Serum concentrations of proinflammatory cytokines in Graves' disease: effect of treatment, thyroid function, ophthalmopathy and cigarette smoking

Abstract

Objective: In the present study we have measured the concentrations of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), tumor necrosis factor-a (TNF-a), interleukin-1b (IL-1b) 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). Subjects: 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 signi®cantly higher in both untreated patients (P < 0.001) and treated patients (P < 0.006), when compared with controls. Serum sIL-6R concentrations were signi®cantly 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 in¯uenced by thyroid function and there was a signi®cant interaction between treatment and the presence of active TAO (P 0:003). In hyperthyroid patients with active TAO serum, sIL-6R concentrations were signi®cantly higher than in those with inactive TAO (P 0:003). In untreated GD patients there was no signi®cant effect of thyroid function and TAO activity on the serum concentrations of TNF-a and IL-1b. Serum IL-1Ra concentrations were not affected by the presence of TAO. Smoking had no effect on serum IL-6, sIL-6R, TNF-a, IL-1b and IL-1Ra concentrations, even in the presence of an active TAO. Serum concentrations of IL-6, sIL-6R, TNF-a and IL-1b 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 proin¯ammatory cytokine pattern in GD is greatly in¯uenced 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.

Increased adipose tissue secretion of interleukin-6, but not of leptin, plasminogen activator inhibitor-1 or tumour necrosis factor alpha, in Graves' hyperthyroidism

“…Except in one study (22), no effect of thyroid status on serum levels of TNF-a has been demonstrated (23)(24)(25)(26). Only a few studies on serum PAI-1 levels have been presented showing an increased level in hyperthyroidism (27) and a decreased level in severe hypothyroidism (28).…”

“…However, a prolonged effect of thyroid hormone excess still present after eight or more weeks of anti-thyroid treatment cannot be excluded. Serum concentrations of IL-6 after treatment for Graves' disease have been shown to be both unaltered (23,30) or declined (22,24). Moreover, increased serum levels of IL-6 have also been found in non-autoimmune thyrotoxicosis (22,24).…”

IL-1β Induces IL-6 Expression in Human Orbital Fibroblasts: Identification of an Anatomic-Site Specific Phenotypic Attribute Relevant to Thyroid-Associated Ophthalmopathy

“…Wahrenberg et al (24) have reported that adipose tissues from these individuals release several-fold higher levels of IL-6 than do similar tissues from control subjects. Circulating IL-6 levels have also been found to be elevated in Graves' disease (17)(18)(19)(20)(21)(22). Moreover, treatment of thyrotoxicosis fails to normalize these levels, suggesting strongly that they are a consequence of the underlying autoimmune process.…”

“…Among these, IL-6 has generated considerable interest because it has been implicated in human autoimmune diseases and multiple myeloma (15,16). IL-6 and soluble IL-6R, like several other important cytokines, have been found to be elevated in patients with Graves' disease (17)(18)(19) and those with TAO (20 -23). IL-6 protein can be detected in s.c. fat in these patients (24).…”

Neonatal Thyrotoxicosis and Persistent Pulmonary Hypertension Necessitating Extracorporeal Life Support

“…First, the hyperthyroid state increases levels of proinflammatory cytokines. [26][27][28] Transforming growth factor-␤ is associated with the inhibition of surfactant protein expression in human lung cell cultures. 8 Therefore, in the hyperthyroid state, the increase in transforming growth factor-␤ levels causes a lack of adequate surfactant production and release.…”