Tumor necrosis factor α and β (collectively referred to as “TNF”) are two different cytokines with similar biological effects that are secreted primarily by macrophages and TH1 cells in response to various inflammatory stimuli, including parasitic, bacterial, and viral infection [see Ref. 12 for a review]. While TNF is known to exert many biological effects, it is known to be the mediator whereby cytolytic immune cells induce fatal injury to their targets via induction of apoptosis or necrosis/lysis However, excessive TNF production or exposure, in concert with other inflammatory cytokines, can lead to severe side effects, including shock, cachexia and autoimmune responses, such as rheumatoid arthritis, insulin-dependent diabetes mellitus, Crohn's disease, glomerulonephritis (renal disease), systemic lupus erythematosus and multiple sclerosis.
Effective anti-TNF based therapeutic approaches have been demonstrated in the treatment of several autoimmune conditions, including rheumatoid arthritis and Crohn's disease, and are presently at the clinical trial stage [12,43]. Anti-TNF based therapy has also been shown to have therapeutic effects on experimental allergic encephalomyelitis (EAE), an animal model for multiple sclerosis. However, when a similar therapy was used in human clinical trials with multiple sclerosis patients, the beneficial effects were not obtained, and a clinical worsening was observed. These contradictory results may be due to the multiple and distinct TNF biological as well as immunological actions, which vary between tissues and also between species. For example, TNF has been shown to be involved in both blocking and promoting tumorigenesis and metastasis, and at the site of its anti-cancer action, it is believed to be responsible for the wasting and anemia characteristic of these patients [12 and references therein].
Thus, it would be useful to develop therapeutic options for autoimmune conditions that interfere with TNF-induced autoimmunity, but which do not augment the immune response, and thus worsen the autoimmune process. For example, it would be useful to be able to identify common transcription factors, that regulate the expression of genes known to be induced by TNF, and which are involved in autoimmune disorder development and progression, in order to design therapeutic interventions to inhibit the activity of such factors, and thereby provide more effective therapies for autoimmune disorders.