Serum concentrations of proinflammatory cytokines in Graves' disease: effect of treatment, thyroid function, ophthalmopathy and cigarette smoking.
OBJECTIVE
In the present study we have measured the concentrations of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and IL-1 receptor antagonist (IL-1Ra) in the serum of patients with Graves' disease (GD). By multivariate analysis, we have evaluated the effect of antithyroid treatment, thyroid function, the presence or absence of active thyroid-associated ophthalmopathy (TAO), the patient's smoking habits and the relation to circulating anti-thyrotropin (TSH) receptor (TRAb) and anti-thyroperoxidase antibodies (TPOAb).


METHODS
We studied 84 GD patients, 51 untreated and 33 receiving methimazole (MMI) therapy. Twenty-three (45%) untreated patients and 18 (54%) patients on MMI had active TAO. We also studied 67 normal subjects as controls. Thirty-one GD patients (43%) and 16 controls (36%) were smokers.


RESULTS
Serum IL-6 concentrations were significantly higher in both untreated patients (P<0.001) and treated patients (P<0.006), when compared with controls. Serum sIL-6R concentrations were significantly affected by treatment (P=0.001). Serum IL-1Ra concentrations were not different in GD patients, whether treated or untreated, compared with controls. Serum IL-6 concentrations were not influenced by thyroid function and there was a significant interaction between treatment and the presence of active TAO (P=0.003). In hyperthyroid patients with active TAO serum, sIL-6R concentrations were significantly higher than in those with inactive TAO (P=0.003). In untreated GD patients there was no significant effect of thyroid function and TAO activity on the serum concentrations of TNF-alpha and IL-1 beta. Serum IL-1Ra concentrations were not affected by the presence of TAO. Smoking had no effect on serum IL-6, sIL-6R, TNF-alpha, IL-1 beta and IL-1Ra concentrations, even in the presence of an active TAO. Serum concentrations of IL-6, sIL-6R, TNF-alpha and IL-1 beta and IL-1Ra were not different in patients with and without TRAb or TPOAb, in relation to either thyroid function, TAO activity or smoking.


CONCLUSIONS
Our work shows that: (i) the proinflammatory cytokine pattern in GD is greatly influenced by antithyroid drug treatment; (ii) the increased circulating IL-6/sIL-6R concentrations observed in patients with active TAO may derive from the activation of humoral reactions in sites other than the thyroid; and, (iii) cigarette smoking has no effect on serum IL-1/IL-1Ra concentrations in TAO.
Centro per lo Studio, Prevenzione, Diagnosi e Cura delle Tireopatie, Istituto di Clinica Medica Generale, UniversitA degli Studi di Parma, Parma, Italy.
M
M
Salvi
M
M
Pedrazzoni
G
G
Girasole
N
N
Giuliani
R
R
Minelli
J R
JR
Wall
E
E
Roti
D000293:Adolescent; D000328:Adult; D000368:Aged; D013956:Antithyroid Agents / Q000627:therapeutic use; D001323:Autoantibodies / Q000097:blood; D016207:Cytokines / Q000097:blood*; D005128:Eye Diseases / Q000150:complications; D005260:Female; D006111:Graves Disease / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007453:Iodide Peroxidase / Q000276:immunology; D008297:Male; D008713:Methimazole / Q000627:therapeutic use; D008875:Middle Aged; D017472:Receptors, Interleukin-1 / Q000097:blood; D019947:Receptors, Interleukin-6 / Q000097:blood; D011989:Receptors, Thyrotropin / Q000276:immunology; D012795:Sialoglycoproteins / Q000097:blood; D012907:Smoking; D012995:Solubility; D013961:Thyroid Gland / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D013956:Antithyroid Agents; D001323:Autoantibodies; D016207:Cytokines; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D017472:Receptors, Interleukin-1; D019947:Receptors, Interleukin-6; D011989:Receptors, Thyrotropin; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D008713:Methimazole; D007453:Iodide Peroxidase