INTERLEUKIN-6 EFFECTS ON THE PITUITARY-THYROID AXIS IN THE RAT

It has been postulated recently that cytokines, and in particular interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), may have a role in the pathogenesis of the changes of serum thyroid hormone concentrations that are encountered in patients with non-thyroidal illness (NTI). Many of the IL-1 and TNF-alpha effects are believed to be mediated by the induction of IL-6 synthesis, which might, therefore, represent an important mediator of thyroid hormone changes in NTI. To address this problem, male Wistar rats were injected subcutaneously with 2.5 mu g of recombinant human IL-6 (rhIL-6, in 500 mu l of saline solution), with 2.5 mu g of rhIL-6 preincubated with 100 mu l of anti-IL-6 neutralizing antibody or with saline solution alone (control group). Administration of rhIL-6 resulted in a significant decrease of thyroxine (T-4) from 82 +/- 4 nmol/l (mean+/-SEM) to a nadir of 33 +/- 3 nmol/l (p < 0.0001) after 48 h, and of triiodothyronine (T-3) from 1.6 +/- 0.1 to 0.8 +/- 0.1 nmol/l after 48 h (p < 0.0001). A slight decrease in serum T-4 and T-3 concentrations also was observed in the control group, but the lowest values (T-4) 66 +/- 3 nmol/l; T-3, 1.2 +/- 0.1 nmol/l) were significantly higher (p < 0.0001) than in IL-6-treated rats. The IL-6-induced changes could be prevented by preincubation of rhIL-6 with its neutralizing antibody. Slight but not significant changes occurred in serum reverse T-3 (rT(3)) concentration, so that the T-4/rT(3) ratio remained substantially unchanged after rhIL-6 injection, whereas the T-4/T-3 ratio decreased significantly from 53.6 to 39.9 (p < 0.02) in IL-6-treated rats. The effects of IL-6 on thyrotropin (TSH) were investigated after rendering the rats hypothyroid by methimazole administration for 3 weeks. Serum TSH decreased from 19.0 +/- 6.8 to 13.3 +/- 3.8 mu g/l after 48 h (p < 0.01) in IL-6-treated rats, while it increased from 17.2 +/- 2.8 to 25.8 +/- 4.0 mu g/l (p < 0.01) in the control group. These results show that a single injection of rhIL-6 causes a decrease in serum T-4, T-3 and TSH concentrations in the rat, without affecting serum rT(3) levels. This is compatible with a predominantly central effect of the cytokine. The apparent lack of inhibition of 5'-deiodinating activity, a key feature of NTI, suggests that IL-6, if involved, is only one of the factors responsible for the changes of thyroid hormone secretion and metabolism observed in NTI.