期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1998
卷号：95
期号：14
页码：8211-8215
DOI：10.1073/pnas.95.14.8211
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Tumor necrosis factor (TNF) has been shown to be a major therapeutic target in rheumatoid arthritis with the success of anti-TNF antibody clinical trials. Although signaling pathways leading to TNF 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 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, the natural inhibitor of NF-{kappa}B, that induction of TNF in normal human macrophages by lipopolysaccharide, but not by some other stimuli, was inhibited by 80%. Furthermore the spontaneous production of TNF from human rheumatoid joint cell cultures was inhibited by 75%, indicating that the NF-{kappa}B pathway is an essential step for TNF synthesis in synovial macrophages and demonstrating that NF-{kappa}B should be an effective therapeutic target in this disease.
