THE ROLE OF CYTOKINES IN THE LIPOPOLYSACCHARIDE-INDUCED SICK EUTHYROID SYNDROME IN MICE

To evaluate the role of cytokines in the sick euthyroid syndrome, we tried to establish an animal model of non-thyroidal illness in mice by the administration of a sub-lethal dose of bacterial. endotoxin (lipopolysaccharide; LPS) which induces a variety of cytokines, including tumour necrosis factor (TNF alpha), interleukin-l (IL-1 alpha), interleukin-6 (IL-6) and interferon-gamma (IFN gamma). When compared with pair-fed controls, a single dose of LPS resulted in (a) systemic illness, (b) induction of TNF alpha and IL-6 and (c) a decrease of liver 5'-deiodinase mRNA from 4 h onwards followed by a decrease of serum tri-iodothyronine (T-3) and thyroxine (T-4) at 8 h and of serum free T-3 (fT(3)) and free T-4 (fT(4)) at 24 h; serum TSH remained unchanged. We then studied whether a single dose or a combination of IL-1 alpha, TNF alpha, IL-6 or IFN gamma could induce the sick euthyroid syndrome in mice, again using pair-fed controls. None of the cytokines except IL-1 alpha caused systemic illness, and IL-1 alpha was the only cytokine that decreased liver 5'-deiodinase mRNA transiently. IL-1 alpha, TNF alpha or IL-6 did not decrease serum T-3, T-4 and TSH, but administration of IFN gamma decreased serum T-4, T-3 and fT(3) in a dose-dependent manner without changes in serum TSH. Administration of all four cytokines together had no synergistic effects; observed changes were of a smaller magnitude than after LPS. The following conclusions were reached. (1) Administration of LPS in mice is a suitable experimental model for the acute induction of the sick euthyroid syndrome. (2) Acute administration of IL-1 alpha, TNF alpha or IL-6 in mice does not induce changes in thyroid hormones but IFN gamma results in a dose-dependent decrease of serum T-4, T-3 and fT(3) and IL-1 alpha decreases liver 5'-deiodinase mRNA transiently. (3) Combined administration of IL-1 alpha, TNF alpha, IL-6 and IFN gamma had no synergistic effects; observed changes were of a smaller magnitude than after LPS. (4) The LPS-induced sick euthyroid syndrome is currently best explained by a direct thyroidal inhibition due to IFN gamma and an extrathyroidal inhibition of liver 5'-deiodinase due to IL-1 alpha, but other still unidentified factors seem to be involved as well.