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 2/2 and IL-12 2/2 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)-g-inducing activity. Design: By studying the changes in the HPT-axis during bacterial lipopolysaccharide (LPS)-induced illness in IL-18 2/2 , IFNgR 2/2 and wild-type (WT) mice, we wanted to unravel the putative role of IL-18 and IFNg 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 2/2 mice, while the decrease in D2 activity was similar in both strains. LPS decreased serum thyroid hormone levels and liver D1 mRNA within 24h similarly in IL-18 2/2 , and WT mice. The expression of IL-1, IL-6 and IFNg mRNA expression was significantly lower in IL-18 2/2 mice than in WT, while IL-12 mRNA expression was similar. IFNgR 2/2 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 IFNgR 2/2 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 2/2 , IFNgR 2/2 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 IL18 2/2 mice; in contrast, LPS did not decrease pituitary D1 activity in the IFNgR 2/2 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.