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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >TNF-induced structural joint damage is mediated by IL-1
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TNF-induced structural joint damage is mediated by IL-1

机译：TNF诱导的结构性关节损伤由IL-1介导

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摘要

Blocking TNF effectively inhibits inflammation and structural damage in human rheumatoid arthritis (RA). However, so far it is unclear whether the effect of TNF is a direct one or indirect on up-regulation of other mediators. IL-1 may be one of these candidates because it has a central role in animal models of arthritis, and inhibition of IL-1 is used as a therapy of human RA. We removed the effects of IL-1 from a TNF-mediated inflammatory joint disease by crossing IL-1α and β-deficient mice (IL-1~(-/-)) with arthritic human TNF-transgenic (hTNFtg) mice. Development of synovial inflammation was almost unaffected on IL-1 deficiency, but bone erosion and osteoclast formation were significantly reduced in IL-1~(-/-)hTNFtg mice, compared with hTNFtg mice based on an intrinsic differentiation defect of IL-1-deficient monocytes. Most dramatically, however, cartilage damage was absent in IL-1~(-/-)hTNFtg mice. Chimera studies revealed that protection of cartilage is based on the loss of IL-1 on hematopoietic, but not mesenchymal, cells, leading to decreased expression of ADAMTS-5 and MMP-3. These data show that TNF-mediated cartilage damage is completely and TNF-mediated bone damage is partially dependent on IL-1, suggesting that IL-1 is a crucial mediator for inflammatory cartilage and bone degradation.
机译：阻断TNF可有效抑制类风湿关节炎（RA）的炎症和结构损伤。但是，到目前为止，尚不清楚TNF的作用是直接作用还是间接作用于其他介质的上调。 IL-1可能是这些候选药物之一，因为它在关节炎的动物模型中具有重要作用，并且将IL-1的抑制作用用于治疗人RA。我们通过将IL-1α和β缺陷型小鼠（IL-1〜（-/-））与关节炎的人TNF转基因（hTNFtg）小鼠杂交，从TNF介导的炎性关节疾病中去除了IL-1的作用。滑膜炎症的发展几乎不受IL-1缺乏的影响，但与基于IL-1固有分化缺陷的hTNFtg小鼠相比，IL-1〜（-/-）hTNFtg小鼠的骨侵蚀和破骨细胞形成明显减少。单核细胞不足。然而，最明显的是，在IL-1〜（-/-）hTNFtg小鼠中没有软骨损伤。嵌合体研究表明，软骨的保护基于造血细胞（而非间充质细胞）中IL-1的丧失，从而导致ADAMTS-5和MMP-3的表达降低。这些数据表明，TNF介导的软骨损伤是完全的，而TNF介导的骨损伤部分地依赖于IL-1，这表明IL-1是炎性软骨和骨降解的关键介质。

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