High levels of serum IL-18 promote cartilage loss through suppression of aggrecan synthesis
High levels of serum IL-18 promote cartilage loss through suppression of aggrecan synthesis
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DOI：
10.1016/j.bone.2008.01.031
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发表时间：
2008-06-01
期刊：
影响因子：
4.1
通讯作者：
Nagata, Kensei
中科院分区：
文献类型：
--
作者：
Inoue, Hidetake;Hiraoka, Koji;Nagata, Kensei
骨关节炎（CIA）与多种炎性细胞因子的作用密切相关。据报道，年龄越大，炎性细胞因子IL-18的血清水平越高。在本研究中，我们研究了长期的作用，血清IL-18在软骨损失在体内使用一种新的品系的IL-18转基因小鼠（Tg）与野生型（WT）小鼠相比。我们开发的IL-18 Tg小鼠品系在肺中组成性过量产生可溶性成熟IL-18，但在其他组织（包括关节）中不产生。这些Tg小鼠显示高水平的血清IL-18，但不是IL-1 β。在IL-18 Tg或WT小鼠的膝关节中未观察到炎性细胞、纤维性颤动或滑膜炎。然而，与对照WT小鼠相比，IL-18 Tg小鼠股骨和胫骨髁的软骨细胞构成显著减少。聚集蛋白聚糖仅在Tg小鼠关节软骨深层的少数细胞中检测到。与WT小鼠相比，Tg小鼠关节软骨细胞中聚集蛋白聚糖mRNA的表达也显著降低。与此相反，内源性IL-18 mRNA显着增加，在软骨细胞的Tg小鼠与WT小鼠相比。在Tg小鼠中IFN-γ的表达也显著增加。此外，IL-18转基因阳性的caspase-1缺陷小鼠表现出不依赖于内源性IL-1 β的关节软骨损失。在从WT小鼠分离的培养的软骨细胞中，用重组IL-18处理可剂量依赖性地抑制聚集蛋白聚糖mRNA的表达。相反，IL-18刺激内源性IL-18和IFN-γ的mRNA表达。这些结果表明，高水平的血清IL-18促进关节软骨细胞中内源性IL-18的过度表达，通过抑制聚集蛋白聚糖合成导致软骨丢失。因此，IL-18可能在骨关节炎关节软骨丧失的发病机制中起重要作用。(C)2008年爱思唯尔公司All rights reserved.
Osteoarthritis (CIA) is closely related to the function of several inflammatory cytokines. It has been reported that older age is associated with higher serum levels of the inflammatory cytokine IL-18. In the present study, we investigated the long-term role of serum IL-18 in cartilage loss in vivo using a new strain of IL-18 transgenic mouse (Tg) in comparison with wild-type (WT) mice. The IL-18 Tg mouse strain we developed constitutively overproduces soluble mature IL-18 in the lungs but not in other tissues, including joints. These Tg mice showed high levels of serum IL-18, but not IL-1 beta. No inflammatory cells, fibrillation or synovitis were observed in the knee joints of either IL-18 Tg or WT mice. However, the cartilage cellularity of the femoral and tibial condyles of IL-18 Tg mice was significantly reduced in comparison with control WT mice. Aggrecan was detected in only a few cells in the deep zone of the articular cartilage of Tg mice. The expression of aggrecan mRNA was also significantly decreased in articular chondrocytes from Tg mice when compared with WT mice. In contrast, endogenous IL-18 mRNA was significantly increased in the chondrocytes of Tg mice in comparison with WT mice. Expression of IFN-gamma was also significantly increased in the Tg mice. Moreover, IL-18 transgene-positive caspase-1-deficient mice showed articular cartilage loss that was independent of endogenous IL-1 beta. In cultured chondrocytes isolated from WT mice, the expression of aggrecan mRNA was dosage-dependently suppressed by treatment with recombinant IL-18. In contrast, IL-18 stimulated the expression of mRNA for endogenous IL-18 and IFN-gamma. These results suggest that high levels of serum IL-18 promote the overexpression of endogenous IL-18 in articular chondrocytes, resulting in cartilage loss through suppression of aggrecan synthesis. Thus IL-18 may play an important role in the pathogenesis of articular cartilage loss in osteoarthritis. (C) 2008 Elsevier Inc. All rights reserved.