Abstract
Chemokines are a group of small proteins that recruit different leukocyte subtypes
to sites of inflammation and play important roles in initiating and maintaining immunological
responses in autoimmune endocrine diseases including Graves’ disease (GD) and Hashimoto's
thyroiditis (HT). Previous studies have found increased gene and protein expression
of different kinds of chemokines not only within the thyroid gland but also within
thyroid cells in GD or HT patients. A few studies have determined serum levels of
chemokines, with conflicting results. We measured circulating concentrations of CCL2,
CCL5, CXCL9, and CXCL10 in patients with GD, HT, and nontoxic nodular thyroid disease
(NNT). While CCL2 and CXCL9 concentrations were comparable in patients with either
AITD or NNT, CCL5 was significantly increased in GD patients compared with HT or NNT
subjects. In contrast, CXCL10 levels were lower in patients with GD, but the difference
was statistically significant only when compared with patients with HT (p=0.0018).
Importantly, GD patients who relapsed or went into remission had significantly different
levels of CXCL9 (p=0.0252). Serum levels of CCL2, CCL5, CXCL9, and CXCL10 did not
reveal any correlation with thyroid volume; with the levels of thyrotropin (TSH),
FT3, or FT4; or with the titers of TSH receptor antibody and thyroperoxidase antibody.
These data suggest that the expression patterns of chemokines in various thyroid diseases
differ from each other, which may reflect the distinct immune responses in HT and
GD.
Key words
chemokine - Graves’ disease - Hashimoto's thyroiditis - autoantibodies
References
1
Charo IF, Ransohoff RM.
The many roles of chemokines and chemokine receptors in inflammation.
N Engl J Med.
2006;
354
610-621
2
Zlotnik A, Yoshie O, Nomiyama H.
The chemokine and chemokine receptor superfamilies and their molecular evolution.
Genome Biol.
2006;
7
243
3
Kimura1 H, Caturegli P.
Chemokine orchestration of autoimmune thyroiditis.
Thyroid.
2007;
17
1005-1010
4
Rotondi M, Chiovato L, Romagnani S, Serio M, Romagnani P.
Role of chemokines in endocrine autoimmune diseases.
Endocr Rev.
2007;
28
492-520
5
Yudkin JS.
Inflammation, obesity and the metabolic syndrome.
Horm Metab Res.
2007;
39
707-797
6
Seifarth C, Mack M, Steinlicht S, Hahn EG, Lohmann T.
Transient chemokine receptore blockade does not prevent, but may accelerated type
1 diabetes in prediabetic NOD mice.
Horm Metab Res.
2006;
38
167-171
7
Ruffini PA, Morandi P, Cabioglu N, Altundag K, Cristofanilli M.
Manipulating the chemokine-chemokine receptor network to treat cancer.
Cancer.
2007;
109
2392-2404
8
Muller A, Rotondi M, Lazzeri E, Romagnani P, Serio M.
Role for interferon-γ inducible chemokines in endocrine autoimmunity: an expanding
field.
J Endocrinol Invest.
2003;
26
177-180
9
Nicoletti F, Conget I, Mauro M Di, Marco R Di, Mazzarino MC, Bendtzen K, Messina A,
Gomis R.
Serum concentrations of the interferon-γ-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.
2002;
45
1107-1110
10
Ferrante
Jr
AW.
Obesity-induce inflammation: a metabolic dialogue in the language of inflammation.
J Intern Med.
2007;
262
408-414
11
Sell H, Eckel J.
Monocyte chemotactic protein-1 and its role in insulin resistance.
Curr Opin Lipidol.
2007;
18
258-262
12
Wong CK, Ho AWY, Tong PCY, Yeung CY, Kong APS, Lun SWM, Chan JCN, Lam CWK.
Aberrant activation profile of cytokines and mitogen-activated protein kinases in
type 2 diabetic patients with nephropathy.
Clin Exp Immunol.
2007;
149
123-131
13
Schott M, Eckstein A, Willernberg HS, Nguyen TBT, Morgenthaler NG, Scherbaum WA.
Improved prediction of relapse of Graves’ thyroitoxicosis by combined determination
of TSH receptor and thyroperoxidase antibodies.
Horm Metab Res.
2007;
39
56-61
14
Schott M, Morgenthaler NG, Fritzen R, Feldkamp J, Willenberg HS, Scherbaum WA, Seissler S.
Levels of autoantibodies against human TSH receptor predict relapse of hyperthyroidism
in Graves’ disease.
Horm Metab Res.
2004;
36
92-96
15
Liu C, Papewalis C, Domberg J, Scherbaum WA, Schott M.
Chemokines and autoimmune thyroid diseases.
Horm Metab Res.
, 2008 April 14; [Epub ahead of print]
16
Paunkovic J, Paunkovic N.
Does autoantibody-negative Graves’ disease exist? A second evaluation of the clinical
diagnosis.
Horm Metab Res.
2006;
38
53-56
17
Quadbeck B, Hoermann R, Hahn S, Roggenbuck U, Mann K, Janssen OE.
Binding, stimulating and blocking TSH receptor antibodies to the thyrotropin receptor
antibodies as predictors of relapse of Graves’ disease after withdrawal of antithyroid
treatment.
Horm Metab Res.
2005;
37
745-750
18
Weetman AP.
Cellular immune responses in autoimmune thyroid disease.
Clin Endocrinol.
2004;
61
405-413
19
Kasai K, Banba N, Motohashi S, Hattor Y, Manaka K, Shimoda SI.
Expression of monocyte chemoattractant protein-1 mRNA and protein in cultured human
thyrocytes.
FEBS Letters.
1996;
394
137-140
20
Ashhab Y, Dominguez O, Sospedra M, Roura-Mir C, Lucas-Martin A, Pujol-Borrell R.
A one-tube polymerase chain reaction protocol demonstrates CC chemokine overexpression
in Graves’ disease glands.
J Clin Endocrinol Metab.
1999;
84
2873-2882
21
Simchen C, Lehmann I, Sittig D, Steinert M, Aust G.
Expression and regulation of regulated on activation, normal T cells expressed and
secreted in thyroid tissue of patients with Graves’ disease and thyroid autonomy and
in thyroid-derived cell populations.
J Clin Endocrinol Metab.
2000;
85
4758-4764
22
Aust G, Steinert M, Kieseling S, Kamprad M, Simchen C.
Reduced expression of stromal-derived factor 1 in autonomous thyroid adenomas and
its regulation in thyroid-derived cells.
J Clin Endocrinol Metab.
2001;
86
3368-3376
23
Aust G, Steinert M, Boltze C, Kieseling A, Simchen C.
GRO-a in normal and pathological thyroid tissues and its regulation in thyroid-derived
cells.
J Endocrinol.
2001;
170
513-520
24
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
25
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
26
Kokkotou E, Marafelia P, Mantzos EI, Tritos NA.
Serum monocyte chemoattractant protein-1 is increased in chronic autoimmune thyroiditis.
Metabolism.
2002;
51
1489-1493
27
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
28
Aust G, Sittig D, Becherer L, Anderegg U, Schutz A, Lamesch P, Schmucking E.
The role of CXCR5 and its ligand CXCL13 in the compartmentalization of lymphocytes
in thyroids affected by autoimmune thyroid diseases.
Eur J Endocrinol.
2004;
150
225-234
29
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
30
Antonelli A, Rotondi M, Fallahi1 P, Romagnani P, Ferrari1 SM, Paolicchi A, Ferrannini1 E,
Serio M.
Increase of interferon-g inducible α chemokine CXCL10 but not β chemokine CCL2 serum
levels in chronic autoimmune thyroiditis.
Eur J Endocrinol.
2005;
152
171-177
31
Gianoukakis AG, Douglas RS, King CS, Cruikshank WW, Smith TJ.
Immunoglobulin G from patients with Graves’ disease induces interleukin-16 and RANTES
expression in cultured human thyrocytes: a putative mechanism for T-cell infiltration
of the thyroid in autoimmune disease.
Endocrinology.
2006;
147
1941-1949
32
Ferrer-Francesch X, Caro P, Alcalde L, Armengol MP, Ashhab Y, Lucas-Martin A, Martinez-Caceres EM,
Juan M, Pujol-Borrell R.
One-tube-PCR technique for CCL2, CCL3, CCL4 and CCL5 applied to fine needle aspiration
biopsies shows different profiles in autoimmune and non-autoimmune thyroid disorders.
J Endocrinol Invest.
2006;
29
342-349
33
Antonelli A, Rotondi M, Fallahi P, Romagnani P, Ferrari SM, Barani L, Ferrannini E,
Serio M.
Increase of interferongamma- inducible CXC chemokine CXCL10 serum levels in patients
with active Graves’ disease, and modulation by methimazole therapy.
Clin Endocrinol (Oxf).
2006;
64
189-195
34
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
35
Antonelli A, Fallahi P, Rotondi M, Ferrari SM, Serio M, Miccoli P.
Serum levels of the interferon-gammainducible alpha chemokine CXCL10 in patients with
active Graves’ disease, and modulation by methimazole therapy and thyroidectomy.
Br J Surg.
2006;
93
1226-1231
36
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
37
Aso Y, Matsuura H, Momobayashi A, Inukai Y, Sugawara N, Nakano T, Yamamoto R, Wakabayashi S,
Takebayashi K, Inukai T.
Profound reduction in T-helper (Th) 1 lymphocytes in peripheral blood from patients
with concurrent type 1 diabetes and Graves’ disease.
Endocr J.
2006;
53
377-385
38
Aust G, Krohn K, Morgenthaler NG, Schroder S, Schutz A, Edelmann J, Brylla E.
Graves’ disease and Hashimoto's thyroiditis in monozygotic twins: case study as well
as transcriptomic and immunohistological analysis of thyroid tissues.
Eur J Endocrinol.
2006;
154
13-20
39
Crescioli1 C, Cosmi L, Borgogni1 E, Santarlasci V, Gelmini1 S, Sottili1 M, Sarchielli E,
Mazzinghi1 B, Francalanci1 M, Pezzatini1 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
40
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
41
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
42
Weetman AP, Bennett GL, Wong WL.
Thyroid follicular cells produce interleukin-8.
J Clin Endocrinol Metab.
2002;
75
328-330
43
Schott M, Feldkamp J, Bathan C, Fritzen R, Scherbaum WA, Seissler J.
Detecting TSH-receptor antibodies with the recombinant TBII assay: technical and clinical
evaluation.
Horm Metab Res.
2000;
32
429-435
44
Jager W de, te Velthuis H, Prakken BJ, Kuis W, Rijkers GT.
Simultaneous detection of 15 human cytokines in a single sample of stimulated peripheral
blood mononuclear cells.
Clin Diagn Lab Immunol.
2003;
10
133-139
45
Antonelli A, Rotondi M, Fallahi P, Ferrari SM, Paolicchi A, Romagnani P, Serio M,
Ferrannini E.
Increase of CXCL chemokine CXCL10 and CC chemokine CCL2 serum levels in normal ageing.
Cytokine.
2006;
34
32-38
46
Ledur A, Fitting C, David B, Hamberger C, Cavaillon JM.
Variable estimates of cytokine levels produced by commercial ELISA kits: results using
international cytokine standards.
J Immunol Methods.
1999;
186
171-179
47
Khan SS, Smith MS, Reda D, Suffredini AF, MacCoy JP.
Multiplex bead array assays for detection of soluble cytokines: comparisons of sensitivity
and quantitative values among kits from multiple manufacturers.
Clin Cytometry.
2004;
61B
35-39
48
Liu MY, Xydakis AM, Hoogeveen RC, Jones PH, O’Brian Smith E, Nelson KW, Ballantyne CM.
Multiplexed analysis of biomarkers related to obesity and the metabolic syndrome in
human plasma, using the Luminex-100 System.
Clin Chem.
2005;
51
1102-1109
49
Christen U, MacGavern DB, Luster AD, Herrath MG von, Oldstone MB.
Among CXCR3 chemokines, IFN-γ-inducible protein of 10 kDa (CXC chemokine ligand (CXCL)
10) but not monokine induced by IFN-γ(CXCL9) imprints a pattern for the subsequent
development of autoimmune disease.
J Immunol.
2003;
171
6838-6845
1 Both authors contributed equally to this article.
Correspondence
M. SchottMD
Department of Endocrinology
Diabetes and Rheumatology
University Hospital Düsseldorf
Moorenstr. 5
40225 Düsseldorf
Germany
Phone: +49/211/811 78 10
Fax: +49/211/811 78 60
Email: matthias.schott@med.uni-duesseldorf.de