Regulation of innate and adaptive immune responses by TNFalpha

Tumor necrosis factor alpha (TNFalpha) is a powerful mediator of the inflammatory response, and when dysregulated, will result in pathology. High TNFalpha levels are associated with septic shock and auto-inflammatory diseases. Anti-TNFalpha treatments increase survival of septic patients by 15%. As of now, about 300,000 rheumatoid arthritis, Crohn's disease and psoriasis patients are benefiting from treatment with anti-TNFalpha drugs. Since TNFalpha is essential for response to intracellular infections, anti-TNFalpha therapy results in increased incidence and severity of M. tuberculosis . Unexpectedly, anti-TNFalpha treatment has exacerbated some auto-inflammatory conditions. Multiple sclerosis patients showed no improvement and in some cases exhibited more frequent relapses. Moreover, anti-TNF therapy induces a higher titer of anti-DNA antibodies in 17% of patients treated with infliximab and has resulted in sporadic cases of Lupus erythematosus. This clinical data gives support to a previously unappreciated role of TNFalpha as a regulator of the immune response.; In support of the anti-inflammatory role of TNFalpha, we have shown that IL-12, a major pro-inflammatory mediator and inducer of a Th1 response is negatively regulated by TNF. Exposure of APCs to TNFalpha inhibits their IL-12 production in response to TLR ligands or IFNgamma without affecting secretion of other messenger molecules (MCP-1 and IL-6). In vivo administration of TNFalpha reduces IL-12 levels induced by injecting LPS and IFNgamma. Mice deficient in TNF receptors have elevated systemic levels of IL-12 after infection with Listeria. We have also found that the regulation of IL-12 in vivo is cytokine specific and does not affect IL-6 levels.; In addition to regulating functions of the innate immune system, TNFalpha modulates cells of the adaptive immune response. TNF receptor deficient mice have an increase in frequency of activated T cells based on CD44hi CD62Llo phenotype. Interestingly, the T cell dysregulation is more pronounced in the spleen, but not in peritoneal cavity, at the site of the infection. T cells from TNF receptor deficient mice have normal effector functions based on production of IL-2 and IFNgamma.; Overall our studies describe TNFalpha as an effective negative regulator of the Th1 immune response. With support from other findings in the field, we conclude that TNFalpha is a tissue specific modulator of the immune response that exerts varying effects depending on the cell type and location.