Interleukin 6 effects on the pituitary–thyroid axis in the rat

Abstract

Bartalena L, Grasso L, Brogioni S, Martino E. Interleukin 6 effects on the pituitary–thyroid axis in the rat. Eur J Endocrinol 1994;131:302–6. ISSN 0804–4643 It has been postulated recently that cytokines, and in particular interleukin 1 (IL-1) and tumor necrosis factor-α TNF-α), 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-α 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 μg of recombinant human IL-6 (rhIL-6, in 500 μl of saline solution), with 2.5 μg of rhIL-6 preincubated with 100 μl of anti-IL-6 neutralizing antibody or with saline solution alone (control group). Administration of rhIL-6 resulted in a significant decrease of thyroxine (T4) from 82 ± 4 nmol/l (mean± sem) to a nadir of 33 ± 3 nmol/l (p < 0.0001) after 48 h, and of triiodothyronine (T3) from 1.6 ± 0.1 to 0.8 ± 0.1 nmol/l after 48 h (p < 0.0001). A slight decrease in serum T4 and T3 concentrations also was observed in the control group, but the lowest values (T4, 66 ± 3 nmol/l; T3, 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 T3 (rT3) concentration, so that the T4/rT3 ratio remained substantially unchanged after rhIL-6 injection, whereas the T4/T3 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 μg/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 μg/l (p < 0.01) in the control group. These results show that a single injection of rhIL-6 causes a decrease in serum T4, T3 and TSH concentrations in the rat, without affecting serum rT3 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. Luigi Bartalena, Istituto di Endocrinologia, University of Pisa, Viale del Tirreno 64, 56018 Tirrenia-Pisa, Italy