IMMUNONEUTRALIZATION OF INTERLEUKIN-1, TUMOR-NECROSIS-FACTOR, INTERLEUKIN-6 OR INTERFERON DOES NOT PREVENT THE LPS-INDUCED SICK EUTHYROID SYNDROME IN MICE

The sick euthyroid syndrome is a state of altered thyroid hormone meta bolism which occurs during illness. The pathogenesis is incompletely u nderstood but recent studies indicate a role of cytokines. It is unkno wn if cytokines released during illness are directly responsible for t he changes in thyroid hormone metabolism. Therefore we studied if prev ious immunoneutralization of cytokines can prevent endotoxin (lipopoly saccharide LPS), induced sick euthyroid syndrome. LPS administration r esulted in systemic illness, an increase in necrosis factor (TNF alpha ) serum tumor and interleukin (IL)-6 and a decrease in serum triiodoth yronine (T-3) and thyroxine (T-4). Immunoneutralization of the effects of cytokines was accomplished by administration of monoclonal antibod ies against mouse IL-1 type-1 receptor (IL-1R), TNF alpha, IL-6 or int erferon (IFN gamma) prior to LPS. The LPS-induced release of cytokines was affected by previous immunoneutralization as compared with contro l experiments with normal immunoglobulin (IgG): anti-IL-1R did not aff ect serum TNF alpha but decreased serum IL-6, anti-TNF alpha decreased serum TNF alpha but not IL-6, anti-IL-6 did not affect serum TNF alph a but hugely increased IL-6 and anti-IFN gamma decreased both serum TN F alpha and IL-6. Specific immunoneutralization of IL-1, TNF alpha or IFN gamma did not prevent the LPS-induced decrease In serum T-3, T-4 a nd liver 5'-deiodinase mRNA. However, immunoneutralization of IL-6, al though not preventing the fall in serum T-3 and T-4, did mitigate the LPS-induced decrease in Liver 5'-deiodinase mRNA. In view of possible non-specific effects of the huge dose of immunoglobulins (1 mg), used only in the immunoneutralization of IL-6, we repeated the experiment w ith F(ab')(2) fragments of anti-IL-6 antibodies. Compared with F(ab')( 2) fragments of control IgG, anti-IL-6 F(ab')(2) did not affect the LP S-induced rise in serum TNF alpha or the decrease in serum T-3 and T-4 and liver 5'-deiodinase levels induced by LPS were, more rapidly from the circulation when anti-IL-6 F(ab'), fragments rather than intact a nti-IL-6 were administered. In conclusion, immunoneutralization of IL- 1, TNF alpha or IFN gamma did not prevent the LPS-induced sick euthyro id syndrome in mice; immunoneutralization of IL-6, however, transientl y inhibits the LPS-induced decrease of liver 5'-deiodinase mRNA.