Defining therapeutic targets by using adenovirus:: Blocking NF-κB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators
Defining therapeutic targets by using adenovirus:: Blocking NF-κB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators
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DOI：
10.1073/pnas.96.10.5668
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发表时间：
1999-05-11
影响因子：
11.1
通讯作者：
Feldmann, M
中科院分区：
文献类型：
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作者：
Bondeson, J;Foxwell, B;Feldmann, M
转录因子nf - κ B在类风湿关节炎发病机制中的作用一直是一个有争议的话题。我们使用了一种腺病毒技术，通过过表达抑制亚基I kappa B α来阻断NF-kappa B，其优点是它可以用于病变组织本身，其中>90%的滑膜巨噬细胞、成纤维细胞和T细胞被感染。我们发现，与主要的抗炎介质，如IL-10和-11以及IL-1受体拮抗剂相比，在类风湿性滑膜组织中，肿瘤坏死因子α和其他促炎细胞因子的自发产生依赖于nf - κ b。更有趣的是，I κ B α过表达抑制了基质金属蛋白酶1和3的产生，而不影响它们的组织抑制剂。因此，阻断类风湿关节中的nf - κ B具有非常有益的作用，可以减少炎症反应和组织破坏。这里描述的腺病毒技术具有广泛的适用性，可以在正常细胞培养物或病变组织本身中快速测试阻断潜在治疗靶点的效果。
The role of the transcription factor NF-kappa B in the pathogenesis of rheumatoid arthritis has long been a subject of controversy. We used an adenoviral technique of blocking NF-kappa B through overexpression of the inhibitory subunit I kappa B alpha, which has the advantage that it can be used in the diseased tissue itself, with >90% of the synovial macrophages, fibroblasts, and T cells infected. We found that the spontaneous production of tumor necrosis factor alpha and other pro-inflammatory cytokines is NF-kappa B-dependent in rheumatoid synovial tissue, in contrast to the main anti-inflammatory mediators, like IL-10 and -11, and the IL-1 receptor antagonist. Of even more interest, I kappa B alpha overexpression inhibited the production of matrix metalloproteinases 1 and 3 while not affecting their tissue inhibitor. Blocking NF-kappa B in the rheumatoid joint thus has a very beneficial profile, reducing both the inflammatory response and the tissue destruction. The adenoviral technique described here has widespread applicability, allowing rapid testing of the effects of blocking a potential therapeutic target in either cultures of normal cells or in the diseased tissue itself.