Tumor Necrosis Factor-Alpha Related Signal Pathways and Neuronal Diseases(pp. 1-28)
Authors: (Yuki Murakami, Yukio Imamura, Satoko Mitani, Masato Hoshi, Yuko Arioka, Yasuko Yamamoto, Akitoshi Seiyama, Kuniaki Saito, Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan, and others)
Abstract: Tumor necrosis factor-alpha (TNF- ) 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- (sTNF- ) transmembrane TNF- (tmTNF- )
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- -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 ‘ -jellyroll’ in
which eight antiparallel -strands form a sandwich 3D structure. In
mammals, the TNF- gene is located in tandem within the MHC locus
and it contains four exons and three introns. Recent studies suggest that
not only sTNF- , but also tmTNF- is involved in the inflammatory
TNF- 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- 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- can lead to autoimmune diseases such as rheumatoid arthritis
(RA) and Crohn’s disease. While it is clear that the TNF- signaling
pathway is an appropriate therapeutic target for the treatment of
autoimmune diseases, total inhibition of TNF- leads to some serious
side effects, such as decreased immune functioning, onset of autoimmune
diseases and increased risk of malignancy. In this chapter, TNF- 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.
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