Efficient adenoviral infection with IκBα reveals that macrophage tumor necrosis factor α production in rheumatoid arthritis is NF-κB dependent

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.