SUPPRESSION OF THYROTROPIN-RELEASING-HORMONE GENE-EXPRESSION BY INTERLEUKIN-1-BETA IN THE RAT - IMPLICATIONS FOR NONTHYROIDAL ILLNESS

Nonthyroidal illness is characterized by low thyroid hormone levels an d inappropriately normal or decreased TSH levels. To determine whether the hypothalamus contributes to these responses, TRH gene expression in hypophysiotropic neurons of the paraventricular nucleus (PVN) was i nvestigated using semiquantitative in situ hybridization histochemistr y in an animal model of nonthyroidal illness. Following the systemic a dministration of bacterial lipopolysaccharide (LPS; 250 mu g/100 g BW) , plasma T-4, T-3 and TSH were reduced but this was not associated wit h an increase in the content of proTRH mRNA in the PVN as occurs when plasma T-4 and T-3 concentrations fall during primary hypothyroidism. Constant infusion of human interleukin-1 beta (IL-1 beta) into the cer ebrospinal fluid also reduced plasma T-4 concentration. This persisted for the duration of the infusion but TSH. was only suppressed after 7 days of infusion when body weight had declined. By 24 h, the content of proTRH mRNA in the PVN in IL-1 beta infused animals was significant ly reduced from control values. These studies indicate that the periph eral administration of endotoxin or central administration of IL-1 bet a in the rat is associated with a proTRH mRNA content in the PVN that may be inappropriately normal or reduced for the level of circulating thyroid hormone. We propose that the inability of hypophysiotropic neu rons to induce TRH gene expression in nonthyroidal illness, when circu lating thyroid hormone levels are low, is one of several factors that contributes to the inability of the anterior pituitary to increase its secretion of TSH.