Different effects of continuous infusion of interleukin-1 and interleukin- 6 on the hypothalamic-hypophysial-thyroid axis

The cytokines interleukin-1 (IL-l) and IL-6 are thought to be important mediators in the suppression of thyroid function during nonthyroidal illness. In this study we compared the effects of IL-1 and IL-6 intiion on the hypothalamus-pituitary-thyroid axis in rats. Cytokines were administered by continuous ip infusion of 4 pg IL-la/day for 1, 2, or 7 days or of 15 rg IL-G/day for 7 days. Body weight and temperature, food and water intake, and plasma TSH, T,, free T, (FT,), Tat and corticosterone levels were measured daily, and hypothalamic pro-TRH messenger RNA (mRNA) and hypophyaial TSH/3 mRNA were determined after termination of the experiments. Compared with saline-treated controls, infusion of IL-l, but not of IL-6, produced a transient decrease in food and water intake, a transient increase in body temperature, and a prolonged decrease in body weight. Both cvtokines caused transient decreases in plasma TSH and T,, which were greater and more prolonged with Ii-1 than with IL-6, whereas they effected similar transient increases in the plasma FT, fraction. Infusion with IL-l, but not IL-6, also induced transient decreases in plasma FT, and Ts and a transient increase in plasma corticosterone. Hypothalamic pro-TRH mRNA was significantly decreased (-73%) after 7 days, but not after 1 or 2 days, of IL-l infusion and was unaffected by IL-6 infusion. Hypophysial TSHfl mRNA was significantly decreased after 2 (-62%) and 7 (-62%) days, but not after 1 day, of IL-l infusion and was unaffected by IL-6 infusion. These results are in agreement with previous findings that IL-l, more so than IL-6, directly inhibits thyroid hormone production. They also indicate that IL-l and IL-6 both decrease plasma T, binding. Furthermore, both cytokines induce an acute and dramatic decrease in plasma TSH before (IL-l) or even without (IL-6) a decrease in hypothalamic pro-TRH mRNA or hypophysial TSHfi mRNA, suggesting that the acute decrease in TSH secretion is not caused by decreased pro-TRH and TSHj3 gene expression. The TSH-suppressive effect of IL-6, either administered as such or induced by IL-1 infusion, may be due to a direct effect on the thyrotroph, whereas additional effects of IL-1 may involve changes in the hypothalamic release of somatostatin or TRH. As glucucorticoids are known to suppress hypothalamic TRH mRNA levels, it is speculated that the decrease in pro-TRH gene expression caused by prolonged infusion of IL-l is mediated by the high plasma corticosterone levels. (Endocrinology 135: 1336-1345,1994)