DIFFERENT EFFECTS OF CONTINUOUS-INFUSION OF INTERLEUKIN-1 AND INTERLEUKIN-6 ON THE HYPOTHALAMIC-HYPOPHYSEAL-THYROID AXIS

The cytokines interleukin-1 (IL-1) and IL-6 are thought to be importan t mediators in the suppression of thyroid function during nonthyroidal illness. In this study we compared the effects of IL-1 and IL-6 infus ion on the hypothalamus-pituitary-thyroid axis in rats. Cytokines were administered by continuous ip infusion of 4 mu g IL-1 alpha/day for 1 , 2, or 7 days or of 15 mu g IL-6/day for 7 days. Body weight and temp erature, food and water intake, and plasma TSH, T-4, free T-4 (FT4), T -3, and corticosterone levels were measured daily, and hypothalamic pr o-TRH messenger RNA (mRNA) and hypophysial TSH beta mRNA were determin ed after termination of the experiments. Compared with saline-treated controls, infusion of IL-1, but not of IL-6, produced a transient decr ease in food and water intake, a transient increase in body temperatur e, and a prolonged decrease in body weight. Both cytokines caused tran sient decreases in plasma TSH and T-4, which were greater and more pro longed with IL-1 than with IL-6, whereas they effected similar transie nt increases in the plasma FT4 fraction. Infusion with IL-1, but not I L-6, also induced transient decreases in plasma FT4 and T-3 and a tran sient increase in plasma corticosterone. Hypothalamic pro-TRH mRNA was significantly decreased (-73%) after 7 days, but not after 1 or 2 day s, of IL-1 infusion and was unaffected by IL-6 infusion. Hypophysial T SH beta mRNA was significantly decreased after 2 (-62%) and 7 (-62%) d ays, but not after 1 day, of IL-1 infusion and was unaffected by IL-6 infusion. These results are in agreement with previous findings that I L-1, more so than IL-6, directly inhibits thyroid hormone production. They also indicate that IL-1 and IL-6 both decrease plasma T-4 binding . Furthermore, both cytokines induce an acute and dramatic decrease in plasma TSH before (IL-1) or even without (IL-6) a decrease in hypotha lamic pro-TRH mRNA or hypophysial TSH beta mRNA, suggesting that the a cute decrease in TSH secretion is not caused by decreased pro-TRH and TSH beta gene expression. The TSH-suppressive effect of IL-6, either a dministered as such or induced by IL-1 infusion, may be due to a direc t effect on the thyrotroph, whereas additional effects of IL-1 may inv olve changes in the hypothalamic release of somatostatin or TRH. As gl ucucorticoids are known to suppress hypothalamic TRH mRNA levels, it i s speculated that the decrease in pro-TRH gene expression caused by pr olonged infusion of IL-1 is mediated by the high plasma corticosterone levels.