Tumor necrosis factor-alpha related signal pathways and neuronal diseases

Tumor necrosis factor-alpha (TNF-α) is a potent pro-inflammatory cytokine exerting pleiotropic effects on various cell types and plays a critical role in the pathogenesis of chronic inflammatory diseases. TNFis a type II transmembrane glycoprotein, containing a C terminus that is external to the cell and a cytoplasmic domain. It can theoretically act in two states, as membrane bound or as a soluble form. A precursor of the soluble form of TNF-α(sTNF-α) transmembrane TNF-α(tmTNF-α) is expressed on activated macrophages and lymphocytes as well as other cell types. The sTNF- can be cleaved from the membrane with a proteolysis by the metalloprotease/disintegrin/cysteine-rich family called TNF-α-converting enzyme (TACE). The sTNF- mediates its biological activities through binding to types 1 and 2 TNF receptors (TNFR1/2) of remote tissues. The structure of TNF- is described as ' β-jellyroll' in which eight antiparallel β-strands form a sandwich 3D structure. In mammals, the TNF-αgene is located in tandem within the MHC locus and it contains four exons and three introns. Recent studies suggest that not only sTNF-α, but also tmTNF-α is involved in the inflammatory response. TNF-α is primarily expressed by activated immune cells such as macrophages, monocytes, neutrophils, NK-cells, and T-cells. TNFexpression has been detected in a number of transformed cell lines including astrocytes, microglia, smooth muscle cells, and fibroblast. When TNF-α is induced locally and in a controlled way, it provides many useful signals leading to resolution of infection and initiation of tissue repair. But defective regulation or chronic and excessive production of TNF-α can lead to autoimmune diseases such as rheumatoid arthritis (RA) and Crohn's disease. While it is clear that the TNF-α signaling pathway is an appropriate therapeutic target for the treatment of autoimmune diseases, total inhibition of TNF-α leads to some serious side effects, such as decreased immune functioning, onset of autoimmune diseases and increased risk of malignancy. In this chapter, TNF-α is discussed from molecular mechanism to future therapeutic potential for the patho-physiology, respectively, in the following section: (1) structure and enzyme regulation, (2) signal pathway, (3) therapeutic strategies in the future studies.