism per se, but is specifically sustained by the autoimmune, inflammatory process.  Eur J Endocrinol. 2006;  154 651-658
    Google Scholar
  • 30 Antonelli A, Rotondi M, Fallahi P, Romagnani P, Ferrari SM, Barani L, Ferrannini E, Serio M. Increase of interferon-gamma-inducible CXC chemokine CXCL10 serum levels in patients with active Graves' disease, and modulation by methimazole therapy.  Clin Endocrinol (Oxf). 2006;  64 189-195
    Google Scholar
  • 31 Antonelli A, Rotondi M, Ferrari SM, Fallahi P, Romagnani P, Franceschini SS, Serio M, Ferrannini E. Interferon-gamma-inducible alpha-chemokine CXCL10 involvement in Graves’ ophthalmopathy: modulation by peroxisome proliferator-activated receptor-gamma agonists.  J Clin Endocrinol Metab. 2006;  91 614-620
    Google Scholar
  • 32 Antonelli A, Fallahi P, Rotondi M, Ferrari SM, Serio M, Miccoli P. Serum levels of the interferon-gamma-inducible alpha chemokine CXCL10 in patients with active Graves’ disease, and modulation by methimazole therapy and thyroidectomy.  Br J Surg. 2006;  93 1226-1231
    Google Scholar
  • 33 Antonelli A, Rotondi M, Fallahi P, Grosso M, Boni G, Ferrari SM, Romagnani P, Serio M, Mariani G, Ferrannini E. Iodine-131 given for therapeutic purposes modulates differently interferon-gamma-inducible alpha-chemokine CXCL10 serum levels in patients with active Graves’ disease or toxic nodular goiter.  J Clin Endocrinol Metab. 2007;  92 1485-1490
    Google Scholar
  • 34 Domberg J, Liu C, Papewalis C, Pfleger C, Xu K, Willenberg HS, Hermsen D, Scherbaum WA, Schloot NC, Schott M. Circulating chemokines in patients with autoimmune thyroid diseases.  Horm Metab Res. 2008;  40 416-421
    Google Scholar
  • 35 Sakai H, Togawa Y, Fukuda G, Ito R, Miwa T, Odawara M. Serum chemokine (C-X-C motif) ligand 10 levels are elevated in patients with Graves' disease in long-term remission.  Thyroid. 2010;  20 341-342
    Google Scholar
  • 36 Marx N, Mach F, Sauty A, Leung JH, Sarafi MN, Ransohoff RM, Libby P, Plutzky J, Luster AD. Peroxisome proliferator-activated receptor-gamma activators inhibit IFN-gamma-induced expression of the T cell-active CXC chemokines IP-10, Mig, and I-TAC in human endothelial cells.  J Immunol. 2000;  164 6503-6508
    Google Scholar
  • 37 Nygaard B, Jarlov AE, Kristensen LO, Faber J. Serum levels of the cytokines IL-1beta, IL-6 and ICAM-1 after 131I-treatment of Graves' disease and nodular goiter.  Horm Metab Res. 2000;  32 283-287
    Google Scholar
  • 38 Lazarus JH, Clarke S. Use of radioiodine in the management of hyperthyroidism in the UK: development of guidelines.  Thyroid. 1997;  7 229-231
    Google Scholar
  • 39 Leslie WD, Ward L, Salamon EA, Ludwig S, Rowe RC, Cowden EA. A randomized comparison of radioiodine doses in Graves’ hyperthyroidism.  J Clin Endocrinol Metab. 2003;  88 978-983
    Google Scholar
  • 40 Blomgren H, Petrini B, Wasserman J, Schnell PO, Lundell G. Changes of the blood lymphocyte population following 131I treatment for nodular goiter.  Int J Radiat Oncol Biol Phys. 1987;  13 209-215
    Google Scholar
  • 41 Teng WP, Stark R, Munro AJ, Young SM, Borysiewicz LK, Weetman AP. Peripheral blood T cell activation after radioiodine treatment for Graves’ disease.  Acta Endocrinol (Copenh). 1990;  122 233-240
    Google Scholar
  • 42 Laurberg P. Remission of Graves’ disease during anti-thyroid drug therapy. Time to reconsider the mechanism?.  Eur J Endocrinol. 2006;  155 783-786
    Google Scholar
  • 43 Pedro AB, Romaldini JH, Takei K. Changes of Serum Cytokines in Hyperthyroid Graves’ Disease Patients at Diagnosis and during Methimazole Treatment.  Neuroimmunomodulation. 2010;  18 45-51
    Google Scholar
  • 44 Torring O, Tallstedt L, Wallin G, Lundell G, Ljunggren JG, Taube A, Saaf M, Hamberger B. Graves’ hyperthyroidism: treatment with antithyroid drugs, surgery, or radioiodine--a prospective, randomized study. Thyroid Study Group.  J Clin Endocrinol Metab. 1996;  81 2986-2993
    Google Scholar
  • 45 Crescioli C, Cosmi L, Borgogni E, Santarlasci V, Gelmini S, Sottili M, Sarchielli E, Mazzinghi B, Francalanci M, Pezzatini A, Perigli G, Vannelli GB, Annunziato F, Serio M. Methimazole inhibits CXC chemokine ligand 10 secretion in human thyrocytes.  J Endocrinol. 2007;  195 145-155
    Google Scholar
  • 46 Laurberg P, Wallin G, Tallstedt L, Abraham-Nordling M, Lundell G, Torring O. TSH-receptor autoimmunity in Graves’ disease after therapy with anti-thyroid drugs, surgery, or radioiodine: a 5-year prospective randomized study.  Eur J Endocrinol. 2008;  158 69-75
    Google Scholar
  • 47 Atkinson S, McGregor AM, Kendall-Taylor P, Peterson MM, Smith BR. Effect of radioiodine on stimulatory activity of Graves' immunoglobulins.  Clin Endocrinol (Oxf). 1982;  16 537-543
    Google Scholar
  • 48 Teng CS, Yeung RT, Khoo RK, Alagaratnam TT. A prospective study of the changes in thyrotropin binding inhibitory immunoglobulins in Graves’ disease treated by subtotal thyroidectomy or radioactive iodine.  J Clin Endocrinol Metab. 1980;  50 1005-1010
    Google Scholar
  • 49 Inukai Y, Momobayashi A, Sugawara N, Aso Y. Changes in expression of T-helper (Th) 1- and Th2-associated chemokine receptors on peripheral blood lymphocytes and plasma concentrations of their ligands, interferon-inducible protein-10 and thymus and activation-regulated chemokine, after antithyroid drug administration in hyperthyroid patients with Graves’ disease.  Eur J Endocrinol. 2007;  156 623-630
    Google Scholar
  • 50 McGregor AM, Petersen MM, McLachlan SM, Rooke P, Smith BR, Hall R. Carbimazole and the autoimmune response in Graves’ disease.  N Engl J Med. 1980;  303 302-307
    Google Scholar
  • 51 Cooper DS. Antithyroid drugs.  N Engl J Med. 2005;  352 905-917
    Google Scholar

Correspondence

J. H. Romaldini

Endocrinology Division

Hospital do Servidor Publico

Estadual de São Paulo-IAMSPE

Avenida Indianopolis, 530

042400-000 São Paulo SP

Brazil

Phone: +55/11/3253 4494

Fax: +55/11/3253 4494

Email: jhroma@netpoint.com.br

Email: alexcl@terra.com.br

      >