Evaluation of novel parathyroid hormone analogs using a bovine renal membrane receptor binding assay

To elucidate the mechanism by which low T₃ and low T₄ syndrome occurs in patients with acute or chronic infection or malignancy, recombinant human tumor necrosis factor-α (TNF-α)/cachectin (TNF) was administered ip to mice and thyroid hormone metabolism was studied. Since administration of TNF caused a decrease in food intake and body weight, all experiments were performed using pair-fed control (PFC) mice. Administration of TNF at a dose of 1â€100 Mg/day for 3 days decreased serum T₄, T₃, and rT₃ concentrations in a dosedependent manner. In PFC mice, serum T₄ and T₃ also decreased, but rT₃ was significantly increased. T₃/T₄ ratio was greater in TNF-treated mice than in PFC mice. Type I iodothyronine- 5′-deiodinating activity in the liver was significantly decreased in PFC mice but not in TNF-treated mice. The effect of TNF was reversible and could be abolished by boiling the cytokine. Furthermore, T₃ and T₄ response to TSH was greatly diminished in TNF-treated mice in comparison with PFC mice. These findings suggest that TNF directly inhibited the effect of TSH on the thyroid gland and decreased the serum concentrations of T₄ and T₃. Although TNF decreased food intake and body weight in TNF-treated mice, it did not decrease type 15′- deiodinating activity in the liver, resulting in a greater T₃/T₄ ratio and lower serum rT₃ concentration than those in PFC mice. W speculate that TNF is at least partly involved in the altered thyroid hormone metabolism (decreased serum T₄, T₃, and rT₃ concentrations) caused by infections in mice.