Adenoviral transgene delivery provides an approach to identifying important molecular processes in inflammation: evidence for heterogenecity in the requirement for NF kappa B in tumour necrosis factor production

The success of anti-tumour necrosis factor (TNF) treatment, either using an tibodies or soluble receptors, has defined TNF as a major factor of the inf lammatory response in rheumatoid arthritis (RA). As a result of this succes s, much attention has been devoted to understanding the molecular mechanism s by which TNF expression and activity is elicited and controlled. By under standing these pathways, it is hoped that key elements of the molecular pat hology associated with RA will be uncovered and, as a result, new targets f or therapeutic intervention will be identified. However? studying the cell and molecular biology of model systems for RA, such as primary human macrop hages, or tissue from rheumatoid joints may present technical problems. In an attempt to overcome this, we have investigated the use of adenovirus as a means of delivering transgenes by which different intracellular pathways can be modulated and examined. Our data show that adenovirus can be success fully used to efficiently deliver transgenes to primary human macrophages a nd RA joint tissue. Using a virus encoding I kappaB alpha, the natural inhi bitor of NF kappaB, we show that the requirement for the transcription fact or is not universal, but is dependent on the nature of the stimulus. Furthe rmore, while NF kappaB is of importance for the expression of TNF and other proinflammatory cytokines (for example, interleukin 6) and the destructive matrix metalloproteinases, this factor is not required for the expression of antiinflammatory cytokines interleukin 10 and interleukin 1 receptor ant agonist.