On the role of tumor necrosis factor and receptors in models of multiorganfailure, rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease

The specific role of the tumor necrosis factor (TNF)/TNF receptor (TNFR) sy stem in disease pathogenesis still remains an unresolved puzzle. Recent stu dies in transgenic and knockout animals, where the pathogenic influence of genetically perturbed TNF expression has been evaluated, indicate that seve ral pathways of TNF/TNFR action may contribute independently or in concert to initiate, promote or downregulate disease pathogenesis. Evidently, organ -specific inflammatory or autoimmune pathology may ensue due to sustained a ctivation by TNF of innate immune cells and inflammatory responses, which m ay consequently lead to tissue damage and to organ-specific chronic patholo gy. However, more cryptic functions of this molecule may be considered to p lay a significant part in the development of TNF-mediated pathologies. Dire ct interference of TNF with the differentiation, proliferation or death of specific pathogenic cell targets may be an alternative mechanism for diseas e initiation or progression. In addition to these activities, there is now considerable evidence to suggest that TNF may also directly promote or down regulate the adaptive immune response. It is therefore evident that no gene ral scenario may adequately describe the role of TNF in disease pathogenesi s. In this article, we aim to place these diverse functions of TNF/TNFRs in to context with the development of specific pathology in murine models of m ultiorgan failure, rheumatoid arthritis, multiple sclerosis and inflammator y bowel disease.