Interleukin-18, a proinflammatory cytokine, contributes to the pathogenesis of non-thyroidal illness mainly via the central part of the hypothalamus-pituitary-thyroid axis
Interleukin-18, a proinflammatory cytokine, contributes to the pathogenesis of non-thyroidal illness mainly via the central part of the hypothalamus-pituitary-thyroid axis
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DOI：
10.1530/eje.0.1510497
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发表时间：
2004-10-01
影响因子：
5.8
通讯作者：
Wiersinga, WM
中科院分区：
文献类型：
--
作者：
Boelen, A;Kwakkel, J;Wiersinga, WM
目的：用IL-6（-/-）和IL-12（-/-）小鼠进行的研究表明，促炎细胞因子参与非甲状腺疾病（NTI）的发病机制。白细胞介素（IL）-6改变外周甲状腺激素代谢，IL-12似乎参与疾病期间下丘脑-垂体-甲状腺（HPT）轴中心部分的调节。IL-18是促炎细胞因子，其与IL-12共享重要的生物学特性，例如干扰素（IFN）-γ诱导活性。设计图：通过研究IL-18（-/-）、IFN γ R（-/-）和野生型（WT）小鼠在细菌脂多糖（LPS）诱导的疾病期间HPT轴的变化，我们希望阐明IL-18和IFN γ在NTI发病机制中的假定作用。LPS诱导WT小鼠垂体1型脱碘酶（D1）活性降低（P < 0.05，ANOVA），但IL-18（-/-）小鼠无此作用，而D2活性的降低在两种品系中相似。LPS在24 h内降低IL-18（-/-）和WT小鼠血清甲状腺激素水平和肝脏D1 mRNA水平。IL-18（-/-）小鼠IL-1、IL-6和IFN γ mRNA表达明显低于WT小鼠，而IL-12 mRNA表达与WT小鼠相似。IFN γ R（-/-）小鼠垂体中基础D1活性高于WT小鼠（P < 0.05）; LPS诱导垂体中D2活性降低，但D1活性不降低，这在两种品系中相似。在肝脏中，LPS诱导的细胞因子表达增加在IFN γ R（-/-）小鼠和WT小鼠之间没有差异，血清T-3和T-4水平以及肝脏D1 mRNA的降低也相似。血清T-3和T-4以及肝脏D1 mRNA响应于LPS的相对降低在IL-18（-/-）中相似，IFN γ R（-/-）和WT小鼠，尽管肝脏细胞因子诱导发生了显著变化。然而，IL-18（-/-）小鼠中不存在LPS诱导的WT小鼠垂体中D1活性降低;相反，LPS未降低IFN γ R（-/-）小鼠或其WT中垂体D1活性，这可能是由于小鼠的遗传背景所致。我们的研究结果表明，IL-18也参与疾病期间HPT轴的中央部分的调节。
Objective: Proinflammatory cytokines are involved in the pathogenesis of non-thyroidal illness (NTI), its 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. Design: 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 24h similarly in IL-18(-/-), and WT mice. The expression of IL-1, IL-6 and IFNgamma mRNA expression was sipificantly 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 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(-/-), 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.