Download PDF
Horm Metab Res 2012; 44(13): 957-961
DOI: 10.1055/s-0032-1316352
Humans, Clinical
© Georg Thieme Verlag KG Stuttgart · New York

Circulating CXCL9 and CXCL10 as Markers of Activity of Graves’ Orbitopathy During Treatment with Corticosteroids and Teleradiotherapy

J. Mysliwiec
1   Department of Endocrinology, Diabetology and Internal Diseases, Medical University of Bialystok, Bialystok, Poland
,
I. Palyga
2   Department of Endocrinology, Holycross Cancer Center, Kielce, Poland
,
M. Kosciuszko
1   Department of Endocrinology, Diabetology and Internal Diseases, Medical University of Bialystok, Bialystok, Poland
,
A. Kowalska
2   Department of Endocrinology, Holycross Cancer Center, Kielce, Poland
,
M. Gorska
1   Department of Endocrinology, Diabetology and Internal Diseases, Medical University of Bialystok, Bialystok, Poland
› Author Affiliations
Further Information

Publication History

received 31 March 2012

accepted 04 June 2012

Publication Date:
29 June 2012 (online)

Also available at
    Permissions and Reprints

Abstract

The aim of the study was to assess the usefulness of circulating chemokines CXCL9 and CXCL10 measurements as surrogate markers of GO activity and as a guideline in therapeutic decision-making. Forty-two individuals were divided into 4 groups: 1. 15 euthyroid patients with clinical symptoms of orbitopathy (GO) who underwent corticosteroid therapy consisting of intravenous infusions of methylprednisolone (MP) and teleradiotherapy (TR); 2. 10 patients with hyperthyroid GD (Gtx); 3. 10 patients with GD in euthyreosis (Geu); and 4. 7 healthy volunteers age and sex-matched to groups 1–3. The serum samples were collected 24 h before MP, 24 h after first dose of MP, before TR and at the end of therapy. Serum CXCL9 and CXCL10 were determined by ELISA and TSH-Rab by RIA. There were significant reductions in CXCL9 and CXCL10 serum concentrations during CS and TR treatment as compared both to control group and to basal values in GO patients. Moreover, CXCL9 concentration was significantly diminished in comparison to controls in GO patients who were identified later as corticosteroid-respondent (p<0.001). In this latter group of patients, CXCL9 was also found to be significantly reduced 24 h after first dose of MP as compared to non-respondents (p<0.02). The high-degree positive correlation between CXCL9 and CXCL10 was found (R=0.8; p<0.001). Our results suggest that the increased concentrations of CXCL9 (and CXCL10), at least in part, reflect the activity of orbital inflammation and therefore these chemokines could serve as a guideline in therapeutic decision-making in patients with Graves’ orbitopathy.

Key words

chemokines - CXCR3 - Graves’ disease - ophthalmopathy
 

  • References

  • 1 Consensus statement of the European Group on Graves’ orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol 2008; 158: 273-285
    CrossrefPubMedGoogle Scholar
  • 2 Adams DH, Shaw S. Leukocyte-endothelial interactions and regulation of leukocyte migration. Lancet 1998; 343: 831-836
    PubMedGoogle Scholar
  • 3 Butcher EC, Picker LJ. Lymphocyte homing and homeostasis. Science 1996; 272: 60-66
    CrossrefPubMedGoogle Scholar
  • 4 Rotondi M, Romagnani P, Brozzetti A, Santeusanio F, Serio M, Falorni A. Serum concentrations of the interferon-inducible chemokine IP-10/CXCL10 are augmented in both newly-diagnosed type I diabetes mellitus patients and subjects at risk of developing the disease. Diabetologia 2003; 46: 1020-1021
    CrossrefPubMedGoogle Scholar
  • 5 Lazzeri E, Romagnani P. CXCR3-binding chemokines: novel multifunctional therapeutic targets. Curr Drug Targets Immune Endocr Metabol Disord 2005; 5: 109-118
    CrossrefPubMedGoogle Scholar
  • 6 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
    CrossrefPubMedGoogle Scholar
  • 7 Antonelli A, Ferrari SM, Fallahi P, Frascerra S, Santini E, Franceschini SS, Ferrannini E. Monokine induced by interferon gamma (IFNgamma) (CXCL9) and IFNgamma inducible T-cell alpha-chemoattractant (CXCL11) involvement in Graves’ disease and ophthalmopathy: modulation by peroxisome proliferator-activated receptor-gamma agonists. J Clin Endocrinol Metab 2009; 94: 1803-1809
    CrossrefPubMedGoogle Scholar
  • 8 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Antonelli A, Rotondi M, Fallahi P, Romagnani P, Ferrari S, Paolicchi A, Ferrannini E, Serio M. Increase of interferon-γ inducible chemokine CXCL10 but not chemokine CCL2 serum levels in chronic autoimmune thyroiditis. Eur J Endocrinol 2005; 152: 171-177
    CrossrefPubMedGoogle Scholar
  • 10 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-γ-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
    CrossrefPubMedGoogle Scholar
  • 11 Butera D, Marukian S, Iwamaye AE, Hembrador E, Chambers TJ, Di Bisceglie AM, Charles ED, Talal AH, Jacobson IM, Rice CM, Dustin LB. Plasma chemokine levels correlate with the outcome of antiviral therapy in patients with hepatitis C. Blood 2005; 106: 1175-1182
    CrossrefPubMedGoogle Scholar
  • 12 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 serum levels of IP-10/CXCL10 in the serum of subjects with recent onset Graves’ disease. Am J Pathol 2002; 161: 195-206
    CrossrefPubMedGoogle Scholar
  • 13 Antonelli A, Rotondi M, Fallahi P, Romagnani P, Ferrari SM, Barani L, Ferrannini E, Serio M. Increase of interferon-γ-inducible CXC chemokine CXCL10 serum levels in patients with active Graves’ disease, and modulation by methimazole therapy. Clin Endocrinol (Oxf) 2006; 64: 189-195
    CrossrefPubMedGoogle Scholar
  • 14 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
    CrossrefPubMedGoogle Scholar
  • 15 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-γ inducible chemokine CXCL10 serum levels in patients with active Graves’ disease or with toxic nodular goiter. J Clin Endocrinol Metab 2007; 92: 1485-1490
    CrossrefPubMedGoogle Scholar
  • 16 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
    CrossrefPubMedGoogle Scholar
  • 17 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
    CrossrefPubMedGoogle Scholar
  • 18 Mysliwiec J, Kretowski A, Stepien A, Mironczuk K, Kinalska I. Thyrotropin receptor antibodies detected by the human recombinant TBII assay – a surrogate marker for autoimmune activity in Graves’ ophthalmopathy?. Med Sci Monit 2002; 8: MT159-MT162
    PubMedGoogle Scholar
  • 19 Eckstein AK, Plicht M, Lax H, Neuhäuser M, Mann K, Lederbogen S, Heckmann C, Esser J, Morgenthaler NG. Thyrotropin receptor autoantibodies are independent risk factors for Graves’ ophthalmopathy and help to predict severity and outcome of the disease. J Clin Endocrinol Metab 2006; 91: 3464-3470
    Google Scholar
  • 20 Antonelli A, Rotondi M, Ferrari SM, Fallahi P, Romagnani P, Franceschini SS, Serio M, Ferrannini E. Interferon-γ-inducible-chemokine CXCL10 involvement in Graves’ ophthalmopathy: modulation by peroxisome proliferator- activated receptor-agonists. J Clin Endocrinol Metab 2006; 91: 614-620
    CrossrefPubMedGoogle Scholar
  • 21 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-γ-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
    CrossrefPubMedGoogle Scholar
  • 22 Boumpas DT, Chrousos GP, Wilder RL, Cupps TR, Balow JE. Glucocorticoid therapy for immune-mediated diseases: basic and clinical correlates. Ann Intern Med 1993; 119: 1198-1208
    CrossrefPubMedGoogle Scholar
  • 23 Karin M. New twists in gene regulation by glucocorticoid receptor: is DNA binding dispensable?. Cell 1998; 93: 487-490
    CrossrefPubMedGoogle Scholar
  • 24 Franchimont D, Galon J, Gadina M, Visconti R, Zhou Y, Aringer M, Frucht DM, Chrousos GP, O’Shea JJ. Inhibition of Th1 immune response by glucocorticoids: dexamethasone selectively inhibits IL-12-induced Stat4 phosphorylation in T lymphocytes. J Immunol 2000; 164: 1768-1774
    PubMedGoogle Scholar
  • 25 Hu X, Li WP, Meng C, Ivashkiv LB. Inhibition of IFN-_signaling by glucocorticoids. J Immunol 2003; 170: 4833-4839
    CrossrefPubMedGoogle Scholar
  • 26 Bonecchi R, Bianchi G, Bordignon PP, D’Ambrosio D, Lang R, Borsatti A, Sozzani S, Allavena P, Gray PA, Mantovani A, Sinigaglia F. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med 1998; 187: 129-134
    CrossrefPubMedGoogle Scholar
  • 27 Wakelkamp IM, Gerding MN, Van Der Meer JW, Prummel MF, Wiersinga WM. Both Th1- and Th2-derived cytokines in serum are elevated in Graves’ ophthalmopathy. Clin Exp Immunol 2000; 121: 453-457
    CrossrefPubMedGoogle Scholar
  • 28 Forster G, Otto E, Hansen C, Ochs K, Kahaly G. Analysis of orbital T cells in thyroid-associated ophthalmopathy. Clin Exp Immunol 1998; 112: 427-434
    CrossrefPubMedGoogle Scholar
  • 29 Myśliwiec J, Kretowski A, Topolska J, Siewko K, Jakubczyk D, Szelachowska M, Mikita A, Kinalska I. Serum Th1 and Th2 profile cytokine level changes in patients with Graves’ ophthalmopathy treated with corticosteroids. Horm Metab Res 2001; 33: 739-743
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Hiromatsu Y, Yang D, Bednarczuk T, Miyake I, Nonaka K, Inoue Y. Cytokine profiles in eye muscle tissue and orbital fat tissue from patients with thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 2000; 85: 1194-1199
    CrossrefPubMedGoogle Scholar
  • 31 Aniszewski JP, Valyasevi RW, Bahn RS. Relationship between disease duration and predominant orbital T cell subset in Graves’ disease. J Clin Endocrinol Metab 2000; 85: 776-780
    Google Scholar