Different effects of continuous infusion of interleukin-1 and interleukin-6 on the hypothalamic-hypophysial-thyroid axis.
The cytokines interleukin-1 (IL-1) 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 infusion on the hypothalamus-pituitary-thyroid axis in rats. Cytokines were administered by continuous ip infusion of 4 micrograms IL-1 alpha/day for 1, 2, or 7 days or of 15 micrograms IL-6/day for 7 days. Body weight and temperature, food and water intake, and plasma TSH, T4, free T4 (FT4), T3, and corticosterone levels were measured daily, and hypothalamic pro-TRH messenger RNA (mRNA) and hypophysial TSH beta mRNA were determined after termination of the experiments. Compared with saline-treated controls, infusion of IL-1, 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 cytokines caused transient decreases in plasma TSH and T4, which were greater and more prolonged with IL-1 than with IL-6, whereas they effected similar transient increases in the plasma FT4 fraction. Infusion with IL-1, but not IL-6, also induced transient decreases in plasma FT4 and T3 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-1 infusion and was unaffected by IL-6 infusion. Hypophysial TSH beta mRNA was significantly decreased after 2 (-62%) and 7 (-62%) days, 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 IL-1, more so than IL-6, directly inhibits thyroid hormone production. They also indicate that IL-1 and IL-6 both decrease plasma T4 binding. Furthermore, both cytokines induce an acute and dramatic decrease in plasma TSH before (IL-1) or even without (IL-6) a decrease in hypothalamic pro-TRH mRNA or hypophysial TSH beta mRNA, suggesting that the acute decrease in TSH secretion is not caused by decreased pro-TRH and TSH beta 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.(ABSTRACT TRUNCATED AT 400 WORDS)
van Haasteren
G A
GA
Department of Endocrinology and Reproduction, Faculty of Medicine and Health Sciences, Erasmus University, Rotterdam, The Netherlands.
van der Meer
M J
MJ
Hermus
A R
AR
Linkels
E
E
Klootwijk
W
W
Kaptein
E
E
van Toor
H
H
Sweep
C G
CG
Visser
T J
TJ
de Greef
W J
WJ
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003345:Corticosterone / Q000097:blood / Q000378:metabolism; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D015870:Gene Expression; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D007031:Hypothalamus / Q000737:chemistry; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D008473:Median Eminence / Q000737:chemistry; D010902:Pituitary Gland / Q000737:chemistry; D011498:Protein Precursors / Q000032:analysis / Q000097:blood / Q000235:genetics; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D013972:Thyrotropin / Q000097:blood / Q000235:genetics / Q000378:metabolism; D013973:Thyrotropin-Releasing Hormone / Q000032:analysis / Q000097:blood / Q000235:genetics; D013974:Thyroxine / Q000097:blood / Q000378:metabolism; D014284:Triiodothyronine / Q000097:blood / Q000378:metabolism
D007375:Interleukin-1; D015850:Interleukin-6; D011498:Protein Precursors; D012333:RNA, Messenger; D014284:Triiodothyronine; D013973:Thyrotropin-Releasing Hormone; D013972:Thyrotropin; C046418:pro-thyrotropin releasing hormone; D013974:Thyroxine; D011761:Pyrrolidonecarboxylic Acid; D003345:Corticosterone