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 and 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 investigated using semiquantitative in situ hybridization histochemistry in an animal model of nonthyroidal illness. Following the systemic administration of bacterial lipopolysaccharide (LPS; 250 micrograms/100 g BW), plasma T4, T3 and TSH were reduced but this was not associated with an increase in the content of proTRH mRNA in the PVN as occurs when plasma T4 and T3 concentrations fall during primary hypothyroidism. Constant infusion of human interleukin-1 beta (IL-1 beta) into the cerebrospinal fluid also reduced plasma T4 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 significantly reduced from control values. These studies indicate that the peripheral administration of endotoxin or central administration of IL-1 beta 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 neurons to induce TRH gene expression in nonthyroidal illness, when circulating 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.
Kakucska
I
I
Department of Medicine, New England Medical Center Hospitals, Boston, Mass 02111.
Romero
L I
LI
Clark
B D
BD
Rondeel
J M
JM
Qi
Y
Y
Alex
S
S
Emerson
C H
CH
Lechan
R M
RM
D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D017403:In Situ Hybridization; D007375:Interleukin-1 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013972:Thyrotropin / Q000097:blood; D013973:Thyrotropin-Releasing Hormone / Q000235:genetics*; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014284:Triiodothyronine; D013973:Thyrotropin-Releasing Hormone; D013972:Thyrotropin; D003346:Corticotropin-Releasing Hormone; D013974:Thyroxine