Efficient adenoviral infection with IκBα reveals that macrophage tumor necrosis factor α production in rheumatoid arthritis is NF-κB dependent
Efficient adenoviral infection with IκBα reveals that macrophage tumor necrosis factor α production in rheumatoid arthritis is NF-κB dependent
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DOI：
10.1073/pnas.95.14.8211
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发表时间：
1998-07-07
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：
Foxwell, B;Browne, K;Feldmann, M
肿瘤坏死因子（TNF）α已被证明是类风湿性关节炎的主要治疗靶点，抗TNF α的成功！抗体临床试验。虽然已经详细研究了导致TNF α表达的信号通路，但有证据表明个体细胞类型之间存在相当大的差异。这促使我们研究导致患病的滑膜关节组织中的巨噬细胞的TNF α合成增加的细胞内信号传导途径。使用体外腺病毒系统，我们报告了基因成功递送到超过95%的正常人巨噬细胞。这使我们能够表明，通过使用NF-κ B的天然抑制剂I κ B α的腺病毒转移，在正常人巨噬细胞中由脂多糖而不是由某些其它刺激物诱导的TNF α被抑制了80%。此外，从人类风湿关节细胞培养物自发产生的TNF α被抑制了75%，表明NF-κ B途径是滑膜巨噬细胞中TNF α合成的必要步骤，并证明NF-κ B应该是这种疾病的有效治疗靶点。
Tumor necrosis factor (TNF) alpha has been shown to be a major therapeutic target in rheumatoid arthritis with the success of anti-TNF alpha! antibody clinical trials. Although signaling pathways leading to TNF alpha expression have been studied in some detail, there is evidence for considerable differences between individual cell types. This prompted us to investigate the intracellular signaling pathways that result in increased TNF alpha synthesis from macrophages in the diseased synovial joint tissue, Using an adenoviral system in vitro we report the successful delivery of genes to more than 95% of normal human macrophages. This permitted us to show, by using adenoviral transfer of I kappa B alpha, the natural inhibitor of NF-kappa B, that induction of TNF alpha in normal human macrophages by lipopolysaccharide, but not by some other stimuli, was inhibited by 80%, Furthermore the spontaneous production of TNF alpha from human rheumatoid joint cell cultures was inhibited by 75%, indicating that the NF-kappa B pathway is an essential step for TNF alpha synthesis in synovial macrophages and demonstrating that NF-kappa B should be an effective therapeutic target in this disease.