Interleukin-18, a proinflammatory cytokine, contributes to the pathogenesis of non-thyroidal illness mainly via the central part of the hypothalamus-pituitary-thyroid axis

Abstract

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 24 h 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 T 3 and T 4 levels and hepatic D1 mRNA was also similar. Conclusions: The relative decrease in serum T 3 and T 4 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 IL-18 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.

Toll-like receptor-MyD88 and Fc receptor pathways of mast cells mediate the thyroid dysfunctions observed during nonthyroidal illness

“…Third, the model shows that reverse T3 decreases during bacterial NTI, in contrast to the typical increase observed in patients. Previous murine studies reported that liver type I deiodinase decreases significantly between 4 and 8 h and normalizes at 24 h after LPS injection (18,19,28,29). Our reverse T3 findings suggest that type I deiodinase activity is not significantly impaired, allowing the degradation of reverse T3 to di-iodo-thyronine.…”

“…Serum T4, T3, and TSH decrease, reaching a nadir after 6 h, and then return to baseline by 15 h (16). In mice and rats, LPS induces similar systemic illness (decreased food intake and physical activity, piloerection, hypothermia, and chills) (17); release of proinflammatory cytokines, including TNF-␣, IL-6 (17), IL-12 (18), and IL-18 (19); and decreased serum T4 and T3 (up to 30 h after injection).…”

Interleukin-1β modulates endogenous thyroid hormone receptor α gene transcription in liver cells

“…The IL-1b-induced decrease of TRa1 and TRa2 in HepG2 cells was attenuated when compared with the LPS-induced changes in vivo. This is probably because LPS administration induces a number of cytokines (Boelen et al 2004a) and therefore has more effect than IL-1b alone. Studies from Jakobs et al (2002) have shown that IL-1b is the most potent cytokine to induce decreased D1 mRNA Figure 3 Relative expression of TRa1 and TRa2 mRNA in HepG2 cells after 4-h incubation with medium and 10 ng/ml IL-1b with or without 30-min preincubation with (A) 5 mg/ml actinomycin D (ActD) and (B) 10 mg/ml cycloheximide (Chx).…”

“…LPS activates NFkB and AP-1 and results in a rapid IL1b, IL-6, IL-12, and interferon (IFN)g response in the liver (Boelen et al 2004a, Palsson-McDermott & O'Neill 2004. Secondly, we studied the effects of one specific proinflammatory cytokine (IL-1b) on the endogenous expression of TRa1 and TRa2 mRNA in a liver cell line and investigated the pathways and mechanisms involved.…”

Characteristic Features of Multiple Organ Failure in Cases of Peritoneal Sepsis

“…According to the literature, the mentioned processes cause local activation of immune cells, cytokines and other inflammatory mediators (TNF, IL-1,6,8), which are able to stimulate the production of prostaglandins, free radicals, nitric oxide, which in turn is a powerful factor in adaptive processes at a cellular level [10,11].…”