Interleukin-18, a proinflammatory cytokine, contributes to the pathogenesis of non-thyroidal illness mainly via the central part of the hypothalamus-pituitary-thyroid axis.
OBJECTIVE
Proinflammatory cytokines are involved in the pathogenesis of non-thyroidal illness (NTI), as shown by studies with IL-6-/- and IL-12-/- mice. Interleukin (IL)-6 changes peripheral thyroid hormone metabolism, and IL-12 seems to be involved in the regulation of the central part of the hypothalamic-pituitary-thyroid (HPT) axis during illness. IL-18 is a proinflammatory cytokine which shares important biological properties with IL-12, such as interferon (IFN)-gamma-inducing activity.


METHODS
By studying the changes in the HPT-axis during bacterial lipopolysaccharide (LPS)-induced illness in IL-18-/-, IFNgammaR-/- and wild-type (WT) mice, we wanted to unravel the putative role of IL-18 and IFNgamma in the pathogenesis of NTI.


RESULTS
LPS induced a decrease in pituitary type 1 deiodinase (D1) activity (P<0.05, ANOVA) in WT mice, but not in IL-18-/- mice, while the decrease in D2 activity was similar in both strains. LPS decreased serum thyroid hormone levels and liver D1 mRNA within 24 h similarly in IL-18-/-, and WT mice. The expression of IL-1, IL-6 and IFNgamma mRNA expression was significantly lower in IL-18-/- mice than in WT, while IL-12 mRNA expression was similar. IFNgammaR-/- mice had higher basal D1 activity in the pituitary than WT mice (P<0.05); LPS induced a decrease of D2, but not of D1, activity in the pituitary which was similar in both strains. In the liver, the LPS-induced increase in cytokine expression was not different between IFNgammaR-/- mice and WT mice, and the decrease in serum T3 and T4 levels and hepatic D1 mRNA was also similar.


CONCLUSIONS
The relative decrease in serum T3 and T4 and liver D1 mRNA in response to LPS is similar in IL-18-/-, IFNgammaR-/- and WT mice despite significant changes in hepatic cytokine induction. However, the LPS-induced decrease in D1 activity in the pituitary of WT mice is absent in IL-18-/- mice; in contrast, LPS did not decrease pituitary D1 activity in the IFNgammaR-/- mice or their WT, which might be due to the genetic background of the mice. Our results suggest that IL-18 is also involved in the regulation of the central part of the HPT axis during illness.
Department of Endocrinology, Academic Medical Center, University of Amsterdam, The Netherlands. a.boelen@amc.uva.nl
Anita
A
Boelen
Joan
J
Kwakkel
Marianne
M
Platvoet-ter Schiphorst
Birgit
B
Mentrup
Astrid
A
Baur
Josef
J
Koehrle
Wilmar M
WM
Wiersinga
D000818:Animals; D007030:Hypothalamo-Hypophyseal System / Q000276:immunology / Q000503:physiopathology*; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology; D020382:Interleukin-18 / Q000235:genetics* / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010902:Pituitary Gland / Q000276:immunology / Q000503:physiopathology*; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology; D013961:Thyroid Gland / Q000502:physiology*; D000096743:Interferon gamma Receptor
D020382:Interleukin-18; D008070:Lipopolysaccharides; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor