Signalling, inflammation and arthritis -: NF-κB and its relevance to arthritis and inflammation
Signalling, inflammation and arthritis -: NF-κB and its relevance to arthritis and inflammation
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DOI：
10.1093/rheumatology/kem298
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发表时间：
2008-05-01
期刊：
影响因子：
5.5
通讯作者：
Foxwell, B. M.
中科院分区：
文献类型：
--
作者：
Simmonds, R. E.;Foxwell, B. M.
在RA患者的滑膜细胞中，核因子-κ B（NF-κ B）通路的激活导致大量促成炎性表型的应答基因的反式激活，包括来自巨噬细胞的TNF-α、来自滑膜成纤维细胞的基质金属蛋白酶和将免疫细胞募集至炎症血管翳的趋化因子。这在很大程度上是涉及p50/p65异源二聚体的经典NF-κ B途径活化的结果。虽然已经从小鼠中相应基因的遗传缺陷中收集了关于NF-κ B在炎症中的作用的许多信息，但是在人和鼠免疫细胞和永生化细胞系之间的信号传导网络中存在重要差异。尽管在分子水平上存在这些差异，但NF-κ B在炎症中的重要性是无可争议的，并且广泛认为抑制该途径具有作为RA治疗靶点的巨大潜力。商业上的努力已经进入开发NF-κ B活化的抑制剂。然而，如果巨噬细胞产生的TNF-α不受控制，则NF-κ B活化的抑制可导致炎症恶化。重要的是，这些抑制剂在长期用于慢性炎症性疾病（如RA）之前要仔细监测。
In the synovial cells of patients with RA, activation of the nuclear factor-kappa B (NF-kappa B) pathway results in the transactivation of a multitude of responsive genes that contribute to the inflammatory phenotype, including TNF-alpha from macrophages, matrix metalloproteinases from synovial fibroblasts and chemokines that recruit immune cells to the inflamed pannus. This is largely a consequence of activation of the canonical NF-kappa B pathway that involves heterodimers of p50/p65. Whilst much information on the role of NF-kappa B in inflammation has been gleaned from genetic deficiency of the respective genes in mice, important differences exist in the signalling networks between human and murine immune cells and immortalized cell lines. Despite these differences at the molecular level, the importance of NF-kappa B in inflammation is undisputed and inhibition of the pathway is widely believed to have great potential as a therapeutic target in RA. Commercial effort has gone into developing inhibitors of NF-kappa B activation. However, inhibition of the NF-kappa B activation can result in an exacerbation of inflammation if TNF-alpha production by macrophages is not controlled. It will be important that such inhibitors are carefully monitored before their long-term use in chronic inflammatory conditions such as RA.